Scientific Report 2015

WWW.AUGUSTA.EDU/CANCER/

Angiogenesis

2015 SCIENTIFIC

Report

Biomarkers

Immune

Heat shock proteins

Therapy

Oncogenes

Inflammation

Signaling

GRU Cancer Center 2015 Scientific Programs Table of Contents Introduction……...……...……...……...……...……...……...……...……..5 Cancer immunology, Inflammation, and Tolerance Program (CIT)……...6 Molecular Oncology and Biomarkers Program (MOB)……...……...……20 Tumor Signaling and Angiogenesis Program (TSA)……...……...………..39 Cancer Prevention and Control Program (CPC)……...……...…………...51 Cancer Center Shared Resources………………………………………………………….57 Bioinformatics……...……...……...……...……...……...………...58 Biostatistics……...……...……...……...……...……...……...……59 Cancer Center Flow Cytometry Core……...……...……...………60 GRU Tissue Biorepository……...……...……...……...……...……61 Integrated Genomics: Microarray Technologies……...……...….62 Integrated Genomics: Next-Generation Sequencing……...…….63 Proteomics and Metabolomics……...……...……...……...……..64 Small Animal X-Ray and Imaging……...……...……...…….….…65 2015 GRU Cancer Center Publications……...……...……...……...……...66

Immune Therapy

Angiogenesis

2015 SCIENTIFIC Biomarkers

Programs

About the GRU Cancer Center The GRU Cancer Center at Augusta University (formerly Georgia Regents University) is a multidisciplinary academic cancer center with a mission to reduce the burden of cancer in Georgia and across the globe through superior care, innovation and education. Its patient-centered approach includes first-in-the-nation treatment protocols, an experimental therapeutics program and specialized clinics for state-of-the-art drug and immunotherapy clinical trials. In 2016, in conjunction with the rebranding of Augusta University, the GRU Cancer Center will become the Georgia Cancer Center, the new name reflecting its role as the State of Georgia’s official cancer center.

With strong state support, Augusta University has invested substantially in developing the Cancer Center. In 2006, a $54 million, 151,000 square-foot research building was erected to house Cancer Center scientific laboratories, shared facilities, and administration. In 2010, a $31 million, 64,000 square-foot adult cancer clinical facility opened, providing comprehensive outpatient oncology services and housing a dedicated clinical trials unit. In early 2012, the two units merged to become the Cancer Center, with members recruited from colleges, departments and institutes at Augusta University and from the very finest Cancer Centers across the country.

Today the growth continues. The Cancer Center is currently beginning construction on a 78,000 square foot expansion project that will not only add much needed research and clinical space, but will also quite literally bridge the gap between the Cancer Center’s clinical and research mission. This $62.5 million dollar project will include a five-story addition to the existing research building and a three-story ‘bridge’ building connecting the research and clinical facilities, designed to foster collaboration and communication. The project is expected to be complete in early 2018.

About Augusta University (Formerly GRU) Augusta University generates national and global impact through groundbreaking research, patientcentered clinical expertise and forward-thinking educational programs from three campuses in the beautiful Southern city of Augusta, Georgia, and satellite locations across the state. Nearly 9,000 students choose Augusta for advanced health sciences and liberal arts education. Home to the state’s only public academic medical center, Augusta’s world-class clinicians are bringing the medicine of tomorrow to patient care today.

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GRU Cancer Center Senior Leadership Nationally and internationally recognized leaders in clinical care and scientific research have been recruited to serve at the GRU Cancer Center in the following capacities:

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Samir N. Khleif, MD Director, GRU Cancer Center Director, GRU Cancer Center Service Line

Sharad Ghamande, MD Associate Director Clinical Affairs

Michael Benedict, PharmD Associate Director Administration

Nita J. Maihle, PhD Associate Director Education

John K. Cowell, PhD, DSc, FRCPath Associate Director Basic Science

David H. Munn, MD Senior Advisor to the Director

GRU Cancer Center 2015 Scientific Report of Basic Science Programs Presented here is the Annual Scientific Report of the GRU Cancer Center at Augusta University (formerly Georgia Regents University) in Augusta, Georgia. The following pages describe the 2015 research achievements of Cancer Center members within the Cancer immunology, Inflammation, and Tolerance (CIT), Molecular Oncology and Biomarkers (MOB), and Tumor Signaling and Angiogenesis (TSA) basic science programs, as well as the newly established Cancer Prevention and Control (CPC) program. In addition, new initiatives have been initiated in 2015 as a result of recruitment in the field of natural products. The Cancer Center’s Translational Oncology initiative is progressing with the establishment of infrastructure required to support Phase I/II clinical trials including investigatorinitiated trials that develop from within Cancer Center research laboratories. This fledgling program will be added to the Scientific Report once it establishes inter-programmatic interactions.

Under the leadership of Dr. Samir Khleif, the GRU Cancer Center has undergone unprecedented expansion in the number of research and clinical faculty over the past two years, with the recruitment of more than twenty new faculty. The plan is to further increase this number over the next three years to build the critical mass that is needed to achieve NCI designation through the National Cancer Institute’s Cancer Center Support Grant program by 2020. With this goal in mind, prioritized development of shared research resources provides access to state-of-the-art technologies to all Cancer Center members. Details of these shared facilities and the services they offer are included in this report.

Another essential facet of the GRU Cancer Center’s Research program is its integration with the activities of the GRU Cancer Center’s Educational program. Over the past year, new educational components have been developed to secure the best training for the next generation of physicians and scientists, to provide optimized idea exchange among established physicians and scientists, and to ensure that current clinical professionals integrate the best, most up-to-date practices in medicine. Cooperation between the research and educational programs ensures that GRU Cancer Center patients benefit from the most recent research discoveries from around the world.

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Cancer immunology, Inflammation, & Tolerance Page 6

Cancer immunology, Inflammation, & Tolerance OVERVIEW The field of cancer immunotherapy has exploded due to the approval of several novel immune modulators that have shown remarkable therapeutic effects against several tumor types. The main goal of the Cancer immunology, Inflammation, & Tolerance (CIT) program is studying those immune inflammatory processes that cause cancer and to develop immune-based strategies to treat cancer. This will be accomplished by: understanding how inflammation contributes to malignant transformation; improving immune responses to tumor antigens through the development of therapeutic vaccines or adoptive cell therapies; and blocking immune suppressive activities that limit the effectiveness of anti-tumor immune responses.

A major impetus of all CIT members is to translate knowledge acquired from basic research activities into the clinic setting. To achieve this goal, CIT-specific areas of interest include:   

      

Elucidating how chronic inflammation creates tolerance to protect tumors and healthy tissues from immune-mediated injury; Understanding how the interplay between dietary fiber and gut microbiota suppresses chronic inflammation and carcinogenesis; Discovery research using models of chronic inflammatory diseases to elucidate how immune responses are regulated to create tolerance (unresponsiveness) in tumor microenvironments that inhibit natural and vaccine-induced anti-tumor immunity and to identify novel targets for therapeutic intervention; Development and characterization of molecular and immunological strategies for manipulating innate and adaptive immune responses to malignancy; Translating new discoveries into clinical settings in collaboration with experimental oncologists in the GRU Cancer Center and corporate partners; Evaluating the efficacy of immunotherapy and conventional therapies by developing a system to monitor immune response in conjunction with clinical outcomes; Manipulating tolerogenic mechanisms for clinical benefit; Developing better cancer vaccines; Elucidating novel targets to manipulate immune responses to treat cancer and other chronic inflammatory syndromes; and Understanding how commensal microbiota or commensal dysbiosis influences innate and adaptive immune responses to natural and vaccine-induced anti-tumor immunity.

Interim Co-Leader, CIT Program Georgia Research Alliance/Cecil F. Whitaker Jr MD Eminent Scholar in Cancer Immunology Professor The Celis Laboratory studies the development of T cell-based immunotherapy for various cancer types.

Efforts during 2015 were devoted towards the identification of novel T cell epitopes from tumor antigens and in the development of vaccines that induce anti-tumor T cell responses. In collaboration with investigators from Japan, Dr. Celis helped in the identification of CD4 T cell epitopes from HER-3 for head and neck cancers and described the combination of HER-3 targeted therapy and immunotherapy (Sci. Rep. 2015, 5:e1628). Also, in studies in collaboration with his Japanese collogues, Dr. Celis reported that chemokine signaling can be used as a novel target therapy against nasal natural killer/T cell lymphomas (Cancer Immunol Immunother. 2015, 64(6):697-705). In collaboration with scientists from the Moffitt Cancer Center (Tampa, FL), it was shown that targeting histone deacetylase 6 can increase immunity against melanomas (Mol Oncol. 2015, 9(7):1447-57). In collaboration with the Mayo Clinic, Dr. Celis showed that mutated BRAF oncogene emerges during tumor recurrences in a murine melanoma model after immunotherapy (Mol Ther. 2015, 23(5):845-56). Some studies on overcoming the negative effects of T regulatory cells using PTEN inhibitors were done in collaboration with Dr. D. Munn at the GRU Cancer Center (Sci Adv. 2015, 1(10):e1500845), which will help the optimization of cancer immunotherapy.

In collaboration with investigators in Korea, the Celis Laboratory described an optimized peptide vaccine capable of inducing multiple CD8 T cell responses with strong anti-tumor effects (Oncoimmunol. 2015, 4 (11):e1043504). Lastly, Dr. Celis reported that the combination of STING activator c-di-GMP enhanced the potency of peptide vaccines against melanomas (Cancer Immunol Immunother. 2015, 64(8):105766).

Cancer immunology, Inflammation, & Tolerance

Esteban Celis, MD, PhD

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Cancer immunology, Inflammation, & Tolerance

Jennifer Bradford, PhD

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NEW RECRUIT TO THE CIT PROGRAM Assistant Professor

The Bradford Laboratory focuses on how breast cancer cells and tumor-associated macrophages (TAMs) communicate via the nuclear factor-kappaB (NF-κB) pathway to promote cancer progression. NF-κB is a family of five transcription factors (RelA/p65, RelB, p50, p52, c-Rel) that form different dimers to regulate target gene expression in diverse biological functions, including, normal immune function, synaptic plasticity, and even memory. Aberrant NF-κB activity is associated with autoimmune diseases, and importantly, cancer.

NF-κB is known to be up-regulated in breast cancer subtypes that also have high numbers of infiltrating macrophages, the TAMs. TAMs are found in many types of cancer and can compose upwards of half of total invasive breast cancer tumor mass, which is associated with poor prognosis. The basal and claudinlow subtypes of breast cancer are very aggressive and difficult to treat; interestingly, these subtypes are also associated with high macrophage infiltration. Recent microarray data indicate that NF-κBdependent target genes are strongly up-regulated in basal-like and claudin-low breast cancers, which could be due to the large numbers of infiltrating macrophages. This finding along with the fact that NFκB can also regulate tumor-initiating cells (cancer stem cells) makes the issue of uncovering the role NFκB communication between TAMs and breast cancer cells very important.

The Bradford Laboratory is also collaborating with Dr. Ali Arbab (GRU Cancer Center). Together, they are studying NF-κB signaling in tumor-associated macrophages and the pathway’s influence on angiogenesis and cancer stem cell phenotypes in glioblastoma.

The Cui Laboratory studies tumor-host immune cell interaction that dictates the immunological landscape of the tumor microenvironment (TME). One particular area of interest is the activity of the tumor suppressor p53 in altering host immune function and tumor milieu. Previous studies in the Cui Laboratory and those of others demonstrated that p53 inactivation/dysfunction in the TME skews the immunological landscape towards pro-inflammation. As p53 is the most frequently mutated/inactivated gene in the TME, and chronic inflammation is a causative factor for cancer development, the Cui Laboratory contends that p53 inactivation-induced chronic inflammation contributes immunologically to tumorigenesis and tumor progression. By employing pharmacological p53 activators, they recently demonstrated that targeted activation of the p53 pathway in the TME not only induces tumor apoptosis, but also subsequently elicits antitumor immunity, leading to tumor regression (J Immunother Cancer. 2015, 3(9); doi:10.1186/s40425-015-0053-5). It was shown that p53 activator-induced apoptosis is the so-called immunogenic cell death, which mobilizes and activates immune cells to seek and eliminate distal tumor cells not reached by the p53 activator. The demonstrated immune modulatory function of the p53activation or reactivation regimen is clinically relevant and significant because the currently available small molecule p53 activators or re-activators can be used not just in monotherapy settings, but also in combinational approaches with active immunotherapy, through which a more durable, specific, and systemic antitumor response can be generated leading to tumor elimination. The Cui Laboratory is currently investigating cellular and molecular components that contribute to this p53 activation-induced antitumor immunity. Knowledge gained from this study will allow the use of small molecule p53 activators in combinational therapies for targeted induction of tumor apoptosis and promotion of antitumor immunity leading to ultimate tumor control and elimination.

Cancer immunology, Inflammation, & Tolerance

Yan Cui, PhD Professor

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Cancer immunology, Inflammation, & Tolerance Page 10

Yukai He, MD, PhD Professor

Ongoing research in Dr. He’s laboratory has been focusing mainly on developing effective cancer vaccines and immunotherapy approaches for liver cancer (primarily hepatocellular carcinoma). The incidence of HCC is increasing in the United States, with a high mortality rate due to the lack of effective therapies. Regarding liver cancer vaccine development, Dr. He’s research group has generated a proof-of -principle mouse model showing that antigen engineering by epitope-optimization is a valid approach for creating highly immunogenic cancer vaccines. Published in 2014, this engineered cancer vaccine was found to activate a potent liver cancer antigen (alpha fetoprotein)-specific CD8 response and generate a strong antitumor effect. Currently, in collaboration with Dr. Bjoern Peters at the La Jolla Institute for Allergy and Immunology, Dr. He is using epitope optimization to design liver cancer vaccines that can activate both CD8 and CD4 T cells in an effort to maximally activate liver cancer-specific immune responses.

In addition, the He Laboratory is translating this important finding into developing human liver cancer vaccines that can be used to activate human T cells to prevent, or even to treat, human liver cancers.

Dr. He’s laboratory is also working to identify T cell clones that can effectively recognize and kill human liver cancer cells. The goal of this research is to identify and clone high quality TCR genes that can be used to engineer human T cells for adoptive cell transfer to treat liver cancer patients. Thus far, Dr. He and his laboratory have identified two HLA-A2-restricted human AFP CD8 epitopes. In collaboration with Dr. Celis, Dr. He’s group is working on developing a prime-boost immunization strategy to effectively induce high levels of activation of hAFP-specific CD8 T cells and then identify and clone those T cells that have the best antitumor effect in an adoptive cell transfer setting.

In addition to this translational research, the He Laboratory is also interested in understanding the basic mechanisms of immune activation and in deciphering the parameters that can affect the antitumor efficacy of vaccine-activated immune effector cells. The research led to the discovery of interesting findings that begins to explain why in some cases, high levels of antigen-specific T cells do not correlate with an antitumor effect. This research will promote the design of more effective vaccines that can better correlate with potent antitumor responses. Dr. He’s laboratory also has a continuing interest in understanding the immune suppressive tumor microenvironment and in modulating the inflammation status of the tumor microenvironment to improve the antitumor effect of liver cancer vaccines. In collaboration with Dr. Xue-Feng Bai of Ohio State University, Ebi3 gene-mediated IL27 production was shown to be critical in relieving the immune suppression in the tumor microenvironment (Oncoimmunology. 2015, 4 (7):e989137).

Assistant Professor

The Johnson Laboratory uses animal models of in vivo solid tumor growth to study the contribution of indoleamine 2,3-dioxygenase (IDO) to immunological tumor tolerance. Normally, IDO functions to limit immune responses against innocuous exposures, such as commensal bacteria and normal dying (apoptotic) cells. However, IDO is also widely expressed in human tumors and tumor draining lymph nodes, where it can suppress desirable anti-cancer immune responses (In Kalinski P, ed. The Microenvironment in Cancer Progression and Cancer Therapy. New York: Springer, in press). Recently, the Johnson Laboratory also made the novel discovery that when IDO is blocked: (i) conventional chemotherapy can drive intense intratumoral vasculitis, and (ii) conventional chemotherapy with radiation can drive complement-mediated tumor rejection. Thus, blocking IDO during chemo-radiation therapy elicits synergistic effects on survival and changes the nature of the tumor response in tumor models. The central hypothesis is that the interaction between IDO and complement functions as a previously unrecognized regulator of intratumoral inflammation following chemo-radiation therapy, and that this pathway critically regulates the ability of chemo-radiation to cause tumor destruction. The Johnson Laboratory has ongoing projects to study (i) the role of IDO and complement in tumor immunology, testing the hypothesis that IDO acts as a crucial modulator of therapy-induced inflammation in solid tumors by inhibiting the production of pro-inflammatory cytokines and suppressing activation of complement, and (ii) IDO-based immunotherapy for brain tumors using animal models to test the hypothesis that IDO is a critical vascular quiescence factor in brain tumor biology.

Dr. Johnson’s team has successfully translated laboratory findings to clinical trials using indoximod to block IDO during standard chemotherapy and/or radiation for patients with glioblastoma. Clinical trials developed as a result of research in the Johnson Laboratory include:  “A phase I/II study of the combination of indoximod and temozolomide for adult patients with temozolomide-refractory primary malignant brain tumors” (PI: Frank Mott, GRU Cancer Center; Co-I: Johnson, NCT02052648, open at 11 sites in 9 states for patients 16 years and older with glioblastoma)  “Phase I trial of indoximod in combination with temozolomide-based therapy for children with progressive primary brain tumors” (PI: Johnson, NCT02502708, open at 2 sites in Georgia for children age 3-21 years with relapsed or progressive brain tumors) These clinical trials will test the hypothesis that adding IDO-blockade to standard temozolomide therapy, or to radiation therapy followed by temozolomide, will be safe and tolerable in adults and children with relapsed brain tumors, and that this combination immuno-chemotherapy will show preliminary evidence of synergistic efficacy.

Cancer immunology, Inflammation, & Tolerance

Theodore S. Johnson, MD, PhD

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Cancer immunology, Inflammation, & Tolerance

Samir N. Khleif, MD

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Director, GRU Cancer Center Director, GRU Cancer Center Service Line Georgia Research Alliance Cancer Scientist Professor The Khleif Laboratory focusses on enhancing the anti-tumor immune response by optimizing the activation of tumor-specific cytotoxic T lymphocytes (CD8+ effector T cells) while subsiding the immune suppressive mechanisms within the tumor microenvironment, mostly through minimizing the activity of regulatory T lymphocytes (Tregs). Previous studies demonstrated the major role of the PI3K/Akt signaling pathway and its Class IA isoforms (PI3Ka, PI3Kb, and PI3Kd) in the activation, proliferation, and survival of conventional T cells (Tconv) as well as Tregs. Moreover, PI3K/Akt inhibitors were able to enhance the antitumor immune response that is possibly translated into their therapeutic efficacy.

Akt isoforms, and their specific roles in the proliferation and differentiation of cytotoxic T lymphocytes (CD8+ T cells), have been the subject of an ongoing investigation in the Khleif Laboratory. It was shown previously that Akt1 and Akt2, but not Akt3, drive the terminal differentiation step of CD8+ T cells; hence, their inhibition may enhance the anti-tumor immune response by increasing the population of potent central (TCM) memory cells rather than terminal CD8+ memory cells. Moreover, it has been observed that the inhibition of Akt1 and Akt2, but not Akt 3, preserves na誰ve and central CD8+ memory T cells (CD8+ TCMs), delays CD8+ T-cell exhaustion, and enhances their proliferative as well as cytokine and Granzyme B production ability and eventually prolongs their survival. Based on these investigations, they have also defined a mechanism in which proliferative potential, function, and survival of CD8+ T cells would be enhanced by maintaining a reservoir of TCM and na誰ve cells using only Akt1 and Akt2 inhibition (Oncoimmunology. 2015, 4(5):e1005448). The results of these preclinical studies clarifies the previously unanswered questions regarding the correlation between the signaling pathways and the immune response and may enhance efficacy of the combination therapeutic approach to cancers in the clinical setting.

Considering the possibility of a multidisciplinary approach in cancer treatment, the Khleif Laboratory has been also investigating combining both stimulating (anti-OX40, anti-GITR) and inhibitory (anti-PD-1, antiPD-L1, anti-CTLA-4) monoclonal antibodies, small molecule kinase inhibitors, and the HPV16E7 cancer vaccine in a murine lung-epithelial TC-1 tumor model to induce complete tumor regression. Combining therapeutic cancer vaccines, checkpoint inhibitor monoclonal antibodies, and immune-stimulating modalities is one of the innovative treatment options in oncology that has shown promising results in many tumors previously considered to have poor prognosis, such as malignant melanoma.

Associate Professor

Dr. Z. Kurago investigates the functions of the mucosal defenses of the upper aerodigestive tract in health and disease, including infectious disorders and malignant neoplasia. In collaboration with Drs. D. Malamud and W. Abrams (NYU), and D. Weismann (U. Penn), studies were designed to better understand the differences in HIV transmission at mucosal portals by mapping the periluminal distribution of the HIV-binding molecule gp340 (DMBT1) and HIV targets CD4+ and CD16+ cells in normal oral, cervical, and rectal/sigmoid mucosae. While soluble gp340, present in saliva, can neutralize HIV binding to cells, cell-associated gp340 facilitates transmission. This study defined important distinctions between portals of HIV entry that help explain differences in transmission rates. (PLOS One. 2015, 10(7):e0132942).

The Kurago Laboratory also collaborates with M.E. Elsalanty’s laboratory (GRU), which developed a rat model of osteonecrosis of the jaws related to bisphosphonate treatment. Bisphosphonate treatment is widely used in patients with multiple myeloma, breast cancer, and prostate cancer to reduce bone resorption and suppress bone metastases. This model has proven useful for mechanistic studies of causes and prevention strategies. (PLOS ONE. 2015, 10.1371/journal.pone.0132520).

The Kurago Laboratory also collaborated with C. Cutler’s group (GRU) on a study related to periodontal disease and its systemic implications. This study described the mechanisms of survival of a periodontal pathogen P. gingivalis in human dendritic cells. (PLOS Pathogen. 2015, 10.1371/journal.ppat.1004647).

Cancer immunology, Inflammation, & Tolerance

Zoya Kurago, DDS, PhD

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Cancer immunology, Inflammation, & Tolerance

Kebin Liu, PhD

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Associate Professor

Research in the Liu Laboratory is currently devoted to studying the dynamic interactions between tumor cells and immune cells in the tumor microenvironment. One of their major areas of focus is to elucidate the molecular mechanisms underlying epigenetic regulation of tumor suppressor genes in human colon carcinoma cells. It has recently been shown that FasL of cytotoxic T lymphocytes (CTLs) is essential for host cancer immune surveillance. Fas, the physiological receptor for FasL, is often silenced in advanced human colon carcinoma cells, suggesting that colon carcinoma cells may use silencing Fas as a mechanism to evade host cancer immune surveillance. Using combined approaches of genome-wide ChIP-Seq with an epigenetic inhibitor, the Liu Laboratory determined that H3K9me3 of the FAS promoter is a dominant mechanism underlying FAS silencing, resulting in colon carcinoma immune evasion and progression (J. Immunol. 2015, 195:1868-82). In addition, they determined that GPR109A acts as a tumor suppressor in colon cancer and that the host immune system uses IFNÎł to counteract DNA methylationmediated GPR109A silencing as a mechanism to suppress colon cancer development (Cancer Immunol Res. 2015, 3:795-805). The long-term goal of the Liu Laboratory is to develop molecular target-based cancer therapy to increase cancer cell sensitivity to immunotherapeutic agents, to enhance the efficacy of cancer immunotherapy.

Assistant Professor

The main research focus of Dr. Manicassamy’s laboratory is to understand how commensal flora shapes innate and adaptive immune responses in the intestine and periphery. The compositions of gut microbial communities have profound effects on human health. Alterations in the microbial composition in the intestine have been linked to inflammatory diseases, obesity, and cancer. The Manicassamy Laboratory addresses a central problem in immunology: how the immune system launches robust immunity against pathogens, while maintaining tolerance to self-antigens, food antigens, and commensal bacteria. Addressing this problem will shed light on immunological processes that are critical for maintaining homeostasis with the microbiota and how these interactions can become dys-functional to cause increased risk of inflammatory diseases, infection by microbial pathogens, and cancer. In this context, the laboratory previously showed that activation of the Wnt/beta-catenin pathway in dendritic cells is critical for maintaining intestinal homeostasis. Aberrant Wnt signaling occurs in many tumors, and the tumor microenvironment contains high levels of several Wnt ligands. In recent studies, Dr. Manicassamy’s group has shown how Wnt ligands in the tumor microenvironment program innate immune cells, specifically dendritic cells, to a regulatory state and suppress the immune response against tumor-associated antigens (Cancer Research. 2015, 75(4):656-65; Oncoimmunology. 2015, 4(12); Oncoimmunology. 2015, in press).

Dr. Manicassamy’s group reported for the first time that retinoic acid and Wnts in the tumor microenvironment play a key role in immune suppression, and dendritic cells are the major producers of retinoic acid. These studies describe a novel mechanism by which dendritic cells acquire the ability to metabolize vitamin A and produce retinoic acid, which drives regulatory T cells responses and promotes tumorinduced immune suppression. In another critical study, Dr. Manicassamy’s group reported a novel mechanism by which the canonical Wnt pathway in dendritic cells limits effector T cell responses and reinforces homeostasis in response to chronic inflammation (J Immunol. 2015, 194(7):3295-304). These studies provide the pre-clinical basis for future translation studies aimed at the development of an entierly new class of agents that may have significant therapeutic impact in treating inflammatory diseases and cancer.

Cancer immunology, Inflammation, & Tolerance

Santhakumar Manicassamy, PhD

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Cancer immunology, Inflammation, & Tolerance

David H. Munn, MD

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Senior Advisor to the Cancer Center Director Professor

A major focus of the Munn Laboratory is the immunoregulatory role of tryptophan metabolism via the enzyme indoleamine 2,3-dioxygenase (IDO). The Munn Laboratory generates preclinical data to support clinical trials of IDO-inhibitor drugs. Current clinical trials being conducted by various clinical collaborators, both within the Cancer Center and nationally, include Phase I and Phase II trials of IDO-inhibitor drugs in melanoma, brain tumors, chemo-immunotherapy, and in combination with vaccines.

Recent studies have focused on a newly-discovered form of Treg activation, recently described by the Munn Laboratory, which is driven by a pathway controlled by the PTEN phosphatase. In mice with Tregspecific deletion of PTEN, tumors become unable to create their usual immunosuppressive microenvironment and are barely able to grow. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN during immunotherapy or chemotherapy profoundly reconfigured the tumor microenvironment, changing it from tolerogenic to immunogenic, allowing robust antigen cross-presentation.

Thus, blocking suppression by the previously unrecognized pten-Treg pathway suggests that tumors can be much more spontaneously immunogenic than had been appreciated, and identifies PTEN as an exciting new target for immunotherapy – especially when used in combination with conventional chemotherapy (Sci Adv. 2015, 1(10):e1500845).

The Munn Laboratory, through its focus on tumor immunology, particularly the molecular mechanisms of immune suppression and tolerance created by tumors, also studies the regulation of T cell activation by tolerogenic dendritic cells and regulatory T cells (Tregs) in the setting of cancer. Through this research, the Munn Laboratory has contributed to several studies, including those in collaboration with fellow Cancer Center member Dr. S. Manicassamy (Cancer Res. 2015, 75:656-65; J Immunol. 2015, 194:3295-304); with the University of Minnesota’s Dr. B. Blazar (Blood. 2015, 125:3335-46; Blood. 2015, 126:1621-8); and with Memorial Sloan Kettering Cancer Center’s Dr. J. Wolchok (Cell Rep. 2015, 13:41224).

NEW RECRUIT TO THE CIT PROGRAM Associate Professor

Research performed by the Rodriguez Laboratory focuses (i) on understanding the major mechanisms leading to T cell dysfunction by the chronic inflammation present in solid tumors and (ii) on developing strategies that restore protective immunity in cancer, leading to long-lasting, anti-tumor effector T cell responses and novel immunotherapies. Recent studies have indicated the role of the accumulation of myeloid-derived suppressor cells (MDSCs) in the immunosuppressive effects induced by the deprivation of the non-essential amino acid L-arginine in tumors (Cancer Res. 2015, 75(2):275-83). In addition, Dr. Rodriguez’s group continued exploring the molecular effects by which T cells become suppressed after contacting MDSCs, showing a significant role of decreased signaling through the mammalian target of rapamycin (mTOR). Furthermore, research completed in collaboration with investigators from Louisiana State University (LSU) identified the role of the metabolism of fatty acids in the ability of MDSCs to impair T cell responses in tumor-bearing hosts (Cancer Immunol Res. 2015, 3(11):1236-47). These studies enabled the development of new strategies to overcome the inhibition of immune responses in tumors and the design of necessary approaches to increase the efficacy of radio/chemotherapy and immunotherapies in cancer. Together with a large number of the colleagues in this field, the Rodriguez Laboratory also participated in a major effort in determining the adequate experimental approaches for adequate identification of MDSCs. In collaboration with LSU’s Hamid Boulares, PhD, Dr. Rodriguez has made major contributions to the understanding of molecular pathways leading to polarization of chronic inflammation in asthma. This research revealed the effect of DNA-PK and poly ADP ribose polymerase (PARP) in chronic inflammation (J Allergy Clin Immunol. 2015, 135(2):425-40; J Transl Med. 2015, 13:225; Clin Sci (Lond). 2015, 129 (11):951-62). Now that cancer immunotherapy has gained significant momentum and recognition by the research community studying chronic inflammation, it becomes fundamental to determine the molecular pathways that regulate inflammation in diseases such as cancer and auto immunity, which is expected to lead to generation of novel immunotherapies.

Cancer immunology, Inflammation, & Tolerance

Paulo C. Rodriguez, PhD

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Cancer immunology, Inflammation, & Tolerance

Nagendra Singh, PhD

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Assistant Professor

Research in the Singh Laboratory focuses on studying how the interaction between dietary fiber and gut microbiota influences intestinal inflammation and carcinogenesis. Their recent work demonstrates that dietary fiber’s promotion of good gut bacteria such as Bifidobacterium and suppression of bad bacteria such as Prevotellaceae are dependent on the short chain fatty acid (SCFA) receptor GPR43. Gpr43 is a receptor for acetate, propionate, and butyrate (collectively called SCFA), which are metabolites of dietary fiber by gut bacteria. These findings are relevant, since it was also shown that, while the number of Bifidobacterium in human colon cancer tissue is decreased, that of Prevotellaceae is increased. Moreover, in collaboration with Dr. Ganapathy of Texas Tech University Health Sciences, it was shown that when dietary fiber intake is low, the SCFA transporter SLC5A8 becomes essential for suppressing colon carcinogenesis (Biochem J. 2015, 469:267).

In addition, the laboratories of Drs. Singh and Li (GRU Cancer Center) collaborated to define the role of the Ufm1 (a ubiquitin-like modifier) conjugation system and Ufm1 E3 ligase RCAD/Ufl1 in erythropoiesis (Cell Death Differ. 2015, 22:1922; PLoS Genet. 2015,11:e1005643) .

The Singh Laboratory also contributed to the understanding of the mechanism by which gut microbiota can promote obesity. It was shown that under conditions of chronic inflammation, as seen in mice lacking TLR5 for example, excess production of short chain fatty acids leads to obesity and metabolic syndrome (Cell Metabolism. 2015, 22:983). Recent studies by several laboratories have shown that the interaction between dietary fiber and gut microbiota plays a critical role in carcinogenesis and obesity.

Understanding the molecular mechanisms regulating the effect of gut microbiota and diet on intestinal carcinogenesis and obesity will be very important in designing new therapeutic strategies aimed for prevention and /or treatment for these diseases.

Associate Professor

The Zhou Laboratory studies how to combine standard-of-care chemotherapy and novel immunotherapy in a synergistic manner to treat cancer. Currently, chemotherapy is a major treatment modality for many types of cancer. However, chemotherapy is rarely curative. With recent advances in immune-based therapeutic strategies, there is growing interest in combining immunotherapy with conventional chemotherapy to achieve durable antitumor effects. Dr. Zhou’s group reported that melphalan, an alkylating agent commonly used in treating hematologic malignancy such as multiple myeloma, has immunostimulatory effects as reflected by its ability to induce immunogenic tumor cell death. The combination of melphalan and adoptive T cell therapy can mediate a better antitumor effect than either treatment alone (J Immunol. 2015, 194(4):2011-21). Dr. Zhou participated in a collaborative study with scientists at Zhongshan Medical University in China, which revealed the tumor suppressor function of Vps4A in heptoma cells (Hepatology. 2015, 61(4):1284-94). In addition, Dr. Zhou collaborated with GRU Cancer Center colleagues, Drs. Chunhong Yan and Kebin Liu, to investigate the stress response and myeloid cell differentiation (Nat Commun. 2015, 6:6752; J Immunol. 2015, 194(5):2369-79). Dr. Zhou also contributed to a study conducted by Dr. Lieping Chen’s group at Yale University investigating the role of B7-H3 in autoimmune disease and inflammation (PLoS One. 2015, 10(6)).

Cancer immunology, Inflammation, & Tolerance

Gang Zhou, PhD

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Molecular Oncology & Biomarkers OVERVIEW

Molecular Oncology & Biomarkers

The overall goals of the Molecular Oncology & Biomarkers (MOB) program are to understand the fundamental cellular and molecular processes that contribute to cancer development and progression.

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The research interests of the program can be divided into three broad themes: genetics and epigenetics of cancer development and progression; cell stress and metabolism; and cancer cell metastasis. Collectively, these themes address important topics of tumor cell and molecular biology:          

Genome-wide analysis of epigenetic changes in cancer development as a tool to identify biomarkers for prediction of progression and prognosis; The genetic basis of cancer development and progression through the roles of specific genes and pathways; The genetic basis of metastasis underlying the roles of metastasis suppressor genes, metastasis promoting genes, and microRNAs involved in metastasis; Cancer genomics in primary human tumors and mouse models of cancer using gene expression and Next Gen sequencing; Application of bioinformatics tools to study complex data sets; The role of transcription factors in promoting cancer progression; The role of oncogenes and glycoconjugates in cancer cell progression; Analysis of heat shock chaperones and other stress proteins in cancer development and as targets for cancer therapies; Investigations of natural products as preventative and therapeutic agents; and The role of obesity and metabolic changes in the development of cancer.

Research in this program uses a wide variety of state-of-the-art cell and molecular biology approaches to understand the fundamental events underlying tumorigenesis and to explore how this knowledge impacts the prediction of tumor progression and whether specific genetic changes affecting cancer development can guide targeted therapies, leading to investigator-initiated clinical trials.

Satyanarayana Ande, PhD

The Ande Laboratory focuses on studies related to liver cancer, cancer metabolism, and obesity. In one of the projects, the transcriptional regulator, inhibitor of DNA binding 1 (Id1), was shown to be highly expressed in both brown and white adipose tissues and that it has a unique function in adipose tissue metabolism compared to its other family members Id2, Id3, and Id4. Specifically, Id1 was shown to have a predominant role in brown adipose tissue (BAT) and that it functions as a negative regulator of the PGC1Îą/UCP1 thermogenesis pathway, thereby, negatively regulating BAT-mediated thermogenesis (J Cell Physiol. 2015, 230(10):2311-7). To further investigate the role of Id1 in adipose tissue metabolism, adipose tissue-specific Id1 transgenic mice were generated which demonstrated that adipose-specific overexpression of Id1 causes weight gain and high-fat-diet-induced obesity in male mice. Surprisingly, female mice are resistant to Id1-induced obesity. At the molecular level, Id1 was shown to interact directly with PGC1Îą and Ebf2, the central regulators of BAT thermogenesis and of white adipose tissue (WAT) browning, respectively, to suppress their transcriptional activity. These findings have significant implications in the treatment of obesity and its associated cancers, since obesity is identified as one of the major risk factors for various cancers.

For the first time, the Ande Laboratory provided clues that Id1 has critical functions in metabolism in addition to its well-known functions in cell proliferation and cellular differentiation. These novel unexpected functions of Id1 in adipose metabolism prompted the investigation of whether Id1 also plays any role in cancer metabolism. To this end, it was shown that Id1 is strongly expressed in liver tumors and in hepatocellular carcinoma (HCC) cells. Id1 was also shown to promote both glycolysis and glutaminolysis by regulating c-Myc levels through the MAPK/ERK pathway in HCC cells. Knock-down of Id1 prevented cancer cell metabolic adaptation and suppressed cancer cell growth (FASEB J. 2015, Sep 1). These studies are being expanded into Id1 knock-out and transgenic mouse models, aiming to identify whether Id1 functions as a molecular target to inhibit liver tumor growth by blocking cancer cell metabolic reprogramming.

Molecular Oncology & Biomarkers

Assistant Professor

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Ahmed Chadli, PhD

Molecular Oncology & Biomarkers

Associate Professor

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Dr. Chadli’s laboratory focuses on understanding the biology and clinical implications of molecular chaperones, focusing specifically on the Hsp90 machine. A few years ago, they identified the UNC45A cochaperone as an important regulator of the progesterone receptor (PR) chaperoning and transcriptional activity. Recent studies have shown that UNC45A is essential for cancer cell proliferation. Silencing UNC45A inhibits cancer cell division through interfering with centrosomal function. UNC45A localizes to centrosomes and has been shown to be essential for tethering the kinase ChK1 to the centrosome. Loss of UNC45A significantly reduces the phosphorylation of ChK1 at S345, which is required for ChK1 centrosomal localization (Cancer Lett. 2015, 357:114-20).

To identify novel inhibitors of the Hsp90 machine, the Chadli Laboratory has developed a high throughput screen (HTS) based on the PR using Rabbit Reticulocyte Lysate (RRL). The assay measures the recovery of hormone binding activities of PR after mild heat treatment. This novel technology will likely have a significant impact on Hsp90 machine-targeted drug discovery, and thus a broad impact on human health (J Biomol Screen. 2015, 20:223-9). Approximately 175 natural products from North Africa (Morocco) were screened in collaboration with Drs. A. Debbab and P. Proksch (Institute of Pharmaceutical Biology and Biotechnology, Düsseldorf, Germany). As a result, the bioactive metabolite sclerotiorin was identified, which inhibits the Hsp90 machine (Bioorg Med Chem. 2015, 23:126-31).

In collaboration with Dr. David Fulton at GRU, Dr. Chadli’s group has shown that Nox5 stability and superoxide production is regulated by C-terminal binding of Hsp90 and CO-chaperones in a similar manner to the regulation of steroid receptor complexes. (Free Radic Biol Med. 2015, 89:793-805).

Justin Choi, PhD

The Choi Laboratory has developed a software package, iTagPlot, to analyze ChIP-seq, MBD-seq, and MeDIP-seq (Bioinformatics. 2015, 31(14):2384-7), which accurately computes tag density across function features in parallel using multicores and a grid engine, and supports interactive exploration of tag density in a graphical user interface. iTagPlot is flexible, allowing users to choose individual features or to group features based on function or quantitative values such as gene expression, DNA methylation, CpG density, and even quantiles of quantitative values. Since tag density plots are the mainstay of manuscripts describing epigenomics data based on next-gen sequencing, iTagPlot offers critical assistance to biologists by generating these plots easily.

In collaboration with Dr. K. Robertson, the Choi Laboratory has analyzed ChIP-seq and Infinium 450K microarray data to profile DNA methylation across the genome in cell lines of SETD2 inactivation and SETD2 mutant primary tumors for clear cell renal cell carcinomas (ccRCCs). This study showed that SETD2-depleted cell line models exhibited a DNA hypermethylation phenotype coinciding with ectopic gains in H3K36me3 centered across intergenic regions adjacent to low expressing genes that became upregulated upon dysregulation of the epigenome. SETD2 mutant primary ccRCCs demonstrated a DNA hypermethylation phenotype that segregated tumors by SETD2 genotype and advanced grade. The study concluded that SETD2 mutations drive tumorigenesis by coordinated disruption of the epigenome and transcriptome, and they have important implications for future therapeutic strategies targeting chromatin regulator mutant tumors (Oncotarget. 2015, 7(2):1927-46).

In collaboration with Dr. H. Shi, the Choi Laboratory has examined base resolution DNA methylation in glioblastoma (GBM)-derived cancer stem cells (GSCs) using BSpipe, which is an end-to-end pipeline for BS-seq analysis containing many modules. This study identified groups of hyper- and hypo-methylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. MGMT, AJAP1, and PTPRN2 showed concurrent promoter hypermethylation and gene body hypomethylation. In conclusion, this study demonstrated that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM (J Genet Genomics. 2015 42(7):355-71).

The Choi Laboratory has also collaborated with the laboratories of Drs. K. Liu and M. Thangaraju to investigate the role of H3K9 trimethylation and Fas expression in colon carcinoma (J Immunol. 2015, 195 (4):1868-82) and the role of DNMT1 in mammary stem cell maintenance (Nat Commun. 2015, 6:6910), respectively.

Molecular Oncology & Biomarkers

Assistant Professor

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John K. Cowell, PhD, DSc, FRCPath

Molecular Oncology & Biomarkers

Co-Leader, MOB Program GRU Cancer Center Associate Director, Basic Science Georgia Cancer Coalition Distinguished Scientist Professor

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Mingqiang Ren, PhD

Yong Teng, PhD

Assistant Professor

Assistant Professor

Activation of FGFR1 as a result of chromosome translocations that create chimeric kinases is responsible for a syndromic form of AML that is accompanied by a myeloproliferative disorder and a propensity to also develop T-cell and B-cell lymphomas. Work in the Cowell Laboratory has developed syngeneic and humanized models of these FGFR1-driven leukemias. FGFR1 can be activated by a variety of different chromosome translocations, and one feature of this disorder is the variable phenotypes associated with the different chimeric kinases. To address this issue, we have created a human AML model driven by BCR-FGFR1 in immunocompromized mice (Br. J Hematol, in press) and demonstrate a genetic fingerprint that is similar to other human and mouse models driven by CNTRL-FGFR1 kinase. In addition, we have also created a syngeneic mouse model for the FGFR1OP2-FGFR1 chimeric kinase-driven disease, which develops an aggressive T-lymphoma associated with Notch1 upregulation and AML that shows molecular hallmarks of myeloid cell arrest at early stages in development (Haematologica. 2016, 101(3):e91-4).

The development of these models, which are highly representative of the human disease, are now being used to evaluate anti-FGFR1 therapies as an approach to treat this almost invariably lethal disease.

In a second project, the Cowell laboratory has been studying the role of the WASF3 gene in invasion and metastasis of breast and prostate cancer cells. In some breast cancer cells, invasion is driven by activation of an overexpressed HER2/HER3 receptor complex in response to ligand binding. It has now been shown that WASF3 is recruited to the HER2/3 membrane-bound protein complex, leading to its phosphoactivation, which is known to be essential to drive invasion and metastasis (Oncogene, doi: 10.1038/ onc.2015.527, in press). Knockdown of WASF3 in the same cells leads to suppression of invasion, demonstrating that WASF3 is critical for the HER2/3 promotion of invasion. When WASF3 and HER2 are overexpressed in non-metastasizing breast cancer cells, invasion and metastasis is induced, demonstrating the importance of these protein-protein interactions for this phenotype.

WASF3 function is regulated by the WASF3 regulator complex (WRC), which includes the CYFIP1 and NCKAP1 proteins. Genetic knockdown of either of these proteins leads to destabilization of WASF3 complex and suppression of invasion. In collaboration with Dr. Eileen Kennedy at the University of Georgia, a novel approach to suppress WASF3 function has been developed (Cancer Res. 2016, 76(4):965-73). “Stapled peptides� are locked in an alpha helical conformation through modified amino acids, which confers drug-like properties such as high-level cellular uptake, increased stability and high specificity for intracellular targets once considered undruggable. Stapled peptides were designed to disrupt the interaction between protein surfaces of the WASF3-CYFIP1 complex. These stapled peptides lead to suppression of WASF3 activation in vitro, which leads to suppression of invasion. This data provides a proof-ofprinciple that targeting this particular protein-protein interaction could be developed into an antimetastasis therapy.

Zhonglin Hao, MD, PhD

Research in the Hao Laboratory focuses on combining small molecule inhibitors that effectively attack the hallmarks of cancer. Following their report that the Plk1 inhibitor volasertib synergizes with another small molecule inhibitor (YM155) in killing non-small cell lung cancer cells, volasertib showed promise in improving progression-free survival of acute myeloid leukemia patients when used in combination with cytarabine. This regimen was used for patients who were not candidates for standard induction chemotherapy (Onco Targets Ther. 2015, 8:1-11). In addition to its well-known role in cell cycle regulation, Plk1 has now been shown to be a critical regulator of cancer cell metabolism. The Hao Laboratory’s investigation of YM155’s mechanism of action has shown that YM155 is not a survivin inhibitor and that it induces cell cycle arrest in G1. It was shown that YM155 is neither a DNA chelating agent nor a topoisomerase inhibitor. YM155 causes DNA damage, which cells repair poorly, suggesting the DNA damage is a result of defective DNA repair.

In collaboration with Dr. Jin Xie of University of Georgia, Department of Chemistry, the Hao Laboratory successfully engineered a nanoparticle that was able to overcome the shallow penetrance of conventional photodynamic therapy for use in the treatment of cancers residing deep within tissues (Nano Lett.

2015, 15(4):2249-56). In this approach, a SiO2 nanoparticle core was engineered to convert the X-ray energy to a spectrum of light that can further pass the energy to neighboring photosensitizer molecules and trigger photodynamic therapy. The delivery of the nanoparticle was guided by an EGFR antibody preferentially overexpressed by the cancer cells. Due to the selectivity of the monoclonal antibody and radiation, normal tissue toxicity is projected to be small.

Molecular Oncology & Biomarkers

Co-Leader, Thoracic Oncology Program Associate Professor

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Anatolij Horuzsko, MD, PhD

Molecular Oncology & Biomarkers

Associate Professor

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The Horuzsko Laboratory studies the role of inflammation in cancer initiation and progression. Studies on various mouse cancer models using deletion of the proinflammatory TREM-1 gene, an amplifier of inflammatory response, have shown a remarkable decrease of tumor initiation and cancer development.

Dr. Horuzsko’s group observed that TREM1 plays a critical role in the crosstalk between Kupffer cells and hepatocytes during liver injury and tumorigenesis (J Enzymol Metab. 2015, 1(1).pii: 101).

The Horuzsko Laboratory research interest also addresses the pathogenesis of tissue fibrosis, primarily using the liver as a model where TREM1was shown to play a critical role for macrophages in promoting the development of liver fibrosis.

In collaboration with Dr. L. Mulloy at the MCG Department of Medicine, the Horuzsko Laboratory has studied the role of HLA-G in prolongation of kidney allograft survival. They demonstrated the mechanisms that B cells are reprogrammed by HLA-G and their signatures in kidney transplant patients (Tissue Antigens, 2015).

Dr. Horuzsko’s group is focusing on the investigation of the effects of different HLA-G molecules on modulation of the function of immune cells using NOD (non-obese diabetic) scid (severe combined immunodeficiency) gamma (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) NSG humanized models. They also developed methods and humanized models to control human allograft rejection using classical and modified immunosuppressive therapies. This will allow clinicians to optimize and immunologically “personalize” the treatment of allograft rejection.

Ravindra Kolhe, MBBS, PhD

The majority of melanomas can be accurately diagnosed based on an adequate biopsy. However, for specific subsets of melanocytic proliferations, there exist conflicting and/or ambiguous features that preclude a definitive consensus diagnosis on histologic grounds. The morphologic limitations in the diagnosis of these histologically borderline melanocytic tumors lead to both under- and over-diagnosis of melanoma. To address this limitation, Dr. Kolhe’s laboratory is investigating various methods that will aid in the accurate diagnosis of melanoma. MiRNA expression profiles (n=48) of melanoma vs dysplastic nevus were evaluated using the Affymertrix miRNA microarray platform on GeneChip miRNA 3.0 array and later confirmed by the HTG genomics qNPA molecular technology platform. The miRNA expression profiles of melanoma vs dysplastic Nevus, showed significant (>8 times, p<0.05) upregulation of mir-21 in melanoma. In collaboration with BioGenex Inc., Dr.Kolhe’s laboratory developed chromogenic in-situ hybridization (CISH) probes for mir-21. In comparison to dysplastic nevus, neoplastic cells in melanoma showed prominent nuclear staining for miR-21 (Laboratory Investigation. 2015, 95:75).

By using microarray technology, Dr. Kolhe’s laboratory has developed a more sensitive testing approach for cytogenetically normal acute myeloid leukemia (AML) patients. A large percentage of patients with this most common form of adult leukemia are said to have normal chromosomes but appear instead to have a distinct pattern of genetic abnormalities that could better define their prognosis and treatment.

The Kolhe Laboratory identified 22 cases of AML/myelodysplastic syndrome (MDS) that had normal karyotype and FISH. Subsequently, high resolution SNP microarray using CytoScanHD Microarray (Affymetrix, Inc.) was performed on DNA isolated from methanol-acetic acid-fixed marrow pellets following the American College of Medical-Genetics (ACMG) guidelines for neoplastic disorders. One-hundred percent of kn-AML/MDS cases showed several small common regions of copy neutral regions of homozygosity (ROH), 27% of cases had a gain/loss and/or mosaicism. Interestingly all AML cases showed ROH in chromosome 1p34.3, chromosome 1p32.3, and chromosome 16q22.1 (Laboratory Investigation. 2015, 95:75).

Molecular Oncology & Biomarkers

Clinical Assistant Professor

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Hasan Korkaya, DVM, PhD

Molecular Oncology & Biomarkers

Assistant Professor

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The Korkaya Laboratory studies the role and mechanisms of spatiotemporal tumor plasticity in the metastatic process. These studies involve understanding early molecular crosstalk between malignant cells and the immune system and its role in generating a permissive microenvironment for metastatic growth.

Tumor-secreted cytokines/growth factors may be critical players in that they can modulate the immune system not only to suppress anti-tumor immunity but also to induce them to become pro-tumorigenic.

Accordingly, Dr. Korkayaâ&#x20AC;&#x2122;s team provided evidence that activation of inflammatory cytokines in tumors is associated with the aggressive EMT/CSC phenotype (Oncogene. 2015, 34:671-80). Tumor-secreted cytokines modulate immune responses by regulating the Jak/Stat3/NF-kB pathway, which is negatively regulated by the suppressor of cytokine signaling 3 (SOCS3). One of the cytokines, IL6, is significantly upregulated in aggressive tumors and correlates with poor patient survival in clinical settings.

In collaboration with Dr. Hollingsworth from MedImmune, the Korkaya Laboratory investigated the therapeutic utility of a novel, high-affinity anti-IL6 antibody (MEDI5117) in multiple cancer types. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. In addition, MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Furthermore, these studies demonstrated the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2+ tumor cells, by targeting the CD44+CD24+ cancer stem cell population (Cancer Res. 2016, 76(2):480-90).

The Korkaya Laboratory also demonstrated, in collaboration with Dr. D. Sun of The University of Michigan, that sulforaphane (a compound found in cruciferous vegetables such as broccoli and Brussels sprouts) suppresses the growth of trastuzumab-resistant breast cancer in xenograft models by inhibiting the IL6/Stat3/NF-kB signaling pathway. (Sci Rep. 2015, 5:15821).

Iryna O. Lebedyeva, PhD

The research performed by the Lebedyeva Laboratory focuses on identifying hits for various targets using the molecular docking approach. The laboratory also specializes in organic synthesis, providing small molecules based on predicted bioactivity profiles. The “screen less, get more hits of better quality” paradigm has been employed to develop small compound diversity sets with 3,000-5,000 compounds per set.

Compounds with reactive and undesirable functional groups, compounds potentially unstable in acidic conditions, as well as some imines and pyrimidine-triones have been eliminated from these sets. These sets have been tested for hit identification on several targets such as Akt1, Bcl-xL, Hsp90, the mixedlineage leukemia protein, human nCDase, WDR5, SUV39H2, and TREM1. All compounds in the diversity sets belong to commercially available sources. Once lead compounds have been identified, the Lebedyeva Laboratory provides lead optimization. Leads from commercially available compound libraries often require further optimization that would induce increased potency, lower toxicity, improved solubility, novelty, etc. Thus, the Lebedyeva Laboratory provides “hit-to-lead,” early-stage drug discovery using computational screening of customized small compound diversity sets against various molecular targets.

Research on the synthesis of bioactive compounds has resulted in a book chapter (Top Heterocycl Chem.

2015, pages 1–47) and several manuscripts (J Mater Chem B. 2015, 3(43): 8492-8; Bioorg Med Chem.

2015, 23(15):5056-60; Tetrahedron Lett. 2015, 56(48):6653-5; Org Biomol Chem. 2015, 13(15):4399-403).

Molecular Oncology & Biomarkers

Assistant Professor

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Balakrishna (Bal) L. Lokeshwar, PhD

Molecular Oncology & Biomarkers

NEW RECRUIT TO THE MOB PROGRAM Co-Director, Natural Product Cancer Initiative Co-Director, Biochemistry & Cancer Biology Training Program Dr. J. Harold Harrison Distinguished University Professor Professor

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Dr. Bal Lokeshwar and his group are engaged in two areas of research to develop novel diagnostics and therapeutics for prostate and breast cancers. The first area is to develop targeted cancer prevention using anti-cancer compounds found in edible plant products and combining them to enhance existing systems of therapy, such as chemotherapy. In this area, the group reported anti-breast-cancer activity of compounds present in an edible spice, Pimenta dioica (Allspice). The compounds in this spice selectively killed breast cancer cells in culture dishes and slowed the growth of aggressive, metastatic breast cancer growth in animal models. Oral administration of aqueous allspice extract before the tumors are established significantly decreased tumor incidence and tumor growth. Further, the cellular basis of this antitumor activity was over-induction of autophagy but not directly apoptosis, thus demonstrating a novel mechanism of anticancer action. Interestingly, the extract did not exert any toxic effect on normal cells or non-tumor bearing mice (Oncotarget. 2015, 6(18):16379-95).

The atypical CXC-chemokine receptor CXCR7 is a 7-transmembrane receptor that is over-expressed in estrogen-receptor-positive breast cancer cells, where it functions independently of its chemokine ligand CXCL-12 (SDF-1). The mechanism behind this observation was shown to be a consequence of the CXCR7 regulation of breast cancer cell survival and proliferation by enhancing epidermal growth factor (EGF)-induced stimulation of cancer cell growth and motility, a mechanism that is hormone (17-β estradiol)-independent in early-stage breast cancer tissues and established ER-positive breast cancer cells.

This research showed co-localization of the EGF-Receptor (EGFR) and CXCR7, and migration to the nucleus to enhance cell proliferation. Depletion of CXCR7 in breast cancer cells reduced clonogenic growth of tumor cells and decreased tumor cell motility (Mol Cancer. 2014, 13:198). Ongoing studies also show that the CXCR7-EGFR interaction is regulated by the scaffold protein β-Arrestin 2.

Dr. Bal Lokeshwar also participated in an international effort to bring together cancer experts engaged in exploring a multi-targeted approach to suppress tumor-promoting inflammation and in identifying natural products that exploit these targets to destroy tumors. This multi-national project has produced and reported its findings in a thematic issue of Seminars in Cancer Biology (Semin Cancer Biol. 2015, 35 Suppl:S151-84; Semin Cancer Biol. 2015, 35 Suppl: S276-304).

Vinata B. Lokeshwar, PhD

The research focus of Dr. Vinata Lokeshwar is on the â&#x20AC;&#x153;Biomarker-driven targeted therapyâ&#x20AC;? theme. Her laboratory is investigating the mechanisms of bladder, renal cell carcinoma, and prostate cancer progression for the discovery of novel diagnostic and prognostic tumor markers, and cancer therapeutic and chemopreventive strategies. A major focus is to examine how hyaluronic acid (HA), a glycosaminoglycan, and the hyaluronidase (HAase) family of molecules promote tumor growth, metastasis, and angiogenesis. Her laboratory was one of the first to connect HAase, an endoglycosidase that degrades HA, to tumor biology, and the first to identify and characterize HYAL-1 as a tumor-derived HAase. Furthermore, they have demonstrated that the tumor-associated HA-HAase system promotes tumor growth and progression. In the cancer biomarker area, they have demonstrated that HYAL-1, either alone or together with HA, is an independent predictor of metastasis and disease-specific survival in bladder cancer patients and of biochemical recurrence in prostate cancer patients. They are currently working on a new HAfamily member and its splice variant, which are overexpressed in bladder cancer, and the expression of which correlates with metastasis. This gene has not been linked to any cancer and promotes the cancer stem cell phenotype and chemoresistance.

In the area of targeting the HA family of molecules for cancer chemoprevention and therapy, the V. Lokeshwar Laboratory is working on specific HA and HAase inhibitors. They initially demonstrated that 4methylumbelliferone (4-MU), a HA-synthesis inhibitor, inhibits prostate cancer growth, invasion and angiogenesis, both in vitro and in animal cancer models. More recently, the laboratory demonstrated that 4 -MU is a potent chemopreventive and therapeutic agent that prevents and eliminates prostate cancer development, growth, and metastasis in a transgenic model, and bone metastasis in an experimental bone metastasis model. Mechanistic studies showed that 4-MU specifically inhibited HA signaling in prostate cancer cells (J Natnl Cancer Inst. 2015, 107(7)). They also found that 4-MU synergistically enhances and overcomes resistance to Sorafenib, a second-line, FDA-approved drug for the treatment of metastatic renal cell carcinoma. Their research has identified a novel mechanism of synergy between 4MU and Sorafenib and novel drug targets that are overexpressed and associated with metastatic renal cell carcinoma. Ongoing research in the laboratory is evaluating the antitumor and antimestatic potential of the 4-MU and Sorafenib combination in several preclinical models of renal cell carcinoma. They are also evaluating the pharmacokinetics and pharmacodynamics properties of the combination. For targeting HYAL-1 HAase, they have synthesized sulfated HA derivatives that inhibit HAase activity. Previous work has demonstrated that sulfated-HA has potent anti-tumor activities. The laboratory is currently investigating the antitumor potential of small fragments of sulfate HA in preclinical models of bladder cancer and is determining its mechanism of action, along with pharmacodynamics properties.

Molecular Oncology & Biomarkers

NEW RECRUIT TO THE MOB PROGRAM Department Chair, Biochemistry & Molecular Biology Professor

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Nahid F. Mivechi, PhD

Molecular Oncology & Biomarkers

Co-Leader, MOB Program Professor

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The primary focus of research in the Mivechi Laboratory addresses the regulation and function of mammalian heat shock transcription factors (HSFs) HSF1, HSF2, and HSF4 in cellular stress responses. A second more recent focus has been to study the cellular processes via which organelle-specific molecular chaperones (cytosolic, mitochondrial, and endoplasmic reticulum-resident heat shock proteins) mediate the host response to environmental stressors and the role of these processes in human diseases, including cancer.

One approach to this problem has focused on the function of these proteins in knockout mouse models.

To this effect, in collaboration with Dr. Moskofidis (GRU Cancer Center), several knockout mouse strains (using a conventional or conditional gene-targeted strategy) in which heat shock factors (hsf1, hsf2, hsf4, heat shock factor binding protein 1) or heat shock proteins (HSPs) of interest (e.g., hsp70.1, hsp70.3, hsc70, hsp25, Hsp110, grp75, grp78, grp94, grp170, sil1) can be globally or cell-specifically inactivated. Research with these animal models over the past several years has fully validated the predicted fundamental roles of the HSP70/HSP90 chaperone machineries and of HSFs in tumor biology, as well as their essential function in embryonic development and in the progression of human diseases associated with defective protein processing and folding. This is best exemplified by their earlier and ongoing studies that have demonstrated a dramatically reduced susceptibility of mice with genetic inactivation of hsf1 to tumor formation induced by chemical carcinogens (liver cancer), or driven by oncogenic signals RAS or ErbB2 (breast, lung cancer types), or by mutant p53 and PTEN (T-ALL and AML). Moreover, several tumor types, including liver, breast, and skin, exhibit a remarkable sensitivity to targeted inactivation of HSPs including HSP70/HSC70 and GRP94. The widespread activation of HSFs, and in particular HSF1, and elevated expression of several HSPs have been shown to be associated with disease progression in patients with cancers such as breast, colon, lung, and hepatocellular carcinomas. This information suggests that these quality control proteins might be useful biomarkers to predict progression of earlystage tumors. In particular, HSF1 and selected chaperone proteins are also attractive therapeutic targets for advanced tumors. Based on existing expertise and their current research results, a high priority of the Mivechi research program will be the promotion of cancer-related translational research. Thus, there is good expectation that applying appropriate drug screening approaches to isolate small molecules that are inhibitors or activators of molecular chaperones or modulators of HSF1 will provide opportunities for translation of discoveries to applied knowledge for therapeutics in cancer. In summary, the overall goal of the program is to promote the development of an integrated program of basic and preclinical research with the ultimate goal of improving clinical outcome of cancer and other related human diseases.

Dimitrios Moskofidis, MD, PhD

The Moskofidis laboratory has been conducting basic research in microbial (viral) pathogenesis and immunology/inflammation, as well as in protein homeostasis and molecular chaperone biology. In addition to elucidating basic mechanisms of viral pathogenesis, a major focus of the Moskofidis laboratory is on the mechanisms of chaperone-mediated cancer promotion. These are areas of great medical importance, and there is reasonable expectation that this research will continue to provide the rationale to develop novel strategies to prevent, and perhaps more effectively treat, viral infectious diseases, and cancer. One approach has focused on studying the function of these molecules in different cancer types (liver, breast and lung) using transgenic (knockout) mice and novel cancer mouse models developed by applying the CRISPR/Cas9 editing approach. Specifically, in the Moskofidis laboratory, the development and functional analyses of several conditional knockout mouse models â&#x20AC;&#x201C; including the major members of HSP70 and HSP90 in the endoplasmic reticulum (GRP78, GRP170, SIL1, GRP94), cytoplasm (HSP70, HSC70, HSP25), and mitochondrion (GRP75) â&#x20AC;&#x201C; provides important materials for innovative research in the cancer biology field.

Molecular Oncology & Biomarkers

Professor

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Amyn Rojiani, MD, PhD Department Chair, Pathology Pund Distinguished Chair in Pathology Georgia Research Alliance Cancer Scientist Professor

Molecular Oncology & Biomarkers

Mumtaz V. Rojiani, PhD

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Associate Professor

The Rojiani Laboratory focuses on the role of the tumor microenvironment in brain metastasis; in particular, the role of matrix metalloproteinases and their natural endogenous inhibitors TIMPs (reviewed in J Carcinog Mutagen. 2015, 6:225). Although TIMPs have been regarded as the classical tissue inhibitors of matrix metalloproteinases, over the years they have emerged as truly multifunctional proteins with MMP-independent roles in tumor growth, apoptosis, angiogenesis, invasion, and metastasis. TIMP-1 has also been shown to be an important prognostic marker, as high serum levels of TIMP-1 have been associated with poor prognosis for a number of cancers. The laboratoryâ&#x20AC;&#x2122;s major interest lies in the multifaceted and paradoxical function of TIMP-1 in apoptosis, EMT, angiogenesis, and tumor growth. The tumor promoting activities of TIMP-1 have been attributed to its MMP-independent functions including antiapoptotic activity. Recognizing the role of many chemotherapeutic agents in inducing apoptosis and inhibiting angiogenesis, there is clearly a need to better define the complex interactions of TIMP-1, particularly in the context of metastasis to the central nervous system.

The close correlation between MMP2 expression and increased angiogenesis at the edge of lung carcinoma metastasis to the brain was previously investigated. Subsequent studies used lung adenocarcinoma cells to determine the effects of TIMP-1 on tumor growth. Transfected cells overexpressing TIMP-1 resulted in highly aggressive, more vascularized tumors when injected into the mouse brain and in vitro (J Neuropathol Exp Neurol. 2015, 74(4):293-304). The laboratory has identified the anti-apoptotic function for TIMP-1 as well as enhanced angiogenesis as the basis for its tumor promoting activity. In a recent study, evidence was presented that TIMP-1 overexpression results in increased levels of Bcl-2, resulting in inhibition of apoptosis via inactivation of BAD following its phosphorylation at serine 112. This inhibition of apoptosis occurs through the p90RSK/BAD axis via direct interaction between TIMP-1 and Bcl-2 (Plos One. 2015, 10: e0137673). The current focus of the Rojiani Laboratory seeks to determine the downstream effects of TIMP-1 overexpression, identifying TIMP-1 interactions with miRNA as well as effects on epithelial-mesenchymal transformation.

Huidong Shi, PhD

The Shi Laboratory uses genomic, epigenomic, and proteomic approaches to identify novel mechanisms involved in the pathogenesis of chronic lymphocytic leukemia (CLL), the most common type of leukemia in adults. Despite advancements in treatment regimens over the past decade, CLL remains incurable.

Many expression landscape studies have been pursued to better understand CLL pathogenesis. However, these large-scale studies provide information only at the transcriptional level. To better comprehend the differential protein changes that take place in CLL, the Shi Laboratory performed a reverse-phase protein array (RPPA) analysis using 167 different antibodies on B-cell lysates from primary CLL and normal donor samples. This study showed an enrichment of proteins involved in mRNA translation, including upregulation of the translation initiator eIF4G and hyperphosphorylation of the cap-dependent translation inhibitor 4E-BP1 at serine 65 in CLL. The Shi Laboratory further demonstrated that treatment with NVP-BEZ235, a PI3K/mTOR dual inhibitor, caused greater apoptotic induction, greater apoptotic cleavage of eIF4G, and greater dephosphorylation of 4E-BP1 in primary CLL cells when compared with Ibrutinib (BTK inhibitor) and Idelalisib (PI3K-delta specific inhibitor), two newly approved drugs for the treatment of CLL. These results highlight the importance of inhibiting the translation machinery when implementing treatment strategies for CLL (Oncotarget. 2015, 6(16):14632-45).

In collaboration with Dr. Thangaraju of GRUâ&#x20AC;&#x2122;s Department of Biochemistry and Molecular Biology, the Shi Laboratory participated in a study of the genome-wide DNA methylation landscape in breast cancer stem cells (CSCs). Using reduced representation bisulfite sequencing (RRBS), thousands of differentially methylated regions (DMRs) were identified that were either hypermethylated or hypomethylated in CSC -enriched tumorspheres, including those hypermethylated loci that are associated with known tumor suppressor genes such as Wnt5a, Abi3, Tcf7, and Isl1. Further analysis revealed that ISL1, an endogenous estrogen receptor inhibitor, is frequently hypermethylated and silenced in human breast cancers, and its functional re-expression in breast cancer cells reduces cell growth and CSC formation (Nature Communication. 2015, 6:6910). The results from this study demonstrate that CSCs possess unique epigenetic signatures that may play important roles in the initiation and development of of breast cancer.

The Shi Laboratory also led an investigation identifying global DNA methylation signatures in glioblastoma-derived cancer stem cells (J Genet Genomics. 2015, 42(7):355-71) and conducted studies in collaboration with Dr. K. Taylor of the University of Missouri, investigating the association of RUNDC3B with promoter methylation in lymphoid malignancies (Hematol Oncol, doi: 10.1002/hon.2238, in press) and with Dr. R. Rao of The University of Kansas Cancer Center, studying the role of HSF1 in CLL (Oncotarget.

2015, 6(31):31767-79.

Molecular Oncology & Biomarkers

Georgia Cancer Coalition Distinguished Scientist Professor

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Paul M. Weinberger, MD, FACS

Molecular Oncology & Biomarkers

Assistant Professor

Page 36

Dr. Weinberger’s laboratory focuses on both basic and translational research projects that center around anaplastic thyroid carcinoma and airway reconstruction. These two themes are closely linked, since anaplastic thyroid cancer almost always invades the trachea (windpipe). Using additive manufacturing (3D printing), the Weinberger Laboratory is able to model parts of the airway most vulnerable to accidental damage during airway surgery. These findings will lead to safer surgery for thyroid cancer patients and others requiring reconstruction of their airways (Ann Otol Rhinol Laryngol. 2015, epub ahead of print).

The 3D printing expertise of the Weinberger Laboratory assisted a GRU ear surgeon develop a low-cost, reproducible way to help train surgical residents to perform complex middle ear surgery (Otol Neurotol.

2015, 36(9):1562-5).

In collaboration with researchers at Moffit Cancer Center, the Weinberger Laboratory developed an improved method for deciphering the kinome of cancers, including anaplastic thyroid cancer. Using activity -based protein profiling and phospho-specific protein enrichment combined with mass spectrometry, they were able to quantitatively profile not only protein expression levels but also individual kinase activity (ATP usage) across a wide spectrum of the phosphoproteome. These findings suggested several novel and actionable pathways in anaplastic thyroid cancer that may lead to new and more effective treatments (Methods. 2015, 81:41-9).

Through the Weinberger Laboratory’s long-standing involvement in the NCI’s flagship Cancer Genome Atlas (TCGA) project, large-cohort studies unraveling the interconnected changes that take place in 20 of the most common and deadly cancers have been supported. Recently, this group completed a comprehensive analysis of 279 head and neck squamous cell carcinomas. They found two novel genetic alterations common in HPV-associated HNSCC: amplification of a key cell cycle gene (E2F1) and deletion or truncation of TNF Receptor-Associated Factor 3 (TRAF3). Non-HPV HNSCCs, on the other hand, were typified by inactivating mutations of TP53 and CDKN2A amplification (Nature. 2015, 517:576-82). Most recently, the group completed a similar large-scale genetic study of 161 kidney cancer (papillary renal cell carcinoma) patients. They found two biologically distinct subtypes (type 1 and type 2) of renal cell carcinoma. Among type 2 patients, CDKN2A alterations emerged as a promising prognostic marker. Additionally, several actionable targets novel in the context of renal cell carcinoma were identified, which hold promise for future clinical trials (N Eng J Med. 2016, 374(2):135-45).

Daqing Wu, PhD

The Wu Laboratory has developed ProFine, a proprietary formulation of naturally-occurring flavonoids, and has demonstrated its in vitro and in vivo activity against prostate cancer. Oral administration of ProFine significantly retarded the growth of prostate cancer in mouse models and extended the survival of tumor-bearing mice. In collaboration with Dr. Michael Bartlett at the University of Georgia Pharmacy School, Dr. Wuâ&#x20AC;&#x2122;s group analyzed the pharmacokinetics of the oral formulation. ProFine exhibits no obvious toxicity in mouse models; therefore, its development can be pursued as a safe, affordable, and effective treatment for both low-risk and advanced prostate cancer.

The Wu Laboratory has also developed several small-molecule therapies to selectively target bone metastatic prostate cancer. Using intratibial models, they demonstrated that GH501 effectively suppressed tumor growth at low doses. A combination of BKM1644 and docetaxel significantly inhibited prostate cancer growth in mouse bone. Survivin was identified as a major target of BKM1644 in mechanistic studies. In collaboration with Dr. Jin Xie at the University of Georgia, Dr. Wuâ&#x20AC;&#x2122;s group developed a ferritinbased BKM1644 nanoformulation, which shows high drug loading and comparable in vitro cytotoxicity in metastatic, castration-resistant prostate cancer cells.

In addition, the laboratory has established a cell-based drug screening system to discover new anticancer compounds for therapeutic-resistant cancer. Through a collaboration with the Emory University Chemical Biology Discovery, Dr. Wuâ&#x20AC;&#x2122;s group has identified eight FDA-approved drugs as leads to improve standard chemotherapy in prostate cancer models. Animal experiments are being performed to test the in vivo efficacy of these drugs.

The Wu Laboratory has been collaborating with Dr. Jenny Yang at Georgia State University on the development of new MRI contrast imaging agents for the diagnosis of prostate cancer and with Dr. Hongyan Liu at Augusta University Center for Biotechnology and Genomic Medicine on the development of a bivalent apatamer-dual siRNA chimera for the treatment of prostate cancer.

Molecular Oncology & Biomarkers

Associate Professor

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Chunhong Yan, PhD

Molecular Oncology & Biomarkers

Associate Professor

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One of the long-standing research interests of the Yan Laboratory is the role of the ATF3 transcription factor in the cellular stress response and in cancer. While ATF3 is well known for its rapid induction by a wide range of cellular stresses, the consequence(s) of ATF3 induction by stresses remains largely unclear.

In a recent report, Dr. Yanâ&#x20AC;&#x2122;s group has identified ATF3 as a major regulator of the histone acetyltransferase Tip60 and has revealed that ATF3 contributes to the cellular DNA damage response by promoting Tip60-mediated acetylation and activation of the major stress-sensing kinase ATM (Nat Commun. 2015, 6:6752). These findings are in line with a notion that ATF3 is required for the maintenance of genetic stability and the prevention of cancer. Employing knockout mouse models, Dr. Yanâ&#x20AC;&#x2122;s group has indeed demonstrated that ATF3 delays the progression of prostate cancer caused by PTEN inactivation â&#x20AC;&#x201C; a common genetic alteration occurring in 60% of patients with advanced prostate cancer (Oncogene. 2015, 334: 4975-4984). Further, ATF3 was shown to prevent prostate cancer development in an experimental condition mimicking hormone imbalance in aging men (Oncogene. 2015, doi: 10.1038/onc.2015.417, in press). The latter finding is noteworthy, as aging is a major risk factor for prostate cancer.

The Yan Laboratory is also interested in the development of novel anti-cancer therapies targeting abnormal gene expression in cancer. In light of the current lack of a reliable platform for screening for transcription-targeted lead compounds, the Yan group has recently developed a reporter gene assay based on co-expressing a reporter gene with an endogenous gene under the control of the endogenous promoter and enhancers (Chem Biol. 2015, 22(7): 957-64). This innovative reporter gene assay has been demonstrated to be more effective, reliable, and powerful in identifying compounds that can either inhibit or increase gene expression in cancer cells.

In addition, Dr. Yan has collaborated with Dr. Junran Zhang at Case Western Reserve University to study the regulation and function of proteins (i.e., 53BP1 and BRCA1) involved in the DNA damage response (Nucleic Acid Res. 2015, 43:1659-70; Oncogene. 2015, doi: 10.1038/onc.2015.198, in press).

Tumor Signaling & Angiogenesis OVERVIEW

• A variety of kinase targets involved in cancer cell proliferation and progression; • The basic underlying mechanisms whereby a variety of membrane transporters promote cancer cell survival and how these can be targeted in therapeutic strategies; • Growth factors and lipid signaling molecules that stimulate growth and invasion; • The role of G protein-coupled receptors that are involved in a variety of cancer cell functions and metabolism; • Epigenetic regulation of biosynthetic pathways in cancer cell metabolism and proliferation; • The role of the MYCN oncogene in the development of pediatric tumors; • Novel regulators of apoptosis; • Mechanism of resistance to anti-angiogenesis treatments visualized in vivo using imaging approaches such as MRI and SPECT. Targets identified in this program can be exploited to develop innovative approaches to cancer prevention and therapy that can be translated into clinical trials. The research into cancer cell signaling incorporates animal models in breast and colon cancer, as well as the pediatric cancer neuroblastoma, to study how specific signaling pathways are involved in the progression of cancer.

Tumor Signaling & Angiogenesis

The unifying theme of this program is to build translational clinical trials based on innovative and novel research projects that focus on signaling cascades leading to uncontrolled cell growth and resistance to apoptosis. The program goals are to identify dysregulated molecular signaling pathways that can be used as cancer-specific targets. Collectively, the members of this program work cooperatively to study:

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Ali Arbab, MD, PhD

Tumor Signaling & Angiogenesis

Leader, Tumor Angiogenesis Initiative Professor

Page 40

The Tumor Angiogenesis Laboratory (Arbab Laboratory) is devoted to determining mechanisms of resistance to antiangiogenic treatments (AAT) and to studying the involvement of bone marrow-derived cells in modulating the tumor microenvironment and in initiating tumor neovascularization in glioma and breast cancers. Dr. Arbabâ&#x20AC;&#x2122;s group observed that bone marrow-derived myeloid cells orchestrate resistance to AAT in glioma (Cancer Letter. 2015, 369:416-26). To understand the involvement of bone marrow cells in developing the resistance to AAT, the Arbab group has developed chimeric animal models, where bone marrow of the recipient animal is replaced with GFP+ bone marrow. The accumulation of GPF+ bone marrow cells can be determined by in vivo optical imaging (Cancer Biol Ther. 2016, 17 (3):280-90). Dr. Arbabâ&#x20AC;&#x2122;s group is also working with IV formulation of the HET0016 drug for the treatment of glioma and breast cancers.

In collaboration with different institutes, Dr. Arbab has shown the utility of nanoparticle-based MRI probes (Contrast Media Mol Imaging. 2015, doi: 10.1002/cmmi.1651) and has used iron-based nanoparticles to separate cardiac precursor cells from body fat (Int. J Nanomedicine. 2015, 10:711-26). His collaborator also showed CXCR2 PDZ-mediated endothelial cell homing and angiogenesis (Stem Cell Res. 2015, 14:133-43).

The Arbab Laboratory is also working with different natural products for the treatment of breast cancers, especially targeting tumor neovascularization and metastasis which have shown promising results (J of Pineal Res. 2015, doi: 10.1111/jpi.12270; Anticancer Agents Med Chem. 2015, 15:1285-96).

Erhard Bieberich, PhD Professor

Guanghu Wang, PhD

The Bieberich Laboratory is interested in the function of lipids for cell signaling in cancer cells, a study started and continued in collaboration with the laboratory of Dr. Guanghu Wang. In particular, Dr. Bieberich’s work focuses on the signaling nexus between cholesterol derivatives (secondary bile acids) and sphingolipids (ceramide). Dr. Bieberich’s original observation was that at physiologically relevant serum concentration (<10 µM), the secondary bile acid salt sodium deoxycholate promotes migration and survival of breast cancer cells and stem-like cells, respectively. These results were in sharp contrast to previously published studies describing the pro-apoptotic activity of deoxycholate at nonphysiological concentration (>50 µM). Further studies in the Bieberich Laboratory showed that at physiological concentration, deoxycholate reduces generation of the pro-apoptotic sphingolipid ceramide from sphingomyelin by suppressing expression and activity of neutral sphingomyelinase 2 via activation of the nuclear farnesoid X receptor FXR. This effect can be reversed by the FXR antagonist guggulsterone, a potential treatment of breast cancer targeting cancer stem cells.

In new studies (Int J Cancer. 2015, 137(7):1610-20), Dr. Bieberich showed that the effect of guggulsterone is enhanced by bexarotene, an agonist of the nuclear retinoid X receptor (RXR) that forms dimers with FXR. Combinatorial treatment with guggulsterone and bexarotene tremendously increased sensitivity of MDA-MB-231 cells to doxorubicin, suggesting that this treatment is a promising strategy to overcome multidrug resistance of breast cancer cells. Multidrug resistance was obliterated by neutral sphingomyelinase 2/ceramide-induced secretion of breast cancer resistance protein-associated lipid vesicles termed exosomes. The Bieberich Laboratory plans to extend these studies to other cancer cell types and develop a lipid therapy for cancer.

Tumor Signaling & Angiogenesis

Assistant Professor

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Wendy B. Bollag, PhD, FAHA

Tumor Signaling & Angiogenesis

Professor

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The Bollag Laboratory is interested in the signals that regulate normal cell processes and what goes wrong in cancer, with the idea that prevention of cancer may be as effective, or perhaps even more effective, than treatment of the disease. A particular focus investigates the signaling mechanisms that regulate the growth (proliferation) and maturation (differentiation) of epidermal keratinocytes, the primary cell constituents of the outer layer of the skin (the epidermis). Keratinocytes can transform into non-melanoma skin cancers, which are the most common cancer in the world, with approximately one million new cases diagnosed each year in the United States alone. While most non-melanoma skin cancers are remedied by surgical removal, treatment is often disfiguring, as these cancers occur mostly on visible skin. The etiology of non-melanoma skin cancers is not entirely understood, although the most important risk factor for these cancers is chronic sun exposure, that is, ultraviolet radiation. The Bollag Laboratory is studying the role of protein kinase D in promoting keratinocyte proliferation and survival and in inhibiting differentiation. Previously studies showed that protein kinase D levels are increased in the non-melanoma skin cancer basal cell carcinoma, that protein kinase D is activated by ultraviolet irradiation of epidermal keratinocytes, and that this activated protein kinase D protects keratinocytes from ultraviolet-induced cell death (apoptosis). This work provides a potential link between protein kinase D, sun-induced non-melanoma skin cancers, and epidermal tumorigenesis. The Bollag Laboratory is currently examining the mechanism by which protein kinase D protects keratinocytes from UV-induced apoptosis, including the potential role of the water, glycerin, and hydrogen peroxide transporter aquaporin-3 as a protection against skin cancer. Aquaporin-3 may also be involved in the skin disease psoriasis, which is characterized by excessive (non-cancerous) proliferation of keratinocytes, abnormal keratinocyte differentiation, and skin inflammation. In addition, the Bollag Laboratory collaborates with a number of other laboratories to understand the cell signaling mechanisms that regulate various cell processes, including breast and metastatic colon cancer cell proliferation and/or apoptosis (Cancer Lett.

2015, 365:122-31; J Immunol. 2015, 195:1868-82), as well as hormone secretion, bone formation, and corneal wound healing.

Darren D. Browning, PhD

The Browning Laboratory is focused on developing novel cGMP-focused treatment strategies for gastrointestinal diseases. Recent studies reported evidence demonstrating that type ll cGMP-dependent protein kinase (PKG2) can protect the epithelial barrier in the colon, and that activation using the PDE5 inhibitor Vardenafil protected against colitis in a preclinical model. It has been shown that a PKG2dependent signaling pathway that contributes to barrier protection by activating antioxidant gene expression in the colon mucosa to protect the epithelium from reactive oxygen species. While the paper is currently under review, these findings and a related project involving PDE5 inhibitor effects on irritable bowel syndrome (manuscript in preparation) were presented both orally and in poster format at the 2015 national Digestive Disease Week meeting in Washington, DC (Gastroenterology. 2015,148(4): S-42 and S-733).

As colitis is a significant factor in colon tumorigenesis, the Browning Laboratory is actively engaged in determining whether increasing cGMP levels in the intestinal epithelium is chemopreventative in preclinical models of colon cancer. Using the PDE5 inhibitor Sildenafil and the guanylate cyclase agonist Linaclotide, they have demonstrated that both have significant but different therapeutic potential for colon cancer. Preliminary results were presented in poster form at the 2015 annual American Association for Cancer Research (AACR) meeting in Philadelphia, PA, and also as an invited lecture at the international cGMP meeting in Germany (Cancer Res. 2015, 75(15): Supplement:1918; BMC Pharmacol Toxicol.

2015, 16(Supplement 1): A11).

Tumor Signaling & Angiogenesis

Co-Director, Biochemistry & Cancer Biology Training Program Associate Professor

Page 43

Han-Fei Ding, PhD

Tumor Signaling & Angiogenesis

Georgia Cancer Coalition Distinguished Scientist Professor

Page 44

The Ding Laboratory studies the molecular and cellular basis of cancer development in model systems. It is well established that cancer cells reprogram their metabolism to meet the biosynthetic challenge of growth and proliferation. How cancer metabolism is initiated and maintained in cancer cells is a central question of cancer research. A major research area of the Ding Laboratory is to investigate the role of histone methylation states in the transcriptional regulation of cancer metabolism. The histone lysine demethylase KDM4C is often overexpressed in cancers, primarily through gene amplification. The molecular mechanisms of KDM4C action in tumorigenesis are not well defined. In a recent study (Cell Reports.

2016, 14(3):506-19), Dr. Ding and colleagues reported that KDM4C transcriptionally activates amino acid biosynthesis and transport, leading to a significant increase in intracellular amino acid levels. Examination of the serine-glycine synthesis pathway revealed that KDM4C epigenetically activates the pathway genes under steady-state and serine deprivation conditions by removing the repressive histone modification H3 lysine 9 (H3K9) trimethylation. This action of KDM4C requires ATF4, a transcriptional master regulator of amino acid metabolism and stress responses. KDM4C activates ATF4 transcription and interacts with ATF4 to target serine pathway genes for transcriptional activation. In addition, this study presented evidence for KDM4C in transcriptional coordination of amino acid metabolism and cell proliferation. These findings suggest a molecular mechanism linking KDM4C-mediated H3K9 demethylation and ATF4-mediated transactivation in reprogramming amino acid metabolism for cancer cell proliferation.

In another study, Dr. Ding and his collaborators in the Southwest University of China reported that HOXC9, a master regulator of development, is an oncogene in the pathogenesis of glioblastoma, a deadly brain tumor. The study found that high expression of HOXC9 is associated with poor prognosis in glioblastoma. HOXC9 knockdown induces autophagy in glioblastoma cells, leading to a significant reduction in tumor cell viability, migration, invasion, and tumorigenicity. HOXC9 prevents autophagy of glioblastoma cells by directly repressing the expression of death-associated protein kinase 1 (DAPK1), a key activator of Beclin-mediated autophagy. These findings suggest a therapeutic strategy for glioblastoma (Neuro -Oncology, 2015, in press).

Honglin Li, PhD

The Li Laboratory studies the Ufm1 conjugation system, a novel ubiquitin-like protein modification system. Protein modification by Ubiquitin (Ub) and Ubiquitin-like (Ubl) proteins plays pivotal roles in a wide range of cellular functions and signaling pathways, and dysfunction of this fundamental mechanism leads to the etiology and progression of many human diseases. The Ufm1 (ubiquitin-fold modifier 1) conjugation system is a novel ubiquitin-like system that shares common features with other Ubl systems, yet its downstream targets and the functional impact of modifying these targets remains poorly understood. Ufl1 and Ufbp1 are two key components of the Ufm1 E3 ligase, but little is known about their physiological functions and working mechanism. By using genetic mouse models, the Li Laboratory reported that both Ufl1 and Ufbp1 are essential for murine erythropoiesis, a process to generate mature red blood cells (Cell Death Differ. 2015, 22:1922-34; PLoS Genet. 2015, 11(11):e1005643). These studies suggest that the ufmylation pathway may represent a novel therapeutic target in treatment of blood diseases such as anemia.

Tumor Signaling & Angiogenesis

Associate Professor

Page 45

Nita Maihle, PhD

Tumor Signaling & Angiogenesis

GRU Cancer Center Associate Director, Education Professor

Page 46

Dr. Maihle’s laboratory focuses on ligand-independent signaling by the EGFR/HER family of receptor tyrosine kinases, including ways to apply fundamental aspects of EGFR/HER family signaling to the early detection of cancer and to ‘precision medicine.’ The Maihle Laboratory has developed isoform-specific immuno-reagents/assays for the detection of two novel cancer biomarkers (i.e., sEGFR/sHER3) that circulate in human blood; both proteins change in blood concentration months prior to the clinical detection of certain cancers. Supported by the Komen Foundation, precise changes in the circulating levels of these proteins are being studied to facilitate early cancer detection and to determine which patients will respond to which drugs. With support from the Lloyd Foundation, biochemical and molecular characterization of the sEGFR and sHER3 biomarkers in blood, as well as their expression patterns in tumor and normal tissues, are being conducted to understand the functional roles of these proteins in human tissues, and also to determine how the observed changes in their expression contribute to the malignant phenotype.

In addition to their work in basic science research, the Maihle Laboratory has functioned as a translational collaborator on several key clinical trials that helped to bring new drugs targeting this signaling pathway into the clinic (e.g., trastuzumab; cetuzimab). Dr. Maihle’s basic science and translational research interests have led to her extended study of ‘big picture’ questions regarding how to facilitate the incorporation of new scientific discoveries into clinical practice, as well as how to optimize the effectiveness of teaching efforts in academic medical centers.

Along these lines, a recent collaborative publication, “A World without Cancer,” explores ways in which academic medical centers: can create public/private partnerships to more effectively bring the benefit of scientific discoveries into the clinic; can create transformative and integrative ‘virtual’ learning centers to support the instruction of both biomedical professionals as well as individuals in the communities they serve; can promote the involvement of patients/consumers in the research process; and finally, can change the incentives in academic medicine – away from those that promote ‘hero-driven’ science – toward more mindful, inclusive, and collaborative models of research.

In an effort to work toward incorporating some of these goals into training the next generation of scientists, a new virtual training program has been established, called ‘The Ovarian Cancer Academy: A Team Science Approach. ’ This program supports the early career development of investigators who share the aim of eliminating ovarian cancer. This visionary training program is being directed by Dr. Maihle, and Dr. Douglas Levine (Memorial Sloan Kettering, NY), and is supported by the U.S. Department of Defense.

Dr. Maihle has also been involved in a project supported by the NCI to develop new biobanking models, including the creation of natural languages to facilitate clinical data sharing, resulting in a ‘federated’ approach to biospecimen/data sharing (Cancer Res. 2015, 75(24):5194-201).

Daitoku Sakamuro, PhD

Deficiency of the retinoblastoma (RB1) protein or dysregulation of the RB1-related pathway (due to deregulation of cyclin D1, etc.) are among the hallmarks of human malignancies. RB1 deficit induces deregulation of the E2F family of transcription factors, including E2F1, thereby enabling cell-cycle progression and apoptosis. However, loss of RB1 is essential, but not sufficient, to trigger RB1-deficient tumor formation, implying that there is an RB1-independent anti-E2F1 factor, the expression of which may be induced after RB1 is inactivated. The Sakamuro Laboratory discovered that BIN1, which was originally identified as a c-MYC-binding adaptor protein with features of a pro-apoptotic tumor suppressor, interacts directly with E2F1 and hinders its transactivation independent of RB1, but in cooperation with poly (ADP-ribose) polymerase 1 (PARP1). PARP1 is a nuclear enzyme that promotes not only DNA repair, but also controls gene transcription and chromatin remodeling. The BIN1–E2F1 interaction depended on the BIN1’s coiled-coil BAR domain, which is essential for BIN1-dependent cancer suppression, and the E2F1 Marked Box domain, which is required for E2F1-specific transactivation. Irrespective of RB1 expression status, overexpression of BIN1 suppressed E2F1 transactivation. In contrast, reduction of BIN1 was sufficient to release endogenous E2F1 activity. Interestingly, depletion of PARP1 compromised the BIN1 nuclear localization and reduced BIN1 levels on an E2F1-sensitive promoter, thereby increasing endogenous E2F1 activity. Consistently, in the absence of PARP1, heterologously expressed BIN1 did not inhibit tumor colony formation and failed to suppress oncogenic H-Ras cotransformation mediated by the human papillomavirus E7 in rodent fibroblast cell systems. Nonetheless, RB1-induced E2F1 repression did not require PARP1 expression, indicating that PARP1 is specifically required for BIN1-mediated E2F1 repression. The discovery that the human BIN1 promoter is activated by E2F1, suggested a unique positivefeedback loop for E2F1-dependent apoptosis by which BIN1 expression is accelerated by either RB1 inactivation or in the presence of PARP1 (Cell Death Diff. 2015, 22:311-322; Mol Cell Oncol. 2015, 2:2, e981447). Although the BIN1-E2F1-PARP1 model requires further validation, particularly in human primary tissues, this study may explain why most women with persistent high-risk HPV infections of the cervical epithelial tissues (i.e., pap-smear positive cervical tissues), where RB1 protein has most likely been deficient for decades, do not develop cervical cancer. Because ‘druggability’ is a key word for the development of anticancer intervention based on the function of tumor suppressors, the Sakamuro Laboratory also investigated the current status of small molecule inhibitors that can rescue the activity of ‘tumor suppressors’, such as RB1, p53, and BIN1 (Mol. Cell. Oncol. 2:3, e991225, 2015).

Tumor Signaling & Angiogenesis

Associate Professor

Page 47

Patricia V. Schoenlein, PhD

Tumor Signaling & Angiogenesis

Associate Professor

Page 48

Studies in the Schoenlein Laboratory are focused on understanding the role of autophagy in breast cancer cells undergoing conventional therapies, such as hormonal therapy and/or chemotherapy. Autophagy is a stress response that occurs in normal and cancer cells. Stresses that induce autophagy include reactive oxygen species (ROS), ceramide accumulation, and nutrient deprivation. Previously, the Schoenlein Laboratory demonstrated that pro-survival autophagy facilitated the development of antiestrogen resistance. They also uniquely identified the dephosphorylated form of BimEL as a key death effector of antiestrogen and antiprogestin treatment of ER+ breast cancer cells and determined that MEK1/MAPK1/2 blockade is required to produce high levels of dephosphorylated BimEL, particularly under conditions of growth factor stimulation. Recent studies have demonstrated that long-term antiestrogen treatment selects for breast cancer cells that are estrogen receptor alpha (ERÎą)-negative and that show increased activation of pMAPK1/2. Importantly, targeting MEK1 in these antiestrogenresistant breast cancer cells causes a significant reduction in pMAPK1/2 activity and restores BimELdependent apoptosis. However, pro-autophagy is induced by MEK1 inhibition with U0126 and the clinically approved MEK1 inhibitor AZD6244. These results suggest that eradicating antiestrogen-resistant breast cancer will require optimal activation of BimEL via targeting MEK1/MAPK1/2 as well as the inhibition of pro-survival autophagy to eliminate cells surviving BimEL-dependent apoptosis. In vivo studies testing the efficacy of Tamoxifen (TAM) monotherapy versus TAM in combination with AZD6244 have been initiated utilizing antiestrogen-sensitive and -resistant orthotopic models of breast cancer. Current studies aim to identify the pro-survival autophagy pathway induced by MEK1 blockade in antiestrogensensitive and -resistant breast cancer cells, with the goal of identifying a druggable molecular target.

Treatments that can be combined with MEK1 blockade to optimally upregulate BimEL in ER+ and triple negative breast cancer cells with a focus on HDAC inhibitors are also under investigation. In collaboration with other investigators, the Schoenlein Laboratory provided expertise in the area of autophagy (PLOS Pathogens. 2015, 10(2):e1004647.)

Muthusamy Thangaraju, PhD

The Thangaraju Laboratory studies the role of epigenetics, especially DNA methylation and histone acetylation, in the regulation of Mammary Stem Cells (MaSCs) and Cancer Stem Cells (CSCs) using spontaneous mouse mammary tumor models. Using a mammary gland-specific Dnmt1-knockout mouse, Dnmt1 was shown to be indispensable for MaSC formation and maintenance. Further, mammary gland-specific Dnmt1 deletion was shown to protect mice from mammary tumorigenesis by limiting the CSC pool.

Through genome-scale methylation studies, ISL1 was identified as a direct DNMT1 target, hypermethylated and downregulated in mammary tumors and in CSCs. DNMT inhibition or ISL1 expression in breast cancer cells limits the CSC population. Altogether, studies in the Thangaraju Laboratory have uncovered an essential role for DNMT1 in MaSC and CSC maintenance and identify the DNMT1-ISL1 axis as a potential therapeutic target for breast cancer treatment (Nat Commun. 2015, 6:6910).

Although CSCs are believed to contribute to resistance to chemotherapy and radiation therapy, an effective therapeutic strategy to overcome this resistance is yet to be identified. Using the MMTV-Neu-Tg mouse mammary tumor model, the Thangaraju Laboratory found that both luminal progenitor and basal stem cells are susceptible to genetic and epigenetic modifications, which leads to activation of unactivated Neu-Tg into a transformed, tumor-forming phenotype. Combination of 5-Azacytidine (5-AzaC) and butyrate markedly reduces CSCs and consequently increases the overall survival of the animal. RNAseq analysis of the CSCs treated with 5-AzaC+butyrate provides evidence that combined inhibition of DNMTs and HDACs reduces the CSC pool in the mammary gland by blocking growth-promoting signaling molecules like RAD51AP1 and SPC25. RAD51AP1 and SPC25, which are known to play a key role in DNA damage repair and kinetochore assembly, are significantly overexpressed in breast tumor tissues and are associated with decreased overall patient survival. Overall, this work provides convincing evidence that breast CSCs are susceptible to genetic and epigenetic modifications that are associated with resistance to chemo- and radiotherapy. Thus, combining DNMT and HDAC inhibitors may serve as an effective therapeutic strategy to block mammary tumor growth and to overcome drug resistance by inhibiting CSCs (Cancer Res. 2015, in press).

Tumor Signaling & Angiogenesis

Associate Professor

Page 49

Guangyu Wu, PhD

Tumor Signaling & Angiogenesis

Professor

Page 50

The Wu Laboratory is interested in dissecting the molecular mechanisms underlying the intracellular trafficking and signaling of G protein-coupled receptors (GPCRs) and the role of GPCR/G proteinmediated signaling in the development of human diseases, including cancers. The laboratory has recently demonstrated that ADP-ribosylation factor 1 (ARF1), a Ras-like small G protein, plays a crucial role in activating the oncogenic MAPK pathway (Cell Signal. 2015, 27:2035-44). They have also demonstrated that mutating a single residue (Lys308) markedly disrupts the cell surface export and signaling of angiotensin II type 1 receptor (Cell Signal. 2015, 27:2371-9) and, in collaboration with Dr. Yin Hua Zhang, they have investigated the role of angiotensin II receptor trafficking in nNOS expression and activation in cardiac myocytes (Basic Res Cardio. 2015, 110:21). In addition, it was shown that Rab5 mediates betaadrenergic receptor trafficking and cadherin internalization and that these processes regulate the barrier function of the lung microvascular endothelium (Cell Mol Life Sci. 2015, 72:4849-66; Int J Biol Sci. 2015, 11:868-78).

Cancer Prevention & Control OVERVIEW As the GRU Cancer Center builds it focus in cancer prevention, a major theme is bringing these efforts to medically underserved regions of the state of Georgia that show significant disparity in outcomes in minority populations. Current efforts involve the relationship between HPV and cervical cancer supported by clinical research centers in Georgia and in rural districts of Peru where there is a significantly increased incidence of cervical cancer. In this area, the focus is on diagnostics and prevention as well as behavioral research associated with screening. These studies are also extended to epidemiology studies about uptake of HPV vaccination in rural Georgia.

Additional studies are using the SEER database to investigate the relationship between demographic factors and disease outcomes as well as the role of NSAIDs and diet in outcomes of breast cancer in postmenopausal women.

Cancer Prevention & Control

Lung cancer is one of the more prevalent cancers in Georgia, and early detection can impact survival. To address this issue, the GRU Cancer Center has developed a lung cancer screening program that is offered at no charge. Encouraging results have been obtained so far in a relatively large cohort of volunteers.

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Candace Best, PhD Assistant Professor

Cancer Prevention & Control

Dr. Bestâ&#x20AC;&#x2122;s research laboratory is focused on Cancer Prevention and Control related to human papillomavirus (HPV). Specifically, Dr. Best and colleagues have focused on increasing HPV vaccine uptake in Georgia and eventually throughout the country, since HPV vaccine uptake remains low. Likewise, HPV infection, disease, and related cancers continue to have an enormous burden in the lives of many in Georgia, the US and throughout the world. Moreover, current intervention strategies to improve HPV vaccine uptake have been less than effective for reasons still left unanswered by the scientific literature.

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The Best research strategy is to utilize a systematic mixed-method approach to improve HPV vaccine uptake. First, considerable time and effort is being taken to identify health care providers (HCPs) in Georgia who are engaging in high and low levels of HPV vaccination. Georgia is one of few states that collect and store county-level vaccination records in a centralized database. Accordingly, the Best Laboratory has gained access to these databases and is currently conducting secondary data analyses to identify counties with high and low levels of HPV vaccination. This data is then being mapped onto an HCP database of HCPs who are currently licensed and who frequently administer the HPV vaccine (e.g., pediatricians) in those specific counties. Second, a random subset of HCPs who practice in these counties will be identified and interviewed. They expect that the qualitative interviews will provide meaningful characteristics of HCPs who engage in different HPV vaccination practices across the state.

Finally, the Best Laboratory will analyze this data using a grounded-theory approach and use it to develop an electronic survey. This survey will be disseminated to HCPs throughout the state of Georgia. It is anticipated that this large survey will help discriminate between HCPs who do and do not regularly administer HPV vaccination to eligible patients. More importantly, the survey will provide information about where and how to target future HPV uptake interventions.

Overall, this novel research approach will instruct the future development of a national HPV vaccine uptake intervention to improve HPV vaccine rates and reduce the immense burden of this disease.

Daron G. Ferris, MD Director, HPV Epidemiology & Prevention Program Professor

Dr. Ferris and colleagues have determined the potential benefits of polarized light colposcopy compared with standard colposcopy examinations in the evaluation of women with abnormal cervical cytology.

Polarized and standard colposcopy examinations were performed on 330 subjects. Respective images and biopsy annotations were obtained. Sensitivity and specificity; differences in the severity of cervical neoplasia; agreement of colposcopy impression, biopsy intent, and biopsy site; and differences in the number of biopsies were determined using the ROC, Bowker's test of symmetry, kappa statistic, and paired t test, respectively. It was determined that polarized light colposcopy was not useful as an adjunct to conventional colposcopy in this study. Further research needs to be performed to determine the overall utility of polarized light colposcopy in clinical practice. (J Low Genit Tract Dis. 2015, 19(3):234-8.)

Dr. Ferris also determined the potential impact of accessible secondary cervical cancer prevention efforts in indigenous Peruvian women living in the rural Andes Mountain region of Peru in the Dia del Mercado research project. This study enrolled 4,560 Peruvian women presenting for a Pap test or visiting a local marketplace, clinic, or public facility who were asked to complete a questionnaire that assessed their response to the rural Pap screening program. Researchers identified the following: 1) barriers to care, 2) patient knowledge of cervical cancer and Pap tests, and 3) perceptions of and reactions to the market clinic model. They concluded that many poor indigenous women living in isolated regions are unable to travel to distant health-care facilities. Using a novel mobile clinic model, the "Dia del Mercado Project" successfully reduced barriers to cervical cancer screening by using local marketplaces. (J Low Genit Tract Dis. 2015, 19(3):229-33.)

Dr Ferris and his research team also assessed the impact of an educational video on impoverished rural Peruvian women seeking loop excision surgery. Women completed baseline, postvideo and postsurgery questionnaires that assessed knowledge and attitudes about the procedure. Differences between groups were examined using repeated measures analysis of variance. Women who watched the video were significantly more calm, relaxed, and content at postvideo and postsurgery assessments compared with mean results at the baseline assessment. The same women were also significantly more tense, upset, and worried at baseline compared with postvideo and postsurgery results. Approximately 93% of women believed that other women scheduled to have loop excision surgery should also watch the video. This trial was the first to determine that dissemination of culturally sensitive video information minimizes adverse emotional responses associated with loop excision procedures before surgery. Such an intervention quickly improves the psychological well-being of women eventually subjected to surgical management of cervical neoplasia. (J Low Genit Tract Dis. 2015, 19(3):224-8.)

Cancer Prevention & Control

Dr. Daron Ferrisâ&#x20AC;&#x2122; research focuses on the prevention, screening, diagnosis, and treatment of HPVinduced cancers, primarily those involving the anogenital tract. His clinical trials are conducted in both the US and at his clinical research center, CerviCusco (www.cervicusco.org), located in Peru.

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Sangmi Kim, PhD Assistant Professor

Cancer Prevention & Control

Dr. Sangmi Kim conducts both population-based and clinical studies to understand cancer etiology and survivorship for cancer prevention and control.

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Dr. Kim and her collaborators at NIEHS have shown that among postmenopausal women who did not regularly use nonsteroidal anti-inflammatory drugs (NSAIDs), high levels of PGE2 metabolite (PGE-M), an index of systemic PGE2 synthesis, is associated with an increased risk of breast cancer. In a recent report, Dr. Kimâ&#x20AC;&#x2122;s group has demonstrated that a healthy diet such as increased fruit consumption and low saturated fat intake is independently associated with reduced levels of PGE-M, suggesting the utility of measuring PGE-M in assessing cancer prevention efficacy (Nutr Cancer. 2015, 67(4): 580-6). In some human cell lines, endogenously produced PGE2 was shown to directly increase expression of DNA methyltransferases. However, there was no association between NSAID usage and whole genome methylation patterns in blood DNA. The results suggest that any effect of NSAID use on DNA methylation might be specific to tissues other than blood (PloS One. 2015, 10(9): e0138920). Given insufficient epidemiological evidence to support the use of NSAIDs for breast cancer prevention in the general population, Dr. Kim has also conducted the analysis of data from a prospective cohort of more than 50,000 women with family histories of breast cancer. The findings do not show a protective effect from NSAIDs in the overall cohort of women, but raise an intriguing hypothesis that the use of NSAIDs, particularly aspirin, may reduce risk among premenopausal women at higher risk of breast cancer on the basis of family history (BMC Cancer. 2015, 15:960).

In addition, Dr. Kim is interested in improving cancer-related fatigue (CRF), one of the most common and devastating complications of cancer and its treatment. Inflammation is thought to be a distinct component of CRF, but detailed mechanisms remain unknown. As reviewed in a recent publication, the indoleamine 2,3-dioxygenase (IDO) pathway that is induced by inflammatory stimuli to produce neuroactive metabolites may provide a link between inflammation and CRF (Cancer. 2015, 121(13): 2129-36). Dr. Kim is currently testing the hypothesis by evaluating fatigue and other patient-reported outcomes in advanced cancer patients before and after treatment with investigational IDO inhibitors (indoximod or NLG919).

Ramses Sadek, PhD Head, Cancer Center Clinical Trials Biostatistics Unit Professor

Dr. Sadek performed data mining using SEER and GRU Cancer Center disease registry databases to understand the association between demographic factors and disease outcomes. Several cancer clinical trials were designed, and meta-analyses for different cancer treatment settings were conducted.

For cancer overall and specifically for lung and bronchus, breast, lymphoma, colon, and prostate cancer, the distribution of gender, race, marital status, insurance for cancer cases, cancer stages, age at diagnosis, and survival time in months were summarized and compared between CSRA and Atlanta, as well as between the CSRA and outside of the CSRA. The study produced a summary of all cancers and for each of the five cancer types for all considered demographic factors, in addition to disease stage at diagnosis, survival status, and type of health insurance. The data demonstrate that a larger percentage of blacks present with late stage tumor at diagnosis.

Meta-analysis data will be presented at the upcoming ASCO meeting 1) â&#x20AC;&#x153;All immune inhibitors are not created equal: A meta-analysis of immune related adverse events from cancer clinical trials, and 2) â&#x20AC;&#x153;Treatment-related deaths after concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: A meta-analysis of randomized studies.

Cancer Prevention & Control

These studies describe the CSRA cancer profile in comparison to 1) the Metro Atlanta area, and 2) the rest of the state of Georgia, using the SEER database reflecting 2008-2012. In addition, the GRU Cancer Center disease registry was used to investigate the distribution of stage of disease at diagnosis by race compared with the state registry to investigate risk factors for health disparities.

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Carsten Schroeder, MD Director, Cancer Center Thoracic Oncology Surgery Service Associate Professor

Dr. Carsten Schroeder is the thoracic oncology surgeon at Augusta University. His practice and research focus on screening, prevention, diagnosis, and management of lung cancer.

Cancer Prevention & Control

Dr. Schroeder is particularly involved in research related to lung cancer screening and recently published his research into the uneven distribution of cancer histology in the National Lung Screening Trial. (Am J Med Sci. 2015, 350:219.)

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Dr. Schroeder has pioneered improving lung cancer screening specifically in the local community, as it is an underserved region in the southeast with a higher proportion of smokers. Working with the Department of Radiology and Imaging and the Cancer Center, he developed a free lung cancer screening program utilizing modified National Comprehensive Cancer Network criteria to determine eligibility. Within the first year, 398 patients enrolled, 355 qualified for screening, and 272 underwent screening. Although designed to help the local community, participants have traveled as far as 151 miles to take advantage of this free lung cancer screening. From just this first year of the free screening program, eight pathologically proven lung cancers were diagnosed, an incidence of 1/34 high-risk persons screened.

This incidence was significantly higher than those of the National Lung Screening Trial and the Lahey Hospital Free Lung Cancer Screening Program.

Early detection of lung cancer is imperative for operative intervention and potential cure. Unfortunately, most institutions do not offer free screening yet, and insurance companies just recently started converge for screening following narrower criteria. By developing a free lung cancer screening program, Dr. Schroeder and his team were able to include an indigent population that may otherwise not seek help at all or delay diagnosis until highly symptomatic with advanced disease. Not only was there a higher incidence of lung cancer, six out of eight lung cancers were diagnosed in early stages amenable to surgical intervention and potential cure.

Dr. Schroeder continues to work with the free lung cancer screening program, ensuring that screened patients receive proper follow-up. He hopes to influence other large institutions, especially those in underserved regions, to also develop free lung cancer screening.

In addition to his efforts in lung cancer screening, Dr. Schroeder has also published findings of three synchronous primary lung cancers within a single lobe. This case was notable since three primary lung cancers with histologically distinct tumor types have not been documented until now. (J Clin Case Rep. 2015, 5:3)

GRU Cancer Center Shared Resources

The Cancer Center Shared Resources provide services that are needed by many investigators to conduct their research, but are generally too expensive, complex or specialized for investigators to provide and sustain themselves. By this definition, cores contribute to the body of knowledge generated by providing state-of-the-art technologies and the expertise to administer these services. As such, the Shared Resources personnel are required to sustain an up-to-date understanding of the technologies they support and to aid in the education of the individual scientists who enlist their help. During the last 12 months, GRU Cancer Center Shared Resources have been involved in a vast array of different projects and collaborations as outlined throughout this scientific report.

GRU Cancer Center Shared Resources

OVERVIEW

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Bioinformatics Director: Justin Choi, PhD Scientific Director: Huidong Shi, PhD http://www.augusta.edu/cancer/research/shared/bioinformatics/

GRU Cancer Center Shared Resources

Mission

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Our mission is to provide expertise in integrative computational-based analysis solutions to basic, clinical, and translational research applications. Bioinformatics support ranges in scope from simple consultations to more in-depth collaborations. We require the participation of the investigator during the course of our data analysis because we believe that input into the biological parameters are tantamount to the success of the analysis.

Equipment Cancer Center Computer Cluster Two HP Rack Servers 2 AMD 12-core CPUs 64 GB RAM 1 TB Disk Eight HP Blade Servers 4 AMD 12-core CPUs 64 GB RAM 500 GB Disk

HP Modular Storage Array 3 MSA disk arrays 24 x 500 GB disks RAID5 : 32 TB Xyratex Cstor 1500 Luster file system Up to 110 GB/s sustained reads and writes 60 TB

Services Quality assessment

Methylation profile

Read mapping

Differential methylation

Sequence variants

Enrichment identification

Structure variants

Differential enrichment

Expression profile

Sequence motif

Differential expression

Gene set enrichment analysis

Alternative splicing Gene fusion RNA Editing NCBI Data submission RNA editing

De novo genome assembly & annot

Biostatistics Director: Ramses Sadek, PhD

The Biostatistics Core has strong ties the campus biostatistics department and several individuals are cross appointed to both. The primary mission of the Biostatistics core is to support the Cancer Center members in their investigative studies. The group also supports database design and management of clinical research data for Quality Assurance office for Clinical Trials (QACT) and the Office for Protection of Research Subjects (OPRS). The personnel also conduct independent research in statistical and quantitative analysis thereby developing novel methodological strategies designed to benefit the work of Cancer Center members.

Services Expertise for the planning, conduct, analysis and reporting of clinical trials, epidemiologic and population based studies, studies in genetic susceptibility of cancer, and experiments in basic research in the biology of cancer.

Design and monitor of clinical trials, experimental design, power and sample size calculation, data analysis.

Collaborative research supports throughout all phases of grant proposal preparation and funded research.

Education for members of the CC in the areas of study design, data collection, computerization, and statistical methods for laboratory, clinical and population based studies.

Methodological research in quantitative methods.

Comprehensive manuscript support.

GRU Cancer Center Shared Resources

Mission

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Cancer Center Flow Cytometry Core

GRU Cancer Center Shared Resources

Director: Ningchun Xu, PhD Scientific Director: Esteban Celis, PhD http://www.augusta.edu/cancer/research/shared/flow/

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Mission The Cancer Center Flow Core provides high-end flow analysis, sorting expertise, and technologies to the researcher. The analytical instruments are capable of detecting as many as 18 different concurrent colors using 4 and 5 different laser configurations. For sorting applications, the core has a BD FACSAria II with 4 lasers that enable detection as many as 18 fluorochromes. This instrument is used for sorting live populations of mixed cells into sub-types for further analysis and experimentation. It is housed in the biosafety cabinet in the BSL2+ facility to allow sorting of unfixed human cells. The Flow Core also houses a BD Influx, which is also a multi-parameter sorting instrument.

Equipment and Lasers

Services   

Sorting of cells is performed on the BD FACSAria or Influx by core personnel.

Training on the use of analytical instruments is available on demand.

Workstations with a variety of software for analysis are also available.

GRU Tissue Biorepository Director: Roni Bollag, MD, PhD Manager: Sameera Qureshi http://www.augusta.edu/cancer/research/shared/tumor/

The repository collects and stores specimens under standardized conditions with accompanying clinical and demographic information. In addition to procuring samples from GRU for research use, the biorepository provides a centralized service for biospecimen procurement and distribution across the State of Georgia to advance cancer research. The Biorepository Alliance of Georgia –Oncology (BRAG-Onc) was established to represent the diversity of the cancer patient population in Georgia and to enhance cancer research in the state and is housed within the GRU Biorepository. The primary mission of the Biorepository is to provide de-identified cryopreserved biospecimens with accompanying clinical information.

Specimens and Services             

Tumors from all sites, as well as any specimens that can be used as controls (including tissues, blood, saliva, urine, etc.), are collected and banked following appropriate patient consent.

Other types of specimens may be procured as needed by specific studies following approval of the tissue biorepository committee.

Most tumor specimens and adjacent normal tissues are flash frozen in liquid nitrogen.

Blood samples are routinely separated into plasma and buffy coat components prior to freezing.

Alternative methods of tissue collection are considered for specific studies.

Tissues are maintained at -150oC to -190oC liquid nitrogen vapor phase; blood derivatives and biofluids are maintained at -50oC to -90oC. A specialized bone marrow repository has been established for hematopoietic malignancies and disorders. The collection consists of viable, frozen mononuclear cells enriched using density centrifugation.

The database of samples is managed using the TissueMetrix biorepository management system for tracking procurement and distribution of samples with annotated clinical information.

Collection is supported by a web-accessible database for inventory management and annotation, and a long-term storage facility with backups of cryopreserved specimens.

Over the last year, the Biorepository has supported over 20 individual projects distributing over 180 individual samples.

During 2015, more than 6,000 samples were procured, including 1,259 tumor samples.

Supplies tissues to The Cancer Genome Atlas project (TCGA).

Supports a collaborative effort between Roswell Park Cancer Institute and the University of Pittsburg to implement TIES (Text Information Extraction System), a natural language processing pipeline and clinical document search engine. The software de-identifies, annotates, and indexes clinical documents, allowing researchers to search for cases that they are most interested in.

GRU Cancer Center Shared Resources

Mission

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Integrated Genomics Microarray Technologies Director: Eiko Kitamura, PhD Scientific Director: Lesleyann Hawthorn, PhD http://www.augusta.edu/cancer/research/shared/genomics/ affymetrix/

GRU Cancer Center Shared Resources

Mission The Microarray facility offers Gene Expression Profiling, SNP, miRNA, and CNV analysis using array technologies. The Resource houses both Affymetrix and Agilent microarray platforms that facilitate exonspecific oligonucleotide and genome-wide arrays, as well as a host of DNA analysis array designs and validation technologies. The facility personnel also have extensive expertise in the evaluation of nucleic acid quality. Bioinformatic support is available for data analysis for all types of microarray data.

Equipment         

Affymetrix ® GeneChip Scanner 3000 7G Plus Affymetrix ® Hybridization Oven 640 Affymetrix ® Fluidics Station 450 (x2) Agilent ® Microarray Scanner Agilent ® Hybridization Oven for Array Slides Agilent ® 2100 Bioanalyzer Agilent ® 2200 TapeStaion Applied Biosystems GeneAmp 9700 Thermocycler NanoDrop 1000

Data Analysis *        

Affymetrix ® Genotyping Console Affymetrix ® Expression Console Agilent ® GeneSpringGX Agilent ® Feature Extraction Ingenuity Pathway Analysis Partek Genomics Suite Gene Set Enrichment Analysis (GSEA) BioConductor

Services The Core aims to provide Cancer Center researchers access to microarray technology and bioinformatics at an affordable cost. It offers consultation, training, and educational seminars on:  Analysis of microarray data  Software designed to analyze large data sets  Gene expression  Roles of DNA sequence variation in the genome  Software, training and support are also available for researchers to enable them to analyze large data sets and obtain meaningful results from these experiments. A large number of state-of-the-art programs are available to afford analyses of different data types, and the expertise is available to implement and advise on their usage.

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Integrated Genomics Next-Generation Sequencing Director: Chang-Sheng (Sam) Chang, PhD Scientific Director: Lesleyann Hawthorn, PhD http://www.augusta.edu/cancer/research/shared/genomics/nextgeneration-sequencing.php The Integrated Genomics Next-Generation Sequencing (NGS) Resource provides quality, massively parallel, high-throughput sequencing data using the most current instrumentation. This is a full-service facility providing library preparation, sequencing, and bioinformatics services. The facility currently operates Illumina and Ion Torrent sequencing systems. Expertise for performing DNA-Seq, RNA-Seq, Chip-Seq, Methyl-Seq, and targeted re-sequencing is available.

Equipment     

Agilent ® 2100 Bioanalyzer Agilent ® 2200 TapeStation NanoDrop 1000 QuBit Fluorometer Illumina HiSeq 2500 (Rapid & Hi-Throughput Modes)  Illumina Miseq

    

Thermo-Fisher Ion Proton Sequencer Ion Proton Chef- Sample Preparation Station cBot Cluster Generation System Applied Biosystems GeneAmp 9700 Thermocycler Pyrosequencer

  

Cytogenetic Analysis DNA-Protein Interaction Analysis (ChIP-Seq) Sequencing-Based Methylation Analysis

      

VarScan2 Tophat2 & Cufflinks GSNAP & GMAP RSEM (de novo RNA assembly) ExomeCNV FusionMap IPA Pathway Analysis

Services    

DNA Sequencing Gene Regulation Analysis Sequencing-Based Transcriptome Analysis SNP Discovery and Structural Variation Analysis

Data Analysis       

CASAVA Partek Genomics Suite TrueSeq Enrichment Analysis Tool BWA Alignment Bowtie Alignment GATK2 (dbSNP137) Annovar

GRU Cancer Center Shared Resources

Mission

Sequencing Analysis/Computing Server 4 Dell Rack 610 servers: 16 core CPUs 48 GB RAM 16 x 73 GB disk 10 Gb NIC card

2 Dell Rack 710 servers: 24 core CPUs 48 GB RAM 4 x 146 GB disk 10 Gb NIC card 5 EMC Isilon IQ 12000X Storage 5 x12 TB disks Page 63

Proteomics and Metabolomics Director: Lambert Ngoka, PhD Scientific Director: John Cowell, PhD, DSc, FRCPath http://www.augusta.edu/cancer/research/shared/proteomics/

GRU Cancer Center Shared Resources

Mission The Proteomics and Metabolomics Resource provides broad mass spectrometry services to academic and industry investigators. The mission is to provide access to advanced mass spectrometry techniques for quantitation and identification of proteins and metabolites in biological samples. The facility proffers the resources and expertise to perform both proteomics and metabolomics experiments for a variety of samples such as cells, sub-cellular fractions, secreted media, tissues, and biological fluids.

Equipment Thermo Fisher Scientific LTQ Orbitrap Velos Pro Hybrid FT MS  Thermo Scientific- Dionex UltiMate 3000 RSLCnano  Agilent 1200 Series Nanoflow LC System for MS  Agilent 1200 Series capillary pump Software:  Chromeleon 6.80 SR12 (Thermo Fisher Scientific)  ChemStation for LC systems Rev. B.04.01 SP1 (Agilent Technologies)  Xcalibur™ 2.2 SP1 Build 48 (Thermo Fisher Scientific)  Proteome Discoverer 1.4-SP1 (Thermo Fisher Scientific)  BioWorks™ Rev.3.3.1 SP1 (Thermo Fisher Scientific)  Scaffold 3.65 & 4.0 (Proteome Software )  Scaffold PTM 2.1.0 (Proteome Software ) Agilent Technologies Q-TOF  6520 Accurate-Mass Quadrupole Time-of-Flight MS  1200 Series Binary LC System Software:  MassHunter, Qual. Anal. (Agilent Technologies)  MassHunter, Data Acq. for 6400 (Agilent Technologies)  MassHunter , Quant. Analysis (Agilent Technologies)  Mass Profiler Professional B.02.01

Agilent Technologies QQQ  6410 Triple Quad LC/MS System  1200 Series Binary LC System Software:  MassHunter, LC/MS Data Acq. (Agilent Technologies).  MassHunter, Qual. Analysis (Agilent Technologies)  MassHunter, Quant. Analysis (Agilent Technologies) Page 64

Small Animal X-RAY and Imaging

Mission The Small Animal X-RAY, Imaging, and Radiotherapy Core (SAXI), provides a range of imaging resources for small animals. The core provides a mechanism for studying animal models in vivo and ex vivo for the GRU Cancer Center research community. Efforts of the Core are focused on elucidating the pathophysiology of disease and on providing a better evaluation of the efficacy of pharmaceutical and interventions.

Services   

Utilize established imaging protocols and develop new ones, to include segmentation and quantitative analysis of structures of interest.

Offer image data analysis and processing for quantifying and qualifying in vivo and in vitro research.

Offer biomedical project consultation that will help better the understanding of the roles noninvasive whole body magnetic resonance, bioluminescent, x-ray and fluorescent imaging can play in achieving research objectives.

Equipment 

Bruker Biospin MRI 7T horizontal bore scanner and ParaVision® software.

 

Bioluminescent/ Fluorescent Imaging (BLI/FLI)/ X-Ray SPECT/CT Imaging single-photon emission computed tomography to monitor the level of biological activity at each place in the 3-D region being analyzed.

SAARP Small Animal Radiation Research Platform permits Image-Guided Micro-Irradiation (IGMI) techniques on in vivo models, thus allowing the replication of the clinical radiotherapy process including imaging, target localization, dose planning, and treatment delivery.

Faxitron MX-20 cabinet X-ray System. This high-throughput planar X-ray system can scan two to three animals at a time and has up to 5X geometric magnification capabilities to deliver ultrahigh resolution images of small animals and specimens.

PIXImus II Densitomter employs dual energy X-ray absorptiometry (DEXA) technology.

  

GRU Cancer Center Shared Resources

Director: MRI, SPECT, Bioluminescence Imaging: Ping-Chan Ling, PhD Director: SAARP, Targeted X-RAY Systems: Jian-Yue Jin, PhD Scientific Advisor: Ali Arbab, MD, PhD http://www.augusta.edu/cancer/research/shared/smallanimal/

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2015 GRU Cancer Center Publications

2015 GRU Cancer Center Publications

Achyut BR, Shankar A, Iskander AS, Ara R, Angara K, Zeng P, Knight RA, Scicli AG, Arbab AS. Bone marrow derived myeloid cells orchestrate antiangiogenic resistance in glioblastoma through coordinated molecular networks. Cancer Lett. 2015 Dec 28;369(2):416-26.

Achyut BR, Shankar A, Iskander AS, Ara R, Knight RA, Scicli AG, Arbab AS. Chimeric Mouse model to track the migration of bone marrow derived cells in glioblastoma following anti-angiogenic treatments. Cancer Biol Ther. 2016 Mar 3;17(3):280-90.

Alleyne CH, Vaibhav K, Baban B, Hoda N, Dhandapani KM. 155 Remote ischemic conditioning improves neurovascular outcomes after intracerebral hemorrhage in mice. Neurosurgery. 2015 Aug;62 Suppl 1:216.

Amin C, Adam S, Mooberry MJ, Kutlar A, Kutlar F, Esserman D, Brittain JE, Ataga KI, Chang JY, Wolberg AS, Key NS. Coagulation activation in sickle cell trait: an exploratory study. Br J Haematol. 2015 Nov;171(4):638-46.

Anea CB, Lyon M, Lee I, Gonzales JN, Adeyemi A, Falls G, Kutlar A, Brittain JE. Pulmonary platelet thrombi and vascular pathology in acute chest syndrome in patients with sickle cell disease. Am J Hematol. 2015 Oct 22. doi: 10.1002/ ajh.24224. [Epub ahead of print] Aronsson CA, Lee HS, Liu E, Uusitalo U, Hummel S, Yang J, Hummel M, Rewers M, She JX, Simell O, Toppari J, Ziegler AG, Krischer J, Virtanen SM, Norris JM, Agardh D; TEDDY STUDY GROUP. Age at gluten introduction and risk of celiac disease. Pediatrics. 2015 Feb;135(2):239-45.

Babu E, Bhutia YD, Ramachandran S, Gnanaprakasam JP, Prasad PD, Thangaraju M, Ganapathy V. Deletion of the amino acid transporter Slc6a14 suppresses tumour growth in spontaneous mouse models of breast cancer. Biochem J. 2015 Jul 1;469(1):17-23.

Bardhan K, Paschall AV, Yang D, Chen MR, Simon PS, Bhutia YD, Martin PM, Thangaraju M, Browning DD, Ganapathy V, Heaton CM, Gu K, Lee JR, Liu K. IFNÎł Induces DNA Methylation-Silenced GPR109A Expression via pSTAT1/p300 and H3K18 Acetylation in Colon Cancer. Cancer Immunol Res. 2015 Jul;3(7):795-805.

Berger PK, Pollock NK, Laing EM, Chertin V, Bernard PJ, Grider A, Shapses SA, Ding KH, Isales CM, Lewis RD. Zinc supplementation increases procollagen type 1 amino-terminal propeptide in premenarcheal girls: a randomized controlled trial. J Nutr. 2015 Dec;145(12):2699-704.

Beyerlein A, Liu X, Uusitalo UM, Harsunen M, Norris JM, Foterek K, Virtanen SM, Rewers MJ, She JX, Simell O, Lernmark Ă&#x2026;, Hagopian W, Akolkar B, Ziegler AG, Krischer JP, Hummel S; TEDDY study group. Dietary intake of soluble fiber and risk of islet autoimmunity by 5 y of age: results from the TEDDY study. Am J Clin Nutr. 2015 Aug;102(2):345 -52.

Bharucha AE, Dunivan G, Goode PS, Lukacz ES, Markland AD, Matthews CA, Mott L, Rogers RG, Zinsmeister AR, Whitehead WE, Rao SS, Hamilton FA. Epidemiology, pathophysiology, and classification of fecal incontinence: State of the Science Summary for the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Workshop.

Am J Gastroenterol. 2015 Jan;110(1):127-36. Review.

Bhuiyan MP, Aryal MP, Janic B, Karki K, Varma NR, Ewing JR, Arbab AS, Ali MM. Concentration-independent MRI of pH with a dendrimer-based pH-responsive nanoprobe. Contrast Media Mol Imaging. 2015 Jul 14. doi: 10.1002/ cmmi.1651. [Epub ahead of print] Bi LL, Sun XD, Zhang J, Lu YS, Chen YH, Wang J, Geng F, Liu F, Zhang M, Liu JH, Li XW, Mei L, Gao TM. Amygdala NRG1 -ErbB4 is critical for the modulation of anxiety-like behaviors. Neuropsychopharmacology. 2015 Mar;40(4):974-86.

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Block KI, Gyllenhaal C, Lowe L, Amedei A, Amin AR, Amin A, Aquilano K, Arbiser J, Arreola A, Arzumanyan A, Ashraf SS, Azmi AS, Benencia F, Bhakta D, Bilsland A, Bishayee A, Blain SW, Block PB, Boosani CS, Carey TE, Carnero A, Carotenuto M, Casey SC, Chakrabarti M, Chaturvedi R, Chen GZ, Chen H, Chen S, Chen YC, Choi BK, Ciriolo MR, Coley HM, Collins AR, Connell M, Crawford S, Curran CS, Dabrosin C, Damia G, Dasgupta S, DeBerardinis RJ, Decker WK, Dhawan P, Diehl AM, Dong JT, Dou QP, Drew JE, Elkord E, El-Rayes B, Feitelson MA, Felsher DW, Ferguson LR,

Bomeli SR, Duke WS, Terris DJ. Robotic facelift thyroid surgery. Gland Surg. 2015 Oct;4(5):403-9. Review.

Boosalis MS, Sangerman JI, White GL, Wolf RF, Shen L, Dai Y, White E, Makala LH, Li B, Pace BS, Nouraie M, Faller DV, Perrine SP. Novel inducers of fetal globin identified through high throughput screening (HTS) are active in vivo in anemic baboons and transgenic mice. PLoS One. 2015 Dec 29;10(12):e0144660. eCollection 2015.

Borin TF, Arbab AS, Gelaleti GB, Ferreira LC, Moschetta MG, Jardim-Perassi BV, Iskander A, Varma NR, Shankar A, Coimbra VB, Fabri VA, de Oliveira JG, de Campos Zuccari DA. Melatonin decreases breast cancer metastasis by modulating ROCK-1 expression. J Pineal Res. 2015 Aug 21. doi: 10.1111/jpi.12270. [Epub ahead of print] Burmeister DW, Smith EH, Cristel RT, McKay SD, Shi H, Arthur GL, Davis JW, Taylor KH. The expression of RUNDC3B is associated with promoter methylation in lymphoid malignancies. Hematol Oncol. 2015 May 25. doi: 10.1002/ hon.2238. [Epub ahead of print] Burnett JP, Korkaya H, Ouzounova MD, Jiang H, Conley SJ, Newman BW, Sun L, Connarn JN, Chen CS, Zhang N, Wicha MS, Sun D. Trastuzumab resistance induces EMT to transform HER2(+) PTEN(-) to a triple negative breast cancer that requires unique treatment options. Sci Rep. 2015 Nov 2;5:15821.

Butterfield LH, Disis ML, Fox BA, Khleif SN, Marincola FM. Preamble to the 2015 SITC immunotherapy biomarkers taskforce. J Immunother Cancer. 2015 Mar 24;3:8. eCollection 2015.

Cai Y, Pi W, Sivaprakasam S, Zhu X, Zhang M, Chen J, Makala L, Lu C, Wu J, Teng Y, Pace B, Tuan D, Singh N, Li H. UFBP1, a key component of the Ufm1 conjugation system, is essential for ufmylation-mediated regulation of erythroid development. PLoS Genet. 2015 Nov 6;11(11):e1005643. eCollection 2015 Nov. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015 Jan 29;517(7536):576-82.

Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, Wheeler DA, Murray BA, Schmidt L, Vocke CD, Peto M, Al Mamun AA, Shinbrot E, Sethi A, Brooks S, Rathmell WK, Brooks AN, Hoadley KA, Robertson AG, Brooks D, Bowlby R, Sadeghi S, Shen H, Weisenberger DJ, Bootwalla M, Baylin SB, Laird PW, Cherniack AD, Saksena G, Haake S, Li J, Liang H, Lu Y, Mills GB, Akbani R, Leiserson MD, Raphael BJ, Anur P, Bottaro D, Albiges L, Barnabas N, Choueiri TK, Czerniak B, Godwin AK, Hakimi AA, Ho TH, Hsieh J, Ittmann M, Kim WY, Krishnan B, Merino MJ, Mills Shaw KR, Reuter VE, Reznik E, Shelley CS, Shuch B, Signoretti S, Srinivasan R, Tamboli P, Thomas G, Tickoo S, Burnett K, Crain D, Gardner J, Lau K, Mallery D, Morris S, Paulauskis JD, Penny RJ, Shelton C, Shelton WT, Sherman M, Thompson E, Yena P, Avedon MT, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Santos T, Wise L, Zmuda E, Demchok JA, Felau I, Hutter CM, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang J, Ayala B, Baboud J, Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Ally A, Balasundaram M, Balu S, Beroukhim R, Bodenheimer T, Buhay C, Butterfield YS, Carlsen R, Carter SL, Chao H, Chuah E, Clarke A, Covington KR, Dahdouli M, Dewal N, Dhalla N, Doddapaneni HV, Drummond JA, Gabriel SB, Gibbs RA, Guin R, Hale W, Hawes A, Hayes DN, Holt RA, Hoyle AP, Jefferys SR, Jones SJ, Jones CD, Kalra D, Kovar C, Lewis L, Li J, Ma Y, Marra MA, Mayo M, Meng S, Meyerson M, Mieczkowski PA, Moore RA, Morton D, Mose LE, Mungall AJ, Muzny D, Parker JS, Perou CM, Roach J, Schein JE, Schumacher SE, Shi Y, Simons JV, Sipahimalani P, Skelly T, Soloway MG, Sougnez C, Tam A, Tan D, Thiessen N, Veluvolu U, Wang M, Wilkerson MD,

2015 GRU Cancer Center Publications

Fimognari C, Firestone GL, Frezza C, Fujii H, Fuster MM, Generali D, Georgakilas AG, Gieseler F, Gilbertson M, Green MF, Grue B, Guha G, Halicka D, Helferich WG, Heneberg P, Hentosh P, Hirschey MD, Hofseth LJ, Holcombe RF, Honoki K, Hsu HY, Huang GS, Jensen LD, Jiang WG, Jones LW, Karpowicz PA, Keith WN, Kerkar SP, Khan GN, Khatami M, Ko YH, Kucuk O, Kulathinal RJ, Kumar NB, Kwon BS, Le A, Lea MA, Lee HY, Lichtor T, Lin LT, Locasale JW, Lokeshwar BL, Longo VD, Lyssiotis CA, MacKenzie KL, Malhotra M, Marino M, Martinez-Chantar ML, Matheu A, Maxwell C, McDonnell E, Meeker AK, Mehrmohamadi M, Mehta K, Michelotti GA, Mohammad RM, Mohammed SI, Morre DJ, Muralidhar V, Muqbil I, Murphy MP, Nagaraju GP, Nahta R, Niccolai E, Nowsheen S, Panis C, Pantano F, Parslow VR, Pawelec G, Pedersen PL, Poore B, Poudyal D, Prakash S, Prince M, Raffaghello L, Rathmell JC, Rathmell WK, Ray SK, Reichrath J, Rezazadeh S, Ribatti D, Ricciardiello L, Robey RB, Rodier F, Rupasinghe HP, Russo GL, Ryan EP, Samadi AK, Sanchez-Garcia I, Sanders AJ, Santini D, Sarkar M, Sasada T, Saxena NK, Shackelford RE, Shantha Kumara HM, Sharma D, Shin DM, Sidransky D, Siegelin MD, Signori E, Singh N, Sivanand S, Sliva D, Smythe C, Spagnuolo C, Stafforini DM, Stagg J, Subbarayan PR, Sundin T, Talib WH, Thompson SK, Tran PT, Ungefroren H, Vander Heiden MG, Venkateswaran V, Vinay DS, Vlachostergios PJ, Wang Z, Wellen KE, Whelan RL, Yang ES, Yang H, Yang X, Yaswen P, Yedjou C, Yin X, Zhu J, Zollo M. Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol. 2015 Dec;35 Suppl:S276-304. Review.

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2015 GRU Cancer Center Publications

Wong T, Wu J, Xi L, Zhou J, Bedford J, Chen F, Fu Y, Gerstein M, Haussler D, Kasaian K, Lai P, Ling S, Radenbaugh A, Van Den Berg D, Weinstein JN, Zhu J, Albert M, Alexopoulou I, Andersen JJ, Auman JT, Bartlett J, Bastacky S, Bergsten J, Blute ML, Boice L, Bollag RJ, Boyd J, Castle E, Chen YB, Cheville JC, Curley E, Davies B, DeVolk A, Dhir R, Dike L, Eckman J, Engel J, Harr J, Hrebinko R, Huang M, HuelsenbeckDill L, Iacocca M, Jacobs B, Lobis M, Maranchie JK, McMeekin S, Myers J, Nelson J, Parfitt J, Parwani A, Petrelli N, Rabeno B, Roy S, Salner AL, Slaton J, Stanton M, Thompson RH, Thorne L, Tucker K, Weinberger PM, Winemiller C, Zach LA, Zuna R. Comprehensive molecular characterization of papillary renalcell carcinoma. N Engl J Med. 2016 Jan 14;374(2):135-45.

Castle PE, Smith KM, Davis TE, Schmeler KM, Ferris DG, Savage AH, Gray JE, Stoler MH, Wright TC Jr, Ferenczy A, Einstein MH. Reliability of the Xpert HPV assay to detect high-risk human papillomavirus DNA in a colposcopy referral population. Am J Clin Pathol. 2015 Jan;143(1):126-33.

Chaudhary K, Shinde R, Liu H, Gnana-Prakasam JP, Veeranan-Karmegam R, Huang L, Ravishankar B, Bradley J, Kvirkvelia N, McMenamin M, Xiao W, Kleven D, Mellor AL, Madaio MP, McGaha TL. Amino acid metabolism inhibits antibody-driven kidney injury by inducing autophagy. J Immunol. 2015 Jun 15;194(12):5713-24.

Chen F, Haigh S, Yu Y, Benson T, Wang Y, Li X, Dou H, Bagi Z, Verin AD, Stepp DW, Csanyi G, Chadli A, Weintraub NL, Smith SM, Fulton DJ. Nox5 stability and superoxide production is regulated by C-terminal binding of Hsp90 and COchaperones. Free Radic Biol Med. 2015 Dec;89:793-805.

Chen H, Wang GD, Chuang YJ, Zhen Z, Chen X, Biddinger P, Hao Z, Liu F, Shen B, Pan Z, Xie J. Nanoscintillatormediated x-ray inducible photodynamic therapy for in vivo cancer treatment. Nano Lett. 2015 Apr 8;15(4):2249-56.

Cho HI, Jung SH, Sohn HJ, Celis E, Kim TG. An optimized peptide vaccine strategy capable of inducing multivalent CD8+ T cell responses with potent antitumor effects. Oncoimmunology. 2015 May 26;4(11):e1043504. eCollection 2015 Nov. Choudhary V, Olala LO, Qin H, Helwa I, Pan ZQ, Tsai YY, Frohman MA, Kaddour-Djebbar I, Bollag WB. Aquaporin-3 reexpression induces differentiation in a phospholipase d2-dependent manner in aquaporin-3-knockout mouse keratinocytes. J Invest Dermatol. 2015 Feb;135(2):499-507.

Chung C, Wu WH, Chen BS. Identification of novel 14-3-3 residues that are critical for isoform-specific interaction with GluN2C to regulate N-methyl-d-aspartate (NMDA) receptor trafficking. J Biol Chem. 2015 Sep 18;290(38):23188 -200.

Coss-Adame E, Rao SS, Valestin J, Ali-Azamar A, Remes-Troche JM. Accuracy and reproducibility of high-definition anorectal manometry and pressure topography analyses in healthy subjects. Clin Gastroenterol Hepatol. 2015 Jun;13(6):1143-1150.e1.

Cui H, Guo M, Xu D, Ding ZC, Zhou G, Ding HF, Zhang J, Tang Y, Yan C. The stress-responsive gene ATF3 regulates the histone acetyltransferase Tip60. Nat Commun. 2015 Apr 13;6:6752.

Cui Y, Chen W, Kong FM, Olsen LA, Beatty RE, Maxim PG, Ritter T, Sohn JW, Higgins J, Galvin JM, Xiao Y. Contouring variations and the role of atlas in non-small cell lung cancer radiation therapy: Analysis of a multi-institutional preclinical trial planning study. Pract Radiat Oncol. 2015 Mar-Apr;5(2):e67-75.

Dahhan A, Maddox WR, Krothapalli S, Farmer M, Shah A, Ford B, Rhodes M, Matthews L, Barnes VA, Sharma GK. Education of physicians and implementation of a formal referral system can improve cardiac rehabilitation referral and participation rates after percutaneous coronary intervention. Heart Lung Circ. 2015 Aug;24(8):806-16.

D'Angelo RC, Ouzounova M, Davis A, Choi D, Tchuenkam SM, Kim G, Luther T, Quraishi AA, Senbabaoglu Y, Conley SJ, Clouthier SG, Hassan KA, Wicha MS, Korkaya H. Notch reporter activity in breast cancer cell lnes identifies a subset of cells with stem cell activity. Mol Cancer Ther. 2015 Feb 11. [Epub ahead of print] PMID:25673823 Dave SR, Samuel TA, Pucar D, Savage N, Williams HT. FDG PET/CT in evaluation of unusual cutaneous manifestations of breast cancer. Clin Nucl Med. 2015 Jan;40(1):e63-7.

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Davis CL, Tkacz JP, Tomporowski PD, Bustamante EE. Independent associations of organized physical activity and weight status with children's cognitive functioning: A matched-pairs design. Pediatr Exerc Sci. 2015 Aug 6. [Epub ahead of print] Dillard TA, Patel RR, Schroeder C. Uneven distribution of cancer histology in the National Lung Screening Trial. Am J Med Sci. 2015 Sep;350(3):219-21.

Dong G, Liu Y, Zhang L, Huang S, Ding HF, Dong Z. mTOR contributes to ER stress and associated apoptosis in renal tubular cells. Am J Physiol Renal Physiol. 2015 Feb 1;308(3):F267-74.

Duke WS, Bush CM, Singer MC, Haskins AD, Waller JL, Terris DJ. Incision planning in thyroid compartment surgery: getting it perfect. Endocr Pract. 2015 Feb 1;21(2):107-14.

Duke WS, Vernon HM, Terris DJ. Reoperative Parathyroidectomy: Overly descended superior adenoma. Otolaryngol Head Neck Surg. 2015 Nov 25. pii: 0194599815619625. [Epub ahead of print] Duke WS, White JR, Waller JL, Terris DJ. Six-year experience with endoscopic thyroidectomy: outcomes and safety profile. Ann Otol Rhinol Laryngol. 2015 Nov;124(11):915-20.

El Refaey M, Watkins CP, Kennedy EJ, Chang A, Zhong Q, Ding KH, Shi XM, Xu J, Bollag WB, Hill WD, Johnson M, Hunter M, Hamrick MW, Isales CM. Oxidation of the aromatic amino acids tryptophan and tyrosine disrupts their anabolic effects on bone marrow mesenchymal stem cells. Mol Cell Endocrinol. 2015 Jul 15;410:87-96. Review.

Elattar S, Satyanarayana A. Can brown fat win the battle against white fat? J Cell Physiol. 2015 Oct;230(10):2311-7.

Review.

El-Awady AR, Miles B, Scisci E, Kurago ZB, Palani CD, Arce RM, Waller JL, Genco CA, Slocum C, Manning M, Schoenlein PV, Cutler CW. Porphyromonas gingivalis evasion of autophagy and intracellular killing by human myeloid dendritic cells involves DC-SIGN-TLR2 crosstalk. PLoS Pathog. 2015 Feb 13;10(2):e1004647. eCollection 2015 Feb. Erdogan A, Rao SS. Small intestinal fungal overgrowth. Curr Gastroenterol Rep. 2015 Apr;17(4):436.

Fang B, Hoffman MA, Mirza AS, Mishall KM, Li J, Peterman SM, Smalley KS, Shain KH, Weinberger PM, Wu J, Rix U, Haura EB, Koomen JM. Evaluating kinase ATP uptake and tyrosine phosphorylation using multiplexed quantification of chemically labeled and post-translationally modified peptides. Methods. 2015 Jun 15;81:41-9.

Farooqi B, Simmons J, Hao Z. Tumor lysis syndrome in metastatic colon cancer following treatment with regorafenib.

J Gastrointest Cancer. 2015 Sep;46(3):314-6.

Fei E, Xiong WC, Mei L. Ephrin-B3 recruits PSD-95 to synapses. Nat Neurosci. 2015 Oct 27;18(11):1535-7.

Ferreira LC, Arbab AS, Jardim-Perassi BV, Borin TF, Varma NR, Iskander A, Shankar A, Ali MM, de Campos Zuccari DA. Effect of curcumin on pro-angiogenic factors in the xenograft model of breast cancer. Anticancer Agents Med Chem.

2015;15(10):1285-96.

2015 GRU Cancer Center Publications

Dinkins MB, Dasgupta S, Wang G, Zhu G, He Q, Kong JN, Bieberich E. The 5XFAD mouse model of Alzheimer's disease exhibits an age-dependent increase in anti-ceramide IgG and exogenous administration of ceramide further increases anti-ceramide titers and amyloid plaque burden. J Alzheimers Dis. 2015 Feb 26. [Epub ahead of print]

Ferris DG, Condorhuaman WS, Waller JL, Allmond L, Goebel A. Polarized light colposcopy compared with standard colposcopy. J Low Genit Tract Dis. 2015 Jul;19(3):234-8.

Ferris DG, Condorhuaman WS, Waller J, Lilienthal A. Impact of a video intervention for rural Peruvian women with cervical neoplasia before loop excisional procedures. J Low Genit Tract Dis. 2015 Jul;19(3):224-8.

Ferris DG, Shapiro J, Fowler C, Cutler C, Waller J, Guevara Condorhuaman WS. The impact of accessible cervical cancer screening in Peru-the DĂ­a del Mercado Project. J Low Genit Tract Dis. 2015 Jul;19(3):229-33.

Finn OJ, Khleif SN, Herberman RB. The FDA Guidance on therapeutic cancer vaccines: the need for revision to include preventive cancer vaccines or for a new guidance dedicated to them. Cancer Prev Res (Phila). 2015 Sep 9. pii: canprevres.0234.2015. [Epub ahead of print]

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Fischer S, Lin D, Simon RM, Howard L, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Freedland SJ, Vidal AC. Pathologic gleason 8-10: do all men do poorly? results from the search database. BJU Int. 2015 Sep 9. doi: 10.1111/bju.13319. [Epub ahead of print] Fletcher M, Ramirez ME, Sierra RA, Raber P, Thevenot P, Al-Khami AA, Sanchez-Pino D, Hernandez C, Wyczechowska DD, Ochoa AC, Rodriguez PC. l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res. 2015 Jan 15;75(2):275-83.

2015 GRU Cancer Center Publications

Foley MP, Barnes VA, Hasson SM. Effects of a community-based multimodal exercise program on physical function and quality of life in cancer survivors: a pilot study. Physiother Theory Pract. 2015 Jul;31(5):303-12.

Fowler DH, Mossoba ME, Halverson DC, Kurlander R, Blacklock Schuver B, Carpenter AE, Hansen B, Steinberg SM, Ali SA, Tageja N, Hakim FT, Gea-Banacloche JC, Sportes C, Hardy NM, Hickstein DD, Pavletic S, Khuu H, Sabatini M, Stroncek DF, Levine B, June CH, Mariotti J, Rixe O, Fojo AT, Bishop MR, Gress RE. High-dose sirolimus and immune selective pentostatin plus cyclophosphamide conditioning yields stable mixed chimerism and insufficient graftversus-tumor responses. Clin Cancer Res. 2015 Jun 12. pii: clincanres.0340.2015. [Epub ahead of print] Ganguly S, Home T, Yacoub A, Kambhampati S, Shi H, Dandawate P, Padhye S, Saluja AK, McGuirk J, Rao R. Targeting HSF1 disrupts HSP90 chaperone function in chronic lymphocytic leukemia. Oncotarget. 2015 Oct 13;6(31):31767-79.

Gao X, Jiang B, Zou S, Zhang T, Qi X, Jin L, Ge X, Tang SC, Hua D, Chen W. Zoledronate can promote apoptosis and inhibit the proliferation of colorectal cancer cells. Tumour Biol. 2015 Feb 15. [Epub ahead of print] PMID: 25682285 Ghonim MA, Pyakurel K, Ibba SV, Al-Khami AA, Wang J, Rodriguez P, Rady HF, El-Bahrawy AH, Lammi MR, Mansy MS, Al-Ghareeb K, Ramsay A, Ochoa A, Naura AS, Boulares AH. PARP inhibition by olaparib or gene knockout blocks asthma-like manifestation in mice by modulating CD4(+) T cell function. J Transl Med. 2015 Jul 14;13:225.

Ghonim MA, Pyakurel K, Ibba SV, Wang J, Rodriguez P, Al-Khami AA, Lammi MR, Kim H, Zea AH, Davis C, Okpechi S, Wyczechowska D, Al-Ghareeb K, Mansy MS, Ochoa A, Naura AS, Boulares AH. PARP is activated in human asthma and its inhibition by olaparib blocks house dust mite-induced disease in mice. Clin Sci (Lond). 2015 Dec;129(11):95162.

Ghonim MA, Pyakurel K, Ju J, Rodriguez PC, Lammi MR, Davis C, Abughazleh MQ, Mansy MS, Naura AS, Boulares AH. DNA-dependent protein kinase inhibition blocks asthma in mice and modulates human endothelial and CD4â ş T-cell function without causing severe combined immunodeficiency. J Allergy Clin Immunol. 2015 Feb;135(2):425-40.

Giles JR, Kashgarian M, Koni PA, Shlomchik MJ. B cell-specific MHC class II deletion reveals multiple nonredundant roles for B cell antigen presentation in murine lupus. J Immunol. 2015 Sep 15;195(6):2571-9.

Gopal E, Babu E, Ramachandran S, Bhutia YD, Prasad PD, Ganapathy V. Species-specific influence of lithium on the activity of SLC13A5 (NaCT): lithium-induced activation is specific for the transporter in primates. J Pharmacol Exp Ther. 2015 Apr;353(1):17-26.

Grayson J, Basciano P, Rawson JV, Klein K. Imaging practice patterns: referral network analysis of a single state of origination. J Am Coll Radiol. 2015 Dec;12(12 Pt B):1413-8.

Guha A, Maddox WR, Colombo R, Nahman NS Jr, Kintziger KW, Waller JL, Diamond M, Murphy M, Kheda M, Litwin SE, Sorrentino RA. Cardiac implantable electronic device infection in patients with end-stage renal disease. Heart Rhythm. 2015 Dec;12(12):2395-401.

Guo G, Cui Y. New perspective on targeting the tumor suppressor p53 pathway in the tumor microenvironment to enhance the efficacy of immunotherapy. J Immunother Cancer. 2015 Mar 24;3:9. eCollection 2015.

Guo JP, Pan JX, Xiong L, Xia WF, Cui S, Xiong WC. Iron chelation inhibits osteoclastic differentiation in vitro and in Tg2576 mouse model of Alzheimer's disease. PLoS One. 2015 Nov 17;10(11):e0139395. eCollection 2015.

Gurav A, Sivaprakasam S, Bhutia YD, Boettger T, Singh N, Ganapathy V. Slc5a8, a Na + -coupled high-affinity transporter for short-chain fatty acids, is a conditional tumor suppressor in colon that protects against colitis and colon cancer under low-fiber dietary conditions. Biochem J. 2015 May 18. [Epub ahead of print]

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Hadley D, Hagopian W, Liu E, She JX, Simell O, Akolkar B, Ziegler AG, Rewers M, Krischer JP, Chen WM, OnengutGumuscu S, Bugawan TL, Rich SS, Erlich H, Agardh D; TEDDY Study Group. HLA-DPB1*04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY Study. Am J Gastroenterol. 2015 Jun;110(6):91520.

Hanyok BT, Howard LE, Amling CL, Aronson WJ, Cooperberg MR, Kane CJ, Terris MK, Posadas EM, Freedland SJ. Is computed tomography a necessary part of a metastatic evaluation for castration-resistant prostate cancer? Results from the Shared Equal Access Regional Cancer Hospital Database. Cancer. 2015 Oct 20. doi: 10.1002/cncr.29748.

[Epub ahead of print] Hao Z, Huang S. E3 ubiquitin ligase Skp2 as an attractive target in cancer therapy. Front Biosci (Landmark Ed). 2015 Jan 1;20:474-490.

Hao Z, Kota V. Volasertib for AML: clinical use and patient consideration. Onco Targets Ther. 2015 Jul 17;8:1761-71. eCollection 2015. Review.

Heimlich JB, Speed JS, O'Connor PM, Pollock JS, Townes TM, Meiler SE, Kutlar A, Pollock DM. Endothelin-1 contributes to the progression of renal injury in sickle cell disease via reactive oxygen species. Br J Pharmacol. 2015 Nov 12. doi: 10.1111/bph.13380. [Epub ahead of print] Helwa I, Patel R, Karempelis P, Kaddour-Djebbar I, Choudhary V, Bollag WB. The antipsoriatic agent monomethylfumarate has antiproliferative, prodifferentiative, and anti-inflammatory effects on keratinocytes. J Pharmacol Exp Ther. 2015 Jan;352(1):90-7.

Holmgaard RB, Zamarin D, Li Y, Gasmi B, Munn DH, Allison JP, Merghoub T, Wolchok JD. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep. 2015 Oct 13;13(2):412-24.

Hong Y, Manoharan I, Suryawanshi A, Majumdar T, Angus-Hill ML, Koni PA, Manicassamy B, Mellor AL, Munn DH, Manicassamy S. β-Catenin promotes regulatory T-cell responses in tumors by inducing vitamin A metabolism in dendritic cells. Cancer Res. 2015 Feb 15;75(4):656-65.

Hossain F, Al-Khami AA, Wyczechowska D, Hernandez C, Zheng L, Reiss K, Valle LD, Trillo-Tinoco J, Maj T, Zou W, Rodriguez PC, Ochoa AC. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloidderived suppressor cells and enhances cancer therapies. Cancer Immunol Res. 2015 Nov;3(11):1236-47.

Hou Y, Wu Y, Farooq SM, Guan X, Wang S, Liu Y, Oblak JJ, Holcomb J, Jiang Y, Strieter RM, Lasley RD, Arbab AS, Sun F, Li C, Yang Z. A critical role of CXCR2 PDZ-mediated interactions in endothelial progenitor cell homing and angiogenesis. Stem Cell Res. 2015 Mar;14(2):133-43.

Howie RN, Borke JL, Kurago Z, Daoudi A, Cray J, Zakhary IE, Brown TL, Raley JN, Tran LT, Messer R, Medani F, Elsalanty ME. A model for osteonecrosis of the jaw with zoledronate treatment following repeated major trauma.

PLoS One. 2015 Jul 17;10(7):e0132520. eCollection 2015.

2015 GRU Cancer Center Publications

Hamad R, Jayakumar C, Ranganathan P, Mohamed R, El-Hamamy MM, Dessouki AA, Ibrahim A, Ramesh G. Honey feeding protects kidney against cisplatin nephrotoxicity through suppression of inflammation. Clin Exp Pharmacol Physiol. 2015 Aug;42(8):843-8.

Huang P, Lu C, Li J, Xu J, Liu Z, Wang Q, Wang Z, Huo J, Li H, Teng Y, Cai Y. Mutations in HSP70-2 gene change the susceptibility to clinical mastitis in Chinese Holstein. Gene. 2015 Mar 15;559(1):62-72.

Huang Z, Wang Y, Hu G, Zhou J, Mei L, Xiong WC. YAP Is a critical inducer of SOCS3, preventing reactive astrogliosis.

Cereb Cortex. 2015 Dec 17. pii: bhv292. [Epub ahead of print] Huby AC, Antonova G, Groenendyk J, Gomez-Sanchez CE, Bollag WB, Filosa JA, Belin de Chantemèle EJ. Adipocytederived hormone leptin is a direct regulator of aldosterone secretion, which promotes endothelial dysfunction and cardiac fibrosis. Circulation. 2015 Dec 1;132(22):2134-45.

Iacopino DG, Maugeri R, Giugno A, Giller CA. A strange case of downward displacement of a deep brain stimulation electrode 10 years following implantation: the gliding movement of snakes theory. World Neurosurg. 2015 Aug;84 (2):591.e1-5.

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Jacobi SK, Yatsunenko T, Li D, Dasgupta S, Yu RK, Berg BM, Chichlowski M, Odle J. Dietary isomers of sialyllactose increase ganglioside sialic acid concentrations in the corpus callosum and cerebellum and modulate the colonic microbiota of formula-fed piglets. J Nutr. 2015 Dec 23. pii: jn220152. [Epub ahead of print] Jacobson RS, Becich MJ, Bollag RJ, Chavan G, Corrigan J, Dhir R, Feldman MD, Gaudioso C, Legowski E, Maihle NJ, Mitchell K, Murphy M, Sakthivel M, Tseytlin E, Weaver J. A federated network for translational cancer research using clinical data and biospecimens. Cancer Res. 2015 Dec 15;75(24):5194-201. Review.

2015 GRU Cancer Center Publications

Jain A, Samykutty A, Jackson C, Browning D, Bollag WB, Thangaraju M, Takahashi S, Singh SR. Curcumin inhibits PhIP induced cytotoxicity in breast epithelial cells through multiple molecular targets. Cancer Lett. 2015 Aug 28;365 (1):122-31.

Jaja C, Bowman L, Wells L, Patel N, Xu H, Lyon M, Kutlar A. Preemptive genotyping of CYP2C8 and CYP2C9 allelic variants involved in NSAIDs metabolism for sickle cell disease pain management. Clin Transl Sci. 2015 Aug;8(4):27280.

Jang JH, Chun JN, Godo S, Wu G, Shimokawa H, Jin CZ, Jeon JH, Kim SJ, Jin ZH, Zhang YH. ROS and endothelial nitric oxide synthase (eNOS)-dependent trafficking of angiotensin II type 2 receptor begets neuronal NOS in cardiac myocytes. Basic Res Cardiol. 2015 May;110(3):477.

Janiak BD, Rawson JV, Clayton SK. Unnecessary repeat radiologic examinations in the emergency department after interfacility transfer. J Am Coll Radiol. 2015 Oct;12(10):1079-81.

Janik JE, Morris JC, O'Mahony D, Pittaluga S, Jaffe ES, Redon CE, Bonner WM, Brechbiel MW, Paik CH, Whatley M, Chen C, Lee JH, Fleisher TA, Brown M, White JD, Stewart DM, Fioravanti S, Lee CC, Goldman CK, Bryant BR, Junghans RP, Carrasquillo JA, Worthy T, Corcoran E, Conlon KC, Waldmann TA. 90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin's lymphoma. Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):13045-50.

Jerath R, Crawford MW, Barnes VA, Harden K. Self-regulation of breathing as a primary treatment for anxiety. Appl Psychophysiol Biofeedback. 2015 Jun;40(2):107-15.

Jerath R, Crawford MW, Barnes VA, Harden K. Widespread depolarization during expiration: A source of respiratory drive? Med Hypotheses. 2015 Jan;84(1):31-7.

Jilani Y, Lu S, Lei H, Karnitz LM, Chadli A. UNC45A localizes to centrosomes and regulates cancer cell proliferation through ChK1 activation. Cancer Lett. 2015 Feb 1;357(1):114-20.

Jin JY, Wang W, Ten Haken RK, Chen J, Bi N, Sadek R, Zhang H, Lawrence TS, Kong FM. Use a survival model to correlate single-nucleotide polymorphisms of DNA repair genes with radiation dose-response in patients with non-small cell lung cancer. Radiother Oncol. 2015 Oct;117(1):77-82.

Jin JY, Zhao B, Kaminski JM, Wen N, Huang Y, Vender J, Chetty IJ, Kong FS. A MLC-based inversely optimized 3D spatially fractionated grid radiotherapy technique. Radiother Oncol. 2015 Aug 12. pii: S0167-8140(15)00408-9. doi: 10.1016/j.radonc.2015.07.047. [Epub ahead of print] Johnson CM, Howell JT, Mettenburg DJ, Rueggeberg FA, Howell RJ, Postma GN, Weinberger PM. Mechanical modeling of the human cricoid cartilage using computer-aided design: applications in airway balloon dilation research. Ann Otol Rhinol Laryngol. 2015 Aug 9. pii: 0003489415598999. [Epub ahead of print] Jones MC, Rueggeberg FA, Cunningham AJ, Faircloth HA, Jana T, Mettenburg D, Waller JL, Postma GN, Weinberger PM. Biomechanical changes from long-term freezer storage and cellular reduction of tracheal scaffoldings. Laryngoscope. 2015 Jan;125(1):E16-22.

Kabbaj FZ, Lu S, Faouzi Mel A, Meddah B, Proksch P, Cherrah Y, Altenbach HJ, Aly AH, Chadli A, Debbab A. Bioactive metabolites from Chaetomium aureum: Structure elucidation and inhibition of the Hsp90 machine chaperoning activity. Bioorg Med Chem. 2015 Jan 1;23(1):126-31.

Karmakar A, Pate MB, Solowski NL, Postma GN, Weinberger PM. Tracheal size variability is associated with sex: implications for endotracheal tube selection. Ann Otol Rhinol Laryngol. 2015 Feb;124(2):132-6.

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Ke XX, Zhang D, Zhao H, Hu R, Dong Z, Yang R, Zhu S, Xia Q, Ding HF, Cui H. Phox2B correlates with MYCN and is a prognostic marker for neuroblastoma development. Oncol Lett. 2015 Jun;9(6):2507-2514.

Kemppainen KM, Ardissone AN, Davis-Richardson AG, Fagen JR, Gano KA, León-Novelo LG, Vehik K, Casella G, Simell O, Ziegler AG, Rewers MJ, Lernmark Å, Hagopian W, She JX, Krischer JP, Akolkar B, Schatz DA, Atkinson MA, Triplett EW; TEDDY Study Group. Early childhood gut microbiomes show strong geographic differences among subjects at high risk for type 1 diabetes. Diabetes Care. 2015 Feb;38(2):329-32.

Kim G, Ouzounova M, Quraishi AA, Davis A, Tawakkol N, Clouthier SG, Malik F, Paulson AK, D'Angelo RC, Korkaya S, Baker TL, Esen ES, Prat A, Liu S, Kleer CG, Thomas DG, Wicha MS, Korkaya H. SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model. Oncogene. 2015 Feb 5;34(6):67180.

Kim S, Miller BJ, Stefanek ME, Miller AH. Inflammation-induced activation of the indoleamine 2,3-dioxygenase pathway: Relevance to cancer-related fatigue. Cancer. 2015 Feb 27. doi: 10.1002/cncr.29302. [Epub ahead of print] Kim S, Rimando J, Sandler DP. Fruit and vegetable intake and urinary levels of prostaglandin e2 metabolite in postmenopausal women. Nutr Cancer. 2015 May-Jun;67(4):580-6.

Kim S, Shore DL, Wilson LE, Sanniez EI, Kim JH, Taylor JA, Sandler DP. Lifetime use of nonsteroidal anti-inflammatory drugs and breast cancer risk: results from a prospective study of women with a sister with breast cancer. BMC Cancer. 2015 Dec 16;15(1):960.

Kim SH, Ezenwoye O, Cho HG, Robertson KD, Choi JH. iTagPlot: an accurate computation and interactive drawing tool for tag density plot. Bioinformatics. 2015 Jul 15;31(14):2384-7.

Kindler JM, Ross HL, Laing EM, Modlesky CM, Pollock NK, Baile CA, Lewis RD. Load-specific physical activity scores are related to tibia bone architecture. Int J Sport Nutr Exerc Metab. 2015 Apr;25(2):136-44.

Klaassen Z, DiBianco JM, Jen RP, Harper B, Yaguchi G, Reinstatler L, Woodard C, Moses KA, Terris MK, Madi R. The impact of radical cystectomy and urinary diversion on suicidal death in patients with bladder cancer. J Wound Ostomy Continence Nurs. 2015 Dec 16. [Epub ahead of print] Klaassen Z, Everett R, Madi R, Terris MK. Re: The effect of race and gender on the surgical management of the small renal mass. Eur Urol. 2015 Jul;68(1):163-4.

Klaassen Z, Fox PJ, McLees L, Zheng M, Sharma S, Donohoe JM, Neal DE Jr. A paratesticular serous borderline tumor in a pediatric patient with proteus syndrome. Urology. 2015 Sep 11. pii: S0090-4295(15)00704-9. doi: 10.1016/ j.urology.2015.07.023. [Epub ahead of print] Klaassen Z, Howard L, Terris MK, Aronson WJ, Cooperberg MR, Amling CL, Kane CJ, Freedland SJ. Does larger tumor volume explain the higher prostate specific antigen levels in black men with prostate cancer-Results from the SEARCH database. Cancer Epidemiol. 2015 Dec;39(6):1066-70.

2015 GRU Cancer Center Publications

Khan MB, Hoda MN, Vaibhav K, Giri S, Wang P, Waller JL, Ergul A, Dhandapani KM, Fagan SC, Hess DC. Remote ischemic postconditioning: harnessing endogenous protection in a murine model of vascular cognitive impairment.

Transl Stroke Res. 2015 Feb;6(1):69-77.

Klaassen Z, Jen RP, DiBianco JM, Reinstatler L, Li Q, Madi R, Lewis RW, Smith AM, Neal DE Jr, Moses KA, Terris MK. Factors associated with suicide in patients with genitourinary malignancies. Cancer. 2015 Jun 1;121(11):1864-72.

Klaassen Z, Peard L, Wilhelm S, Coulson HC, Li Q, Kavuri SK, Terris MK, Moses KA. A heterogeneous renal mass and arm pain in a 38-Year-old African American female. Urology. 2015 Mar 31. pii: S0090-4295(15)00126-0. doi: 10.1016/j.urology.2015.02.002. [Epub ahead of print] No abstract available.

Klaassen Z, Singh AA, Howard LE, Feng Z, Trock B, Terris MK, Aronson WJ, Cooperberg MR, Amling CL, Kane CJ, Partin A, Han M, Freedland SJ. Is clinical stage T2c prostate cancer an intermediate- or high-risk disease? Cancer.

2015 May 1;121(9):1414-21.

Klaassen Z, Yaguchi G, Terris MK. How can we decrease suicide risk in cases of genitourinary cancer? Future Oncol.

2015 Aug;11(15):2113-5.

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Knapp E, Cohen H, Kutlar A, Ghalie R, Manwani D. Intrapatient variability in fetal hemoglobin measurements over time in sickle cell patients not on fetal hemoglobin inducing agents. Am J Hematol. 2015 Dec 10. doi: 10.1002/ ajh.24261. [Epub ahead of print] No abstract available.

Koehn BH, Apostolova P, Haverkamp JM, Miller JS, McCullar V, Tolar J, Munn DH, Murphy WJ, Brickey WJ, Serody JS, Gabrilovich DI, Bronte V, Murray PJ, Ting JP, Zeiser R, Blazar BR. GVHD-associated, inflammasome-mediated loss of function in adoptively transferred myeloid-derived suppressor cells. Blood. 2015 Sep 24;126(13):1621-8.

2015 GRU Cancer Center Publications

Kong FM, Wang S. Nondosimetric risk factors for radiation-induced lung toxicity. Semin Radiat Oncol. 2015 Apr;25 (2):100-109. Review.

Kong JN, Hardin K, Dinkins M, Wang G, He Q, Mujadzic T, Zhu G, Bielawski J, Spassieva S, Bieberich E. Regulation of Chlamydomonas flagella and ependymal cell motile cilia by ceramide-mediated translocation of GSK3. Mol Biol Cell.

2015 Dec 1;26(24):4451-65.

Kong JN, He Q, Wang G, Dasgupta S, Dinkins MB, Zhu G, Kim A, Spassieva S, Bieberich E. Guggulsterone and bexarotene induce secretion of exosome-associated breast cancer resistance protein and reduce doxorubicin resistance in MDA-MB-231 cells. Int J Cancer. 2015 Oct 1;137(7):1610-20.

Koon NA, Itokazu Y, Yu RK. Ganglioside-dependent neural stem cell proliferation in Alzheimer's disease model mice.

ASN Neuro. 2015 Dec 23;7(6).

Krischer JP, Lynch KF, Schatz DA, Ilonen J, Lernmark Ă&#x2026;, Hagopian WA, Rewers MJ, She JX, Simell OG, Toppari J, Ziegler AG, Akolkar B, Bonifacio E; TEDDY Study Group. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia. 2015 May;58(5):980-7.

Kuczma M, Wang CY, Ignatowicz L, Gourdie R, Kraj P. Altered connexin 43 expression underlies age-dependent decrease of regulatory T cell suppressor function in nonobese diabetic mice. J Immunol. 2015 Jun 1;194(11):5261-71.

Kumai T, Nagato T, Kobayashi H, Komabayashi Y, Ueda S, Kishibe K, Ohkuri T, Takahara M, Celis E, Harabuchi Y. CCL17 and CCL22/CCR4 signaling is a strong candidate for novel targeted therapy against nasal natural killer/T-cell lymphoma. Cancer Immunol Immunother. 2015 Jun;64(6):697-705.

Kumai T, Ohkuri T, Nagato T, Matsuda Y, Oikawa K, Aoki N, Kimura S, Celis E, Harabuchi Y, Kobayashi H. Targeting HER-3 to elicit antitumor helper T cells against head and neck squamous cell carcinoma. Sci Rep. 2015 Nov 5;5:16280.

Kumar M, Lambert MP, Breakey V, Buchanan GR, Neier M, Neufeld EJ, Kempert P, Neunert CE, Nottage K, Klaassen RJ; ITP Consortium of North America. Sports participation in children and adolescents with immune thrombocytopenia (ITP). Pediatr Blood Cancer. 2015 Dec;62(12):2223-5.

Kumari A, Iwasaki T, Pyndiah S, Cassimere EK, Palani CD, Sakamuro D. Regulation of E2F1-induced apoptosis by poly (ADP-ribosyl)ation. Cell Death Differ. 2015 Feb;22(2):311-22.

Lan TH, Liu Q, Li C, Wu G, Steyaert J, Lambert NA. BRET evidence that β2 adrenergic receptors do not oligomerize in cells. Sci Rep. 2015 May 8;5:10166.

Lan TH, Wu G, Lambert NA. Lateral diffusion contributes to FRET from lanthanide-tagged membrane proteins. Biochem Biophys Res Commun. 2015 Aug 14;464(1):244-8.

Lang L, Ding HF, Chen X, Sun SY, Liu G, Yan C. Internal ribosome entry site-based bicistronic in situ reporter assays for discovery of transcription-targeted lead compounds. Chem Biol. 2015 Jul 23;22(7):957-64.

Lee EJ, Rath P, Liu J, Ryu D, Pei L, Noonepalle SK, Shull AY, Feng Q, Litofsky NS, Miller DC, Anthony DC, Kirk MD, Laterra J, Deng L, Xin HB, Wang X, Choi JH, Shi H. Identification of global DNA methylation signatures in glioblastomaderived cancer stem cells. J Genet Genomics. 2015 Jul 20;42(7):355-71.

Lemos H, Huang L, McGaha T, Mellor AL. STING, nanoparticles, autoimmune disease and cancer: a novel paradigm for immunotherapy? Expert Rev Clin Immunol. 2015 Jan;11(1):155-65.

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Li Z, Lebedyeva IO, Golubovskaya VM, Cance WG, Alamry KA, Faidallah HM, Dennis Hall C, Katritzky AR. Synthesis and bioactivity of a Goralatide analog with antileukemic activity. Bioorg Med Chem. 2015 Aug 1;23(15):5056-60.

Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, Wheeler DA, Murray BA, Schmidt L, Vocke CD, Peto M, Al Mamun AA, Shinbrot E, Sethi A, Brooks S, Rathmell WK, Brooks AN, Hoadley KA, Robertson AG, Brooks D, Bowlby R, Sadeghi S, Shen H, Weisenberger DJ, Bootwalla M, Baylin SB, Laird PW, Cherniack AD, Saksena G, Haake S, Li J, Liang H, Lu Y, Mills GB, Akbani R, Leiserson MD, Raphael BJ, Anur P, Bottaro D, Albiges L, Barnabas N, Choueiri TK, Czerniak B, Godwin AK, Hakimi AA, Ho TH, Hsieh J, Ittmann M, Kim WY, Krishnan B, Merino MJ, Shaw KR, Reuter VE, Reznik E, Shelley CS, Shuch B, Signoretti S, Srinivasan R, Tamboli P, Thomas G, Tickoo S, Burnett K, Crain D, Gardner J, Lau K, Mallery D, Morris S, Paulauskis JD, Penny RJ, Shelton C, Shelton WT, Sherman M, Thompson E, Yena P, Avedon MT, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Santos T, Wise L, Zmuda E, Demchok JA, Felau I, Hutter CM, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang J, Ayala B, Baboud J, Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Ally A, Balasundaram M, Balu S, Beroukhim R, Bodenheimer T, Buhay C, Butterfield YS, Carlsen R, Carter SL, Chao H, Chuah E, Clarke A, Covington KR, Dahdouli M, Dewal N, Dhalla N, Doddapaneni HV, Drummond JA, Gabriel SB, Gibbs RA, Guin R, Hale W, Hawes A, Hayes DN, Holt RA, Hoyle AP, Jefferys SR, Jones SJ, Jones CD, Kalra D, Kovar C, Lewis L, Li J, Ma Y, Marra MA, Mayo M, Meng S, Meyerson M, Mieczkowski PA, Moore RA, Morton D, Mose LE, Mungall AJ, Muzny D, Parker JS, Perou CM, Roach J, Schein JE, Schumacher SE, Shi Y, Simons JV, Sipahimalani P, Skelly T, Soloway MG, Sougnez C, Tam A, Tan D, Thiessen N, Veluvolu U, Wang M, Wilkerson MD, Wong T, Wu J, Xi L, Zhou J, Bedford J, Chen F, Fu Y, Gerstein M, Haussler D, Kasaian K, Lai P, Ling S, Radenbaugh A, Van Den Berg D, Weinstein JN, Zhu J, Albert M, Alexopoulou I, Andersen JJ, Auman JT, Bartlett J, Bastacky S, Bergsten J, Blute ML, Boice L, Bollag RJ, Boyd J, Castle E, Chen YB, Cheville JC, Curley E, Davies B, DeVolk A, Dhir R, Dike L, Eckman J, Engel J, Harr J, Hrebinko R, Huang M, Huelsenbeck-Dill L, Iacocca M, Jacobs B, Lobis M, Maranchie JK, McMeekin S, Myers J, Nelson J, Parfitt J, Parwani A, Petrelli N, Rabeno B, Roy S, Salner AL, Slaton J, Stanton M, Thompson RH, Thorne L, Tucker K, Weinberger PM, Winemiller C, Zach LA, Zuna R; Cancer Genome Atlas Research Network. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2015 Nov 4. [Epub ahead of print] Lisak RP, Zhang B, Shen C, Mei L, Drachman DB, Kaminski HJ. Neuromuscular junction as Achilles' heel: Yet another autoantibody? Neurology. 2015 Jan 13;84(2):214-5.

Liu H, Wang Y, Sharma A, Mao R, Jiang N, Dun B, She JX. Derivatives containing both coumarin and benzimidazole potently induce caspase-dependent apoptosis of cancer cells through inhibition of PI3K-AKT-mTOR signaling. Anticancer Drugs. 2015 Jul;26(6):667-77.

Liu Z, Liu JQ, Shi Y, Zhu X, Liu Z, Li MS, Yu J, Wu LC, He Y, Zhang G, Bai XF. Epstein-Barr virus-induced gene 3deficiency leads to impaired antitumor T-cell responses and accelerated tumor growth. Oncoimmunology. 2015 Jan 9;4(7):e989137. eCollection 2015 Jul. Lu G, Zhang R, Geng S, Peng L, Jayaraman P, Chen C, Xu F, Yang J, Li Q, Zheng H, Shen K, Wang J, Liu X, Wang W, Zheng Z, Qi CF, Si C, He JC, Liu K, Lira SA, Sikora AG, Li L, Xiong H. Myeloid cell-derived inducible nitric oxide synthase suppresses M1 macrophage polarization. Nat Commun. 2015 Mar 27;6:6676.

2015 GRU Cancer Center Publications

Lilenbaum R, Samuels M, Wang X, Kong FM, J채nne PA, Masters G, Katragadda S, Hodgson L, Bogart J, Bradley J, Vokes E. A phase II study of induction chemotherapy followed by thoracic radiotherapy and erlotinib in poor risk stage III non-small cell lung cancer: Results of CALGB 30605 (Alliance)/RTOG 0972 (NRG). J Thorac Oncol. 2015 Jan;10(1):143-7.

Lu X, Ding ZC, Cao Y, Liu C, Habtetsion T, Yu M, Lemos H, Salman H, Xu H, Mellor AL, Zhou G. Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells. J Immunol. 2015 Feb 15;194(4):2011-21.

Luo L, Zhu G, Xu H, Yao S, Zhou G, Zhu Y, Tamada K, Huang L, Flies AD, Broadwater M, Ruff W, van Deursen JM, Melero I, Zhu Z, Chen L. B7-H3 promotes pathogenesis of autoimmune disease and inflammation by regulating the activity of different T cell subsets. PLoS One. 2015 Jun 11;10(6):e0130126.

Luque JS, Tarasenko YN, Maupin JN, Alfonso ML, Watson LC, Reyes-Garcia C, Ferris DG. Cultural beliefs and understandings of cervical cancer among Mexican immigrant women in southeast Georgia. J Immigr Minor Health. 2015 Jun;17(3):713-21..

Marable DR, Bowers LM, Stout T, Stewart CM, Berg KM, Sankar VS, DeRossi SS, Thoppay JR, Brennan MT. Oral candidiasis following steroid therapy for oral lichen planus. Oral Dis. 2015 Nov 24. doi: 10.1111/odi.12399. [Epub ahead of print]

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Marino M, Scuderi F, Samengo D, Saltelli G, Maiuri MT, Shen C, Mei L, Sabatelli M, Pani G, Antonini G, Evoli A, Bartoccioni E. Flow cytofluorimetric analysis of anti-LRP4 (LDL Receptor-Related Protein 4) autoantibodies in Italian patients with myasthenia gravis. PLoS One. 2015 Aug 18;10(8):e0135378. eCollection 2015.

Markand S, Saul A, Roon P, Prasad P, Martin PM, Rozen R, Ganapathy V, Smith SB. Retinal ganglion cell loss and mild vasculopathy in methylene tetrahydrofolate reductase (Mthfr) deficient mice: a model of mild hyperhomocysteinemia. Invest Ophthalmol Vis Sci. 2015 Mar 12. pii: IOVS-14-16190. doi: 10.1167/iovs.14-16190. [Epub ahead of print]

2015 GRU Cancer Center Publications

McGaha TL. IDO-GCN2 and autophagy in inflammation. Oncotarget. 2015 Sep 8;6(26):21771-2.

McGinley KF, Sun X, Howard LE, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Freedland SJ. Utilization and impact of surgical technique on the performance of pelvic lymph node dissection at radical prostatectomy: Results from the Shared Equal Access Regional Cancer Hospital database. Int J Urol. 2015 Dec 14. doi: 10.1111/ iju.13027. [Epub ahead of print] Miller BJ, Kandhal P, Rapaport MH, Mellor A, Buckley P. Total and differential white blood cell counts, high-sensitivity C-reactive protein, and cardiovascular risk in non-affective psychoses. Brain Behav Immun. 2015 Mar;45:28-35.

Mithal P, Howard LE, Aronson WJ, Kane CJ, Cooperberg MR, Terris MK, Amling CL, Freedland SJ. Prostate-specific antigen level, stage or Gleason score: Which is best for predicting outcomes after radical prostatectomy, and does it vary by the outcome being measured? Results from Shared Equal Access Regional Cancer Hospital database. Int J Urol. 2015 Apr;22(4):362-6.

Mithal P, Howard LE, Aronson WJ, Terris MK, Cooperberg MR, Kane CJ, Amling C, Freedland SJ. Positive surgical margins in radical prostatectomy patients do not predict long-term oncological outcomes: Results from SEARCH. BJU Int. 2015 May 24. doi: 10.1111/bju.13181. [Epub ahead of print] Mohamed R, Jayakumar C, Chen F, Fulton D, Stepp D, Gansevoort RT, Ramesh G. Low-dose IL-17 therapy prevents and reverses diabetic nephropathy, metabolic syndrome, and associated organ fibrosis. J Am Soc Nephrol. 2015 Sep 2. pii: ASN.2014111136. [Epub ahead of print] Mossoba ME, Halverson DC, Kurlander R, Schuver BB, Carpenter A, Hansen B, Steinberg SM, Ali SA, Tageja N, Hakim FT, Gea-Banacloche J, Sportes C, Hardy NM, Hickstein DD, Pavletic SZ, Khuu H, Sabatini M, Stroncek D, Levine BL, June CH, Mariotti J, Rixe O, Fojo AT, Bishop MR, Gress RE, Fowler DH. High-dose sirolimus and immune-selective pentostatin plus cyclophosphamide conditioning yields stable mixed chimerism and insufficient graft-versus-tumor responses. Clin Cancer Res. 2015 Oct 1;21(19):4312-20.

Mowry SE, Jammal H, Myer C 4th, Solares CA, Weinberger P. A novel temporal bone simulation model using 3D printing techniques. Otol Neurotol. 2015 Sep;36(9):1562-5.

Munn DH, Bronte V. Immune suppressive mechanisms in the tumor microenvironment. Curr Opin Immunol. 2015 Nov 20;39:1-6. doi: 10.1016/j.coi.2015.10.009. [Epub ahead of print] Review.

Muthusamy N, Chen YJ, Yin DM, Mei L, Bergson C. Complementary roles of the neuron-enriched endosomal proteins NEEP21 and calcyon in neuronal vesicle trafficking. J Neurochem. 2015 Jan;132(1):20-31.

Myer CM 4th, Johnson CM, Postma GN, Weinberger PM. Comparison of tensile strength of fibrin glue and suture in microflap closure. Laryngoscope. 2015 Jan;125(1):167-70.

Nalluri S, Ghoshal-Gupta S, Kutiyanawalla A, Gayatri S, Lee BR, Jiwani S, Rojiani AM, Rojiani MV. TIMP-1 inhibits apoptosis in lung adenocarcinoma cells via interaction with Bcl-2. PLoS One. 2015 Sep 14;10(9):e0137673. eCollection 2015.

Neunert CE, Arnold DM. Severe bleeding events in adults and children with primary immune thrombocytopenia: a systematic review: reply. J Thromb Haemost. 2015 May 27. doi: 10.1111/jth.13019. [Epub ahead of print] Nguyen-Lefebvre AT, Horuzsko A. Kupffer cell metabolism and function. J Enzymol Metab. 2015;1(1). pii: 101.

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Ortiz ML, Kumar V, Martner A, Mony S, Donthireddy L, Condamine T, Seykora J, Knight SC, Malietzis G, Lee GH, Moorghen M, Lenox B, Luetteke N, Celis E, Gabrilovich D. Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17-producing CD4+ T cells. J Exp Med. 2015 Mar 9;212(3):351-67.

Ovadia AE, Terris MK, Aronson WJ, Kane CJ, Amling CL, Cooperberg MR, Freedland SJ, Abern MR. Agent Orange and long-term outcomes after radical prostatectomy. Urol Oncol. 2015 Jul;33(7):329.e1-6.

Ownby DR, Tingen MS, Havstad S, Waller JL, Johnson CC, Joseph CL. Comparison of asthma prevalence among African American teenage youth attending public high schools in rural Georgia and urban Detroit. J Allergy Clin Immunol. 2015 Sep;136(3):595-600.e3.

Parker Harp CR, Archambault AS, Sim J, Ferris ST, Mikesell RJ, Koni PA, Shimoda M, Linington C, Russell JH, Wu GF. B cell antigen presentation is sufficient to drive neuroinflammation in an animal model of multiple sclerosis. J Immunol. 2015 Jun 1;194(11):5077-84.

Paschall AV, Liu K. Epigenetic regulation of apoptosis and cell cycle regulatory genes in human colon carcinoma cells.

Genom Data. 2015 Sep 1;5:189-191.

Paschall AV, Yang D, Lu C, Choi JH, Li X, Liu F, Figueroa M, Oberlies NH, Pearce C, Bollag WB, Nayak-Kapoor A, Liu K. H3K9 trimethylation silences Fas expression to confer colon carcinoma immune escape and 5-fluorouracil chemoresistance. J Immunol. 2015 Aug 15;195(4):1868-82.

Paschall AV, Zhang R, Qi CF, Bardhan K, Peng L, Lu G, Yang J, Merad M, McGaha T, Zhou G, Mellor A, Abrams SI, Morse HC 3rd, Ozato K, Xiong H, Liu K. IFN regulatory factor 8 represses GM-CSF expression in T cells to affect myeloid cell lineage differentiation. J Immunol. 2015 Mar 1;194(5):2369-79.

Patel N, Fixler J, Unguru Y, Kutlar A, Kutlar F. A new (A)γ-globin chain variant: Hb F-Sykesville MD [(A)γ113(G15)Val → Ile; HBG1: c.340G>A] detected in a Caucasian baby. Hemoglobin. 2015;39(1):52-4.

Patel VK, Kayahara E, Yamago S. Frontispiece: practical synthesis of [n]Cycloparaphenylenes (n=5, 7-12) by H2 SnCl4 -mediated aromatization of 1,4-dihydroxycyclo-2,5-diene precursors. Chemistry. 2015 Apr 7;21(15).

Pathania AS, Wani ZA, Guru SK, Kumar S, Bhushan S, Korkaya H, Seals DF, Kumar A, Mondhe DM, Ahmed Z, Chandan BK, Malik F. The anti-angiogenic and cytotoxic effects of the boswellic acid analog BA145 are potentiated by autophagy inhibitors. Mol Cancer. 2015 Jan 21;14(1):6. [Epub ahead of print] Pathania R, Ramachandran S, Elangovan S, Padia R, Yang P, Cinghu S, Veeranan-Karmegam R, Arjunan P, GnanaPrakasam JP, Sadanand F, Pei L, Chang CS, Choi JH, Shi H, Manicassamy S, Prasad PD, Sharma S, Ganapathy V, Jothi R, Thangaraju M. DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nat Commun. 2015 Apr 24;6:6910.

Patwardhan CA, Alfa E, Lu S, Chadli A. Progesterone receptor chaperone complex-based high-throughput screening assay: identification of capsaicin as an inhibitor of the hsp90 machine. J Biomol Screen. 2015 Feb;20(2):223-9.

Patyka M, Malamud D, Weissman D, Abrams WR, Kurago Z. Periluminal distribution of HIV-binding target cells and Gp340 in the oral, cervical and sigmoid/rectal mucosae: A mapping study. PLoS One. 2015 Jul 14;10(7):e0132942. eCollection 2015.

2015 GRU Cancer Center Publications

Pace BS, Liu L, Li B, Makala LH. Cell signaling pathways involved in drug-mediated fetal hemoglobin induction: Strategies to treat sickle cell disease. Exp Biol Med (Maywood). 2015 Aug;240(8):1050-64.

Pollock NK. Childhood obesity, bone development, and cardiometabolic risk factors. Mol Cell Endocrinol. 2015 Jul 15;410:52-63. Review.

Post MD, Johnson K, Brissette MD, Conran RM, Domen RE, Hoffman RD, McCloskey CB, Raciti PM, Roberts CA, Rojiani AM, Tucker JA, Powell SZ. Employer expectations for newly trained pathologists: report of a survey from the Graduate Medical Education Committee of the College of American Pathologists. Arch Pathol Lab Med. 2015 Oct 2.

[Epub ahead of print] Pucar D, Klein K, Corley J, Williams HT. BK nephritis and venous thrombosis in renal transplant recipient detected by 111In leukocyte imaging. Clin Nucl Med. 2015 Jul;40(7):e382-5.

Pucar D, Munroe J, Holliday L, Williams H. "Reverse Redistribution" pattern on SPECT myocardial perfusion imaging from endothelial dysfunction at rest and from subendocardial ischemia. J Nucl Cardiol. 2015 Aug;22(4):845-8.

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Purohit S, Sharma A, Hopkins D, Steed L, Bode B, Anderson SW, Reed JC, Steed RD, Yang T, She JX. Large-scale discovery and validation studies demonstrate significant reductions in circulating levels of IL8, IL-1Ra, MCP-1, and MIP1β in patients with type 1 diabetes. J Clin Endocrinol Metab. 2015 Sep;100(9):E1179-87.

Pyla R, Pichavaram P, Fairaq A, Park MA, Kozak M, Kamath V, Patel VS, Segar L. Altered energy state reversibly controls smooth muscle contractile function in human saphenous vein during acute hypoxia-reoxygenation: Role of glycogen, AMP-activated protein kinase, and insulin-independent glucose uptake. Biochem Pharmacol. 2015 Sep 1;97(1):77-88.

2015 GRU Cancer Center Publications

Pyndiah S, Sakamuro D. Restoration of tumor suppressor functions by small-molecule inhibitors. Mol Cel Oncol.

2015, Jan 23;2:3, e991225.

Qin H, Wu Q, Cowell JK, Ren M. FGFR1OP2-FGFR1 induced myeloid leukemia and T-cell lymphoma in a mouse model. Haematologica. 2016 Mar;101(3):e91-4.

Qin S, Xu C, Li S, Yang C, Sun X, Wang X, Tang SC, Ren H. Indomethacin induces apoptosis in the EC109 esophageal cancer cell line by releasing second mitochondria-derived activator of caspase and activating caspase-3. Mol Med Rep. 2015 Jun;11(6):4694-700.

Quaynor SD, Ko EK, Chorich LP, Sullivan ME, Demir D, Waller JL, Kim HG, Cameron RS, Layman LC. NELF knockout is associated with impaired pubertal development and subfertility. Mol Cell Endocrinol. 2015 May 15;407:26-36.

Ranganathan P, Hamad R, Mohamed R, Jayakumar C, Muthusamy T, Ramesh G. Histone deacetylase-mediated silencing of AMWAP expression contributes to cisplatin nephrotoxicity. Kidney Int. 2015 Oct 28.

Ranganathan P, Jayakumar C, Tang Y, Park KM, Teoh JP, Su H, Li J, Kim IM, Ramesh G. MicroRNA-150 deletion in mice protects kidney from myocardial infarction-induced acute kidney injury. Am J Physiol Renal Physiol. 2015 Sep 15;309(6):F551-8.

Ranganathan P, Mohamed R, Jayakumar C, Brands MW, Ramesh G. Deletion of UNC5B in kidney epithelium exacerbates diabetic nephropathy in mice. Am J Nephrol. 2015 Apr 16;41(3):220-230. [Epub ahead of print] Rao SS, Parkman HP. Advanced training in neurogastroenterology and gastrointestinal motility. Gastroenterology.

2015 May;148(5):881-5.

Ravishankar B, Liu H, Shinde R, Chaudhary K, Xiao W, Bradley J, Koritzinsky M, Madaio MP, McGaha TL. The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity. Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):10774-9.

Rawson JV. Invited commentary: metrics and value in radiology and the role of the patient. Radiographics. 2015 May -Jun;35(3):876-8.

Rawson JV. Radiology testing in population health. Acad Radiol. 2015 Jul;22(7):805-6.

Rawson JV. Recruitment: a critical leadership task. Acad Radiol. 2015 Dec;22(12):1469-70.

Reinstatler L, Klaassen Z, McCraw CO, Chen R, Terris MK, Neal DE Jr, Lewis RW, Smith AM. Robert Benjamin Greenblatt and his many pursuits: an unlikely founder of the testosterone pellet. Urology. 2015 Feb;85(2):279-82.

Rojiani MV, Ghoshal-Gupta S, Kutiyanawalla A, Mathur S, Rojiani AM. TIMP-1 Overexpression in lung carcinoma enhances tumor kinetics and angiogenesis in brain metastasis. J Neuropathol Exp Neurol. 2015 Apr;74(4):293-304.

Ruble K, Davis CL, Han HR. Endothelial health in childhood acute lymphoid leukemia survivors: pilot evaluation with peripheral artery tonometry. J Pediatr Hematol Oncol. 2015 Mar;37(2):117-20.

Sakamuro D, Folk WP, Kumari A. To die, or not to die: E2F1 never decides by itself during serum starvation. Mol Cel Oncol. 2015, Jan7;2(2):e981447.

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Samadi AK, Bilsland A, Georgakilas AG, Amedei A, Amin A, Bishayee A, Azmi AS, Lokeshwar BL, Grue B, Panis C, Boosani CS, Poudyal D, Stafforini DM, Bhakta D, Niccolai E, Guha G, Vasantha Rupasinghe HP, Fujii H, Honoki K, Mehta K, Aquilano K, Lowe L, Hofseth LJ, Ricciardiello L, Ciriolo MR, Singh N, Whelan RL, Chaturvedi R, Ashraf SS, Shantha Kumara HM, Nowsheen S, Mohammed SI, Keith WN, Helferich WG, Yang X. A multi-targeted approach to suppress tumor-promoting inflammation. Semin Cancer Biol. 2015 Dec;35 Suppl:S151-84. Review.

Sangani R, Periyasamy-Thandavan S, Kolhe R, Bhattacharyya MH, Chutkan N, Hunter M, Isales C, Hamrick M, Hill WD, Fulzele S. MicroRNAs-141 and 200a regulate the SVCT2 transporter in bone marrow stromal cells. Mol Cell Endocrinol. 2015 Jul 15;410:19-26.

Sattin RW, Williams LB, Dias J, Garvin JT, Marion L, Joshua TV, Kriska A, Kramer MK, Venkat Narayan KM. Community trial of a faith-based lifestyle intervention to prevent diabetes among African-Americans. J Community Health. 2015 Jul 28. [Epub ahead of print] Schwarz NF, Krafft CE, Chi L, Weinberger AL, Schaeffer DJ, Pierce JE, Rodrigue AL, Williams CF, DiBattisto CH, Maria BL, Davis CL, McDowell JE. Antisaccade-related brain activation in children with attention-deficit/hyperactivity disorder - A pilot study. Psychiatry Res. 2015 Nov 30;234(2):272-9.

Segel JM, Duke WS, White JR, Waller JL, Terris DJ. Outpatient thyroid surgery: Safety of an optimized protocol in more than 1,000 patients. Surgery. 2015 Oct 12. pii: S0039-6060(15)00626-1. doi: 10.1016/j.surg.2015.08.007. [Epub ahead of print] Seremwe M, Schnellmann RG, Bollag WB. Calpain-10 activity underlies angiotensin II-induced aldosterone production in an adrenal glomerulosa cell model. Endocrinology. 2015 Jun;156(6):2138-49.

Sharma BK, Kolhe R, Black SM, Keller JR, Mivechi NF, Satyanarayana A. Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells. FASEB J. 2015 Sep 1. pii: fj.15-277749.

[Epub ahead of print] Sharma MD, Shinde R, McGaha TL, Huang L, Holmgaard RB, Wolchok JD, Mautino MR, Celis E, Sharpe AH, Francisco LM, Powell JD, Yagita H, Mellor AL, Blazar BR, Munn DH. The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Sci Adv. 2015 Nov 6;1(10):e1500845. eCollection 2015 Nov. Sharma S, Purohit S, Sharma A, Hopkins D, Steed L, Bode B, Anderson SW, Caldwell R, She JX. Elevated serum levels of soluble TNF receptors and adhesion molecules are associated with diabetic retinopathy in patients with type-1 diabetes. Mediators Inflamm. 2015;2015:279393.

Shen C, Xiong WC, Mei L. LRP4 in neuromuscular junction and bone development and diseases. Bone. 2015 Nov;80:101-8. Review.

Shi C, Huang X, Zhang B, Zhu D, Luo H, Lu Q, Xiong WC, Mei L, Luo S. The inhibition of heat shock protein 90 facilitates the degradation of poly-alanine expanded poly (A) binding protein nuclear 1 via the carboxyl terminus of heat shock protein 70-interacting protein. PLoS One. 2015 Sep 28;10(9):e0138936. eCollection 2015.

2015 GRU Cancer Center Publications

Sathyamurthy A, Yin DM, Barik A, Shen C, Bean JC, Figueiredo D, She JX, Xiong WC, Mei L. ERBB3-mediated regulation of Bergmann glia proliferation in cerebellar lamination. Development. 2015 Feb 1;142(3):522-32.

Shinde R, Shimoda M, Chaudhary K, Liu H, Mohamed E, Bradley J, Kandala S, Li X, Liu K, McGaha TL. B cell-intrinsic IDO1 regulates humoral immunity to T cell-independent antigens. J Immunol. 2015 Sep 1;195(5):2374-82.

Shull AY, Noonepalle SK, Awan FT, Liu J, Pei L, Bollag RJ, Salman H, Ding Z, Shi H. RPPA-based protein profiling reveals eIF4G overexpression and 4E-BP1 serine 65 phosphorylation as molecular events that correspond with a pro-survival phenotype in chronic lymphocytic leukemia. Oncotarget. 2015 Jun 10;6(16):14632-45.

Shull AY, Noonepalle SK, Lee EJ, Choi JH, Shi H. Sequencing the cancer methylome. Methods Mol Biol.

2015;1238:627-51.

Silva J, Sharma S, Cowell JK. Homozygous deletion of the LGI1 gene in mice leads to developmental abnormalities resulting in cortical dysplasia. Brain Pathol. 2015 Sep;25(5):587-97.

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Simon PS, Sharman SK, Lu C, Yang D, Paschall AV, Tulachan SS, Liu K. The NF-κB p65 and p50 homodimer cooperate with IRF8 to activate iNOS transcription. BMC Cancer. 2015 Oct 23;15:770.

Simon RM, Howard L, Freedland SJ, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Vidal AC. Adverse pathology and undetectable ultrasensitive prostate-specific antigen after radical prostatectomy: Is adjuvant radiation warranted? BJU Int. 2015 May 24. doi: 10.1111/bju.13182. [Epub ahead of print]

2015 GRU Cancer Center Publications

Singh V, Chassaing B, Zhang L, San Yeoh B, Xiao X, Kumar M, Baker MT, Cai J, Walker R, Borkowski K, Harvatine KJ, Singh N, Shearer GC, Ntambi JM, Joe B, Patterson AD, Gewirtz AT, Vijay-Kumar M. Microbiota-dependent hepatic lipogenesis mediated by stearoyl CoA desaturase 1 (SCD1) promotes metabolic syndrome in TLR5-deficient mice.

Cell Metab. 2015 Dec 1;22(6):983-96.

Sukumari-Ramesh S, Alleyne CH Jr, Dhandapani KM. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) confers acute neuroprotection after intracerebral hemorrhage in mice. Transl Stroke Res. 2015 Sep 4.

[Epub ahead of print] Sukumari-Ramesh S, Prasad N, Alleyne CH, Vender JR, Dhandapani KM. Overexpression of Nrf2 attenuates Carmustine-induced cytotoxicity in U87MG human glioma cells. BMC Cancer. 2015 Mar 13;15(1):118.

Sun X, Jiang S, Liu J, Wang H, Zhang Y, Tang SC, Wang J, Du N, Xu C, Wang C, Qin S, Zhang J, Liu D, Zhang Y, Li X, Wang J, Dong J, Wang X, Xu S, Tao Z, Xu F, Zhou J, Wang T, Ren H. MiR-208a stimulates the cocktail of SOX2 and β-catenin to inhibit the let-7 induction of self-renewal repression of breast cancer stem cells and formed miR208a/let-7 feedback loop via LIN28 and DICER1. Oncotarget. 2015 Oct 20;6(32):32944-54.

Sun X, Tang SC, Xu C, Jin L, Mirabelli E, Zhou J, Qin Q, Ren H. Dicer regulated let-7 expression levels in p53-induced cancer repression requires cyclin D1. J Cell Mol Med. 2015 Feb 20. doi: 10.1111/jcmm.12522. [Epub ahead of print] Sun X, Tang SC, Xu C, Wang C, Qin S, Du N, Liu J, Zhang Y, Li X, Luo G, Zhou J, Xu F, Ren H. DICER1 regulated let-7 expression levels in p53-induced cancer repression requires cyclin D1. J Cell Mol Med. 2015 Jun;19(6):1357-65.

Suryawanshi A, Manicassamy S. Tumors induce immune tolerance through activation of β-catenin/TCF4 signaling in dendritic cells: A novel therapeutic target for cancer immunotherapy. Oncoimmunology. 2015 Jun 26;4 (12):e1052932. eCollection 2015 Dec. Suryawanshi A, Manoharan I, Hong Y, Swafford D, Majumdar T, Taketo MM, Manicassamy B, Koni PA, Thangaraju M, Sun Z, Mellor AL, Munn DH, Manicassamy S. Canonical wnt signaling in dendritic cells regulates th1/th17 responses and suppresses autoimmune neuroinflammation. J Immunol. 2015 Apr 1;194(7):3295-304.

Switzer JA, Singh R, Mathiassen L, Waller JL, Adams RJ, Hess DC. Telestroke: variations in intravenous thrombolysis by spoke hospitals. J Stroke Cerebrovasc Dis. 2015 Apr;24(4):739-44.

Tang FL, Erion JR, Tian Y, Liu W, Yin DM, Ye J, Tang B, Mei L, Xiong WC. VPS35 in dopamine neurons is required for endosome-to-golgi retrieval of Lamp2a, a receptor of chaperone-mediated autophagy that is critical for α-synuclein degradation and prevention of pathogenesis of Parkinson's disease. J Neurosci. 2015 Jul 22;35(29):10613-28.

Tang FL, Liu W, Hu JX, Erion JR, Ye J, Mei L, Xiong WC. VPS35 deficiency or mutation causes dopaminergic neuronal loss by impairing mitochondrial fusion and function. Cell Rep. 2015 Sep 8;12(10):1631-43.

Tang Y, Wang Y, Park KM, Hu Q, Teoh JP, Broskova Z, Ranganathan P, Jayakumar C, Li J, Su H, Tang Y, Ramesh G, Kim IM. MicroRNA-150 protects the mouse heart from ischaemic injury by regulating cell death. Cardiovasc Res. 2015 Jun 1;106(3):387-97.

Teng Y, Bahassan A, Dong D, Hanold LE, Ren X, Kennedy EJ, Cowell JK. Targeting the WASF3-CYFIP1 complex using stapled peptides suppresses cancer cell invasion. Cancer Res. 2016 Feb 15;76(4):965-73.

Teng Y, Ren X, Li H, Shull A, Kim J, Cowell JK. Mitochondrial ATAD3A combines with GRP78 to regulate the WASF3 metastasis-promoting protein. Oncogene. 2015 Mar 30. doi: 10.1038/onc.2015.86. [Epub ahead of print] Terris DJ, Chaung K, Duke WS. Continuous vagal nerve monitoring is dangerous and should not routinely be done during thyroid surgery. World J Surg. 2015 Oct;39(10):2471-6.

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Tian Y, Tang FL, Sun X, Wen L, Mei L, Tang BS, Xiong WC. VPS35-deficiency results in an impaired AMPA receptor trafficking and decreased dendritic spine maturation. Mol Brain. 2015 Oct 31;8(1):70.

Tiedemann RL, Hlady RA, Hanavan PD, Lake DF, Tibes R, Lee JH, Choi JH, Ho TH, Robertson KD. Dynamic reprogramming of DNA methylation in SETD2-deregulated renal cell carcinoma. Oncotarget. 2016 Jan 12;7(2):1927-46.

Tsai YT, Itokazu Y, Yu RK. GM1 ganglioside is involved in epigenetic activation loci of neuronal cells. Neurochem Res. 2015 Oct 24. [Epub ahead of print] Urken ML, Milas M, Randolph GW, Tufano R, Bergman D, Bernet V, Brett EM, Brierley JD, Cobin R, Doherty G, Klopper J, Lee S, Machac J, Mechanick JI, Orloff LA, Ross D, Smallridge RC, Terris DJ, Clain JB, Tuttle M. Management of recurrent and persistent metastatic lymph nodes in well-differentiated thyroid cancer: A multifactorial decisionmaking guide for the thyroid cancer care collaborative. Head Neck. 2015 Apr;37(4):605-14.

Uusitalo U, Liu X, Yang J, Aronsson CA, Hummel S, Butterworth M, Lernmark Å, Rewers M, Hagopian W, She JX, Simell O, Toppari J, Ziegler AG, Akolkar B, Krischer J, Norris JM, Virtanen SM; TEDDY Study Group. Association of early exposure of probiotics and islet autoimmunity in the TEDDY Study. JAMA Pediatr. 2015 Nov 9:1-9. doi: 10.1001/jamapediatrics.2015.2757. [Epub ahead of print] Veenstra RG, Flynn R, Kreymborg K, McDonald-Hyman C, Saha A, Taylor PA, Osborn MJ, Panoskaltsis-Mortari A, Schmitt-Graeff A, Lieberknect E, Murphy WJ, Serody JS, Munn DH, Freeman GJ, Allison JP, Mak TW, van den Brink M, Zeiser R, Blazar BR. B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality. Blood. 2015 May 21;125(21):3335-46.

Verma VK, Kamaraju SR, Kancherla R, Kona LK, Beevi SS, Debnath T, Usha SP, Vadapalli R, Arbab AS, Chelluri LK. Fluorescent magnetic iron oxide nanoparticles for cardiac precursor cell selection from stromal vascular fraction and optimization for magnetic resonance imaging. Int J Nanomedicine. 2015 Jan 20;10:711-26. eCollection 2015.

Viazzi F, Ramesh G, Jayakumar C, Leoncini G, Garneri D, Pontremoli R. Increased urine semaphorin-3A is associated with renal damage in hypertensive patients with chronic kidney disease: a nested case-control study. J Nephrol.

2015 Jun;28(3):315-20.

Wang J, Ma R, Sharma A, He M, Xue J, Wu J, Dun B, Li G, Wang X, Ji M, She JX, Tang J. Inflammatory serum proteins are severely altered in metastatic gastric adenocarcinoma patients from the chinese population. PLoS One. 2015 Apr 17;10(4):e0123985. eCollection 2015.

Wang J, Ye Z, Huang TH, Shi H, Jin V. A survey of computational methods in transcriptome-wide alternative splicing analysis. Biomol Concepts. 2015 Mar;6(1):59-66. Review.

Wang R, Kwon IK, Singh N, Islam B, Liu K, Sridhar S, Hofmann F, Browning DD. Type 2 cGMP-dependent protein kinase regulates homeostasis by blocking c-Jun N-terminal kinase in the colon epithelium. Cell Death Differ. 2014 Mar;21(3):427-37.

2015 GRU Cancer Center Publications

Törn C, Hadley D, Lee HS, Hagopian W, Lernmark Å, Simell O, Rewers M, Ziegler A, Schatz D, Akolkar B, OnengutGumuscu S, Chen WM, Toppari J, Mykkänen J, Ilonen J, Rich SS, She JX, Steck AK, Krischer J; TEDDY Study Group.

Role of type 1 diabetes-associated SNPs on risk of autoantibody positivity in the TEDDY Study. Diabetes. 2015 May;64(5):1818-29.

Wang X, Chen X, Han W, Ruan A, Chen L, Wang R, Xu Z, Xiao P, Lu X, Zhao Y, Zhou J, Chen S, Du Q, Yang H, Zhang X. miR-200c targets CDK2 and suppresses tumorigenesis in renal cell carcinoma. Mol Cancer Res. 2015 Dec;13 (12):1567-77.

Wang XF, Zhou QM, Lu YY, Zhang H, Huang S, Su SB. Glycyrrhetinic acid potently suppresses breast cancer invasion and metastasis by impairing the p38 MAPK-AP1 signaling axis. Expert Opin Ther Targets. 2015 May;19(5):577-87.

Wang Y, Deng O, Feng Z, Du Z, Xiong X, Lai J, Yang X, Xu M, Wang H, Taylor D, Yan C, Chen C, Difeo A, Ma Z, Zhang J. RNF126 promotes homologous recombination via regulation of E2F1-mediated BRCA1 expression. Oncogene. 2015 Aug 3. doi: 10.1038/onc.2015.198. [Epub ahead of print] Wang Z, Celis E. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice. Cancer Immunol Immunother. 2015 Aug;64(8):1057-66.

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Wang Z, Kim J, Teng Y, Ding HF, Zhang J, Hai T, Cowell JK, Yan C. Loss of ATF3 promotes hormone-induced prostate carcinogenesis and the emergence of CK5+CK8+ epithelial cells. Oncogene. 2015 Nov 2. doi: 10.1038/onc.2015.417.

[Epub ahead of print]

2015 GRU Cancer Center Publications

Wang Z, Xu D, Ding HF, Kim J, Zhang J, Hai T, Yan C. Loss of ATF3 promotes Akt activation and prostate cancer development in a Pten knockout mouse model. Oncogene. 2015 Sep 17;34(38):4975-84.

Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, Odame I, Fuh B, George A, Owen W, Luchtman-Jones L, Rogers ZR, Hilliard L, Gauger C, Piccone C, Lee MT, Kwiatkowski JL, Jackson S, Miller ST, Roberts C, Heeney MM, Kalfa TA, Nelson S, Imran H, Nottage K, Alvarez O, Rhodes M, Thompson AA, Rothman JA, Helton KJ, Roberts D, Coleman J, Bonner MJ, Kutlar A, Patel N, Wood J, Piller L, Wei P, Luden J, Mortier NA, Stuber SE, Luban NL, Cohen AR, Pressel S, Adams RJ. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2015 Dec 4. pii: S0140-6736(15)01041-7. doi: 10.1016/ S0140-6736(15)01041-7. [Epub ahead of print] Wei JX, Lv LH, Wan YL, Cao Y, Li GL, Lin HM, Zhou R, Shang CZ, Cao J, He H, Han QF, Liu PQ, Zhou G, Min J. Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells. Hepatology. 2015 Apr;61(4):1284-94.

Wei Z, Behrman B, Wu WH, Chen BS. Subunit-specific regulation of N-methyl-D-aspartate (NMDA) receptor trafficking by SAP102 protein splice variants. J Biol Chem. 2015 Feb 20;290(8):5105-16.

Whitehead WE, Rao SS, Lowry A, Nagle D, Varma M, Bitar KN, Bharucha AE, Hamilton FA. Treatment of fecal incontinence: State of the Science Summary for the National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Am J Gastroenterol. 2015 Jan;110(1):138-46; quiz 147. Review.

Whitney EM, Stoopler E, Brennan MT, DeRossi SS, Treister NS. Competencies for the new postdoctoral Oral Medicine graduate in the United States. Oral Surg Oral Med Oral Pathol Oral Radiol. 2015 Sep;120(3):324-8.

Williams LB, Franklin B, Evans MB, Jackson C, Hill A, Minor M. Turn the beat around: A stroke prevention program for African-American churches. Public Health Nurs. 2015 Sep 25. doi: 10.1111/phn.12234. [Epub ahead of print] Wilson LE, Kim S, Xu Z, Harlid S, Sandler DP, Taylor JA. Non-steroidal anti-inflammatory drug use and genomic DNA methylation in blood. PLoS One. 2015 Sep 22;10(9):e0138920. eCollection 2015.

Wiranowska M, Rojiani AM, Rojiani MV. Matrix metalloproteinases-modulating the tumor microenvironment. J Carcinog Mutagen. 2015 May 11: 6:225.

Woan KV, Lienlaf M, Perez-Villaroel P, Lee C, Cheng F, Knox T, Woods DM, Barrios K, Powers J, Sahakian E, Wang HW, Canales J, Marante D, Smalley KSM, Bergman J, Seto E, Kozikowski A, Pinilla-Ibarz J, Sarnaik A, SarnailCelis E, Weber J, E.M. Sotomayor EM, Villagra A. Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation. Mol Oncol. 2015 Aug 9(7):1447-57.

Wright CE, Kushner EJ, Du Q, Bautch VL. LGN directs interphase endothelial cell behavior via the microtubule network. PLoS One. 2015 Sep 23;10(9):e0138763. eCollection 2015.

Wu H, Barik A, Lu Y, Shen C, Bowman A, Li L, Sathyamurthy A, Lin TW, Xiong WC, Mei L. Slit2 as a β-catenin/Ctnnb1dependent retrograde signal for presynaptic differentiation. Elife. 2015 Jul 10;4.

Xie CM, Wei D, Zhao L, Marchetto S, Mei L, Borg JP, Sun Y. Erbin is a novel substrate of the Sag-βTrCP E3 ligase that regulates KrasG12D-induced skin tumorigenesis. J Cell Biol. 2015 Jun 8;209(5):721-38.

Xie YJ, Zhou L, Jiang N, Zhang N, Zou N, Zhou L, Wang Y, Cowell JK, Shen Y. Essential roles of leucine-rich glioma inactivated 1 in the development of embryonic and postnatal cerebellum. Sci Rep. 2015 Jan 16;5:7827.

Xiong L, Jung JU, Wu H, Xia WF, Pan JX, Shen C, Mei L, Xiong WC. Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption. Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):3487-92.

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Xiong X, Du Z, Wang Y, Feng Z, Fan P, Yan C, Willers H, Zhang J. 53BP1 promotes microhomology-mediated endjoining in G1-phase cells. Nucleic Acids Res. 2015 Feb 18;43(3):1659-70.

Xu M, Wang X, Tan J, Zhang K, Guan X, Patterson LH, Ding H, Cui H. A novel Lozenge gene in silkworm, Bombyx mori regulates the melanization response of hemolymph. Dev Comp Immunol. 2015 Nov;53(1):191-8.

Yang J, Lynch KF, Uusitalo UM, Foterek K, Hummel S, Silvis K, AndrĂŠn Aronsson C, Riikonen A, Rewers M, She JX, Ziegler AG, Simell OG, Toppari J, Hagopian WA, Lernmark Ă&#x2026;, Akolkar B, Krischer JP, Norris JM, Virtanen SM, Johnson SB; TEDDY Study Group. Factors associated with longitudinal food record compliance in a paediatric cohort study.

Public Health Nutr. 2015 Jun 19:1-10. [Epub ahead of print]

Yang L, Fang D, Chen H, Lu Y, Dong Z, Ding HF, Jing Q, Su SB, Huang S. Cyclin-dependent kinase 2 is an ideal target for ovary tumors with elevated cyclin E1 expression. Oncotarget. 2015 Jun 23. [Epub ahead of print] Yao S, Zheng P, Wu H, Song LM, Ying XF, Xing C, Li Y, Xiao ZQ, Zhou XN, Shen T, Chen L, Liu YH, Lai MD, Mei L, Gao TM, Li JM. Erbin interacts with c-Cbl and promotes tumourigenesis and tumour growth in colorectal cancer by preventing c-Cbl-mediated ubiquitination and down-regulation of EGFR. J Pathol. 2015 May;236(1):65-77.

Yu RK, Usuki S, Itokazu Y, Wu HC. Novel GM1 ganglioside-like peptide mimics prevent the association of cholera toxin to human intestinal epithelial cells in vitro. Glycobiology. 2015 Sep 24. pii: cwv080. [Epub ahead of print] Zaidi S, Blanchard M, Shim K, Ilett E, Rajani K, Parrish C, Boisgerault N, Kottke T, Thompson J, Celis E, Pulido J, Selby P, Pandha H, Melcher A, Harrington K, Vile R. Mutated BRAF emerges as a major effector of recurrence in a murine melanoma model after treatment with immunomodulatory agents. Mol Ther. 2015 May;23(5):845-56.

Zapata DF, Howard LE, Aronson WJ, Kane CJ, Terris MK, Amling CL, Cooperberg MR, Freedland SJ. Smoking is a predictor of adverse pathological features at radical prostatectomy: Results from the Shared Equal Access Regional Cancer Hospital database. Int J Urol. 2015 Jul;22(7):658-62.

Zhang L, Shamaladevi N, Jayaprakasha GK, Patil BS, Lokeshwar BL. Polyphenol-rich extract of Pimenta dioica berries (Allspice) kills breast cancer cells by autophagy and delays growth of triple negative breast cancer in athymic mice.

Oncotarget. 2015 Jun 30;6(18):16379-95.

Zhao E, Ding J, Xia Y, Liu M, Ye B, Choi JH, Yan C, Dong Z, Huang S, Zha Y, Yang L, Cui H, Ding HF. KDM4C and ATF4 cooperate in transcriptional control of amino acid metabolism. Cell Rep. 2016 Jan 26;14(3):506-19.

Zhang M, Zhu X, Zhang Y, Cai Y, Chen J, Sivaprakasam S, Gurav A, Pi W, Makala L, Wu J, Pace B, Tuan-Lo D, Ganapathy V, Singh N, Li H. RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis. Cell Death Differ. 2015 Dec;22(12):1922-34.

Zhong H, Davis A, Ouzounova M, Carrasco RA, Chen C, Breen S, Chang YS, Huang J, Liu Z, Yao Y, Hurt E, Moisan J, Fung M, Tice DA, Clouthier SG, Xiao Z, Wicha MS, Korkaya H, Hollingsworth RE. A novel IL6 antibody sensitizes multiple tumor types to chemotherapy including trastuzumab-resistant tumors. Cancer Res. 2016 Jan 15;76(2):48090.

Zhong X, Zhao E, Tang C, Zhang W, Tan J, Dong Z, Ding HF, Cui H. Antibiotic drug tigecycline reduces neuroblastoma cells proliferation by inhibiting Akt activation in vitro and in vivo. Tumour Biol. 2015 Dec 19. [Epub ahead of print]

2015 GRU Cancer Center Publications

Yang J, Yao W, Qian G, Wei Z, Wu G, Wang G. Rab5-mediated VE-cadherin internalization regulates the barrier function of the lung microvascular endothelium. Cell Mol Life Sci. 2015 Dec;72(24):4849-66.

Zhou F, Dong C, Davis JE, Wu WH, Surrao K, Wu G. The mechanism and function of mitogen-activated protein kinase activation by ARF1. Cell Signal. 2015 Oct;27(10):2035-44.

Zhou Q, Ye M, Lu Y, Zhang H, Chen Q, Huang S, Su S. Curcumin improves the tumoricidal effect of mitomycin C by suppressing ABCG2 expression in stem cell-like breast cancer cells. PLoS One. 2015 Aug 25;10(8):e0136694. eCollection 2015.

Zhu S, Zhang M, Davis JE, Wu WH, Surrao K, Wang H, Wu G. A single mutation in helix 8 enhances the angiotensin II type 1a receptor transport and signaling. Cell Signal. 2015 Dec;27(12):2371-9.

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