Scientific Report 2014

2014 SCIENTIFIC REPORT OF BASIC SCIENCE PROGRAMS

CONTENTS

INTRODUCTION

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CANCER IMMUNOLOGY, INFLAMMATION AND TOLERANCE PROGRAM OVERVIEW CIT REPORTS

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MOLECULAR ONCOLOGY AND BIOMARKERS PROGRAM OVERVIEW MOB REPORTS

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TUMOR SIGNALING AND ANGIOGENESIS PROGRAM OVERVIEW TSA REPORTS

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CANCER CENTER SHARED RESOURCES BIOREPOSITORY AND CENTRAL SOURCE FOR THE BIOREPOSITORY ALLIANCE OF GEORGIA-ONCOLOGY (BRAG-ONC) CORE IMAGING FACILITY FOR SMALL ANIMALS FLOW CYTOMETRY RESOURCE INTEGRATED GENOMICS: MICROARRAY INTEGRATED GENOMICS: NEXT-GEN SEQUENCING MICROSCOPY IMAGING CORE PROTEOMICS AND METABOLOMICS FACILITY BIOINFORMATICS AND BIOSTATISTICS

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2014 GRU CANCER CENTER PUBLICATIONS

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INDEX OF PROGRAM RESEARCHERS

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GRU CANCER CENTER 2014 SCIENTIFIC REPORT OF BASIC SCIENCE PROGRAMS

Presented here is the Annual Scientific Report of the GRU Cancer Center at Georgia Regents University in Augusta, Georgia. The following pages describe the 2014 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. Substantial progress also was made in the emerging Cancer Prevention and Control program with the receipt of a five-year, $3.6M National Cancer Institute Community Oncology Research Program (NCORP) Minority/Underserved Community Site award and a three-year, $1.74M award from the Bristol-Myers Squibb Foundation to support the Cancer Center’s c-CARE (cancer-Community Awareness Access Research and Education) initiative. Both of these grants are designed to reduce the burden of cancer among minority and underserved populations throughout Georgia and beyond. The Cancer Center’s Translational Oncology initiative is also progressing with the establishment of infrastructure required to support Phase I/II clinical trials including investigator-initiated trials that develop from within Cancer Center research laboratories. These two fledgling programs will be added to the Scientific Report once they establish 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, Dr. Khleif has prioritized the development of shared research resources to provide 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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About the GRU Cancer Center About the GRU Cancer Center: With strong state support, GRU 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 administrators.

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 GRU Cancer Center, with members derived from Colleges, Departments, and Institutes throughout the medical campus.

About GRU Founded in 1828, Georgia Regents University (GRU), previously Georgia Health Sciences University, is a comprehensive research university within the University System of Georgia.

Nearly 10,000 students are enrolled in nine colleges that include the nationally ranked Hull College of Business, Georgia’s only College of Dental Medicine, and the sixth largest public medical school in the country – the Medical College of Georgia (MCG).

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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

Nita J. Maihle, PhD Associate Director Education

Michael Benedict, PharmD Associate Director Adminsitration

David H. Munn, MD Senior Advisor to the Director

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

Feng-Ming (Spring) Kong, MD, PhD Medical Director Radiation Oncology

Sharad Ghamande, MD Associate Director Clinical Affairs

Frank Mott, MD Medical Director Outpatient Clinic

CANCER IMMUNOLOGY, INFLAMMATION AND TOLERANCE (CIT) PROGRAM

Co-Leader // Dr. A. Mellor

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cancer immunology, inflammation and tolerance program //

OVERVIEW OF THE PROGRAM

The principal goals of the program are to elucidate molecular pathways and cellular processes active in tumor microenvironments in order to develop, characterize, and apply immunological approaches to prevention, diagnosis, treatment, and monitoring of premalignant and malignant diseases. Specific aims include: • discovery research using models of chronic inflammatory diseases (i) to elucidate how immune responses are regulated to create tolerance (unresponsiveness) in tumor microenvironments that inhibit natural and vaccine-induced anti-tumor immunity and (ii) 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; • understanding how chronic inflammation creates tolerance to protect tumors and healthy tissues from immune-mediated injury; • 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.

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overview // cit program

Long before clinical presentation of cancer pre-malignant lesions create local inflammation that inhibits natural anti-tumor immunity. On presentation established tumors are highly resistant to tumor vaccines because immune tolerance in the tumor microenvironment inhibits vaccineinduced immunity. Successful immunotherapies must therefore disrupt local microenvironments that protect tumors from immunity. Hence, program research focuses on tolerogenic pathways in the innate and adaptive immune systems that protect healthy tissues and tumors from immunemediated destruction but represent formidable barriers to cancer immunotherapy. The program is also active in pursuing opportunities to translate the fruits of basic scientific research into clinical settings to improve treatments for cancer patients.

Researchers in the CIT program use a variety of techniques to study how the immune system impedes and promotes tumorigenesis, and how to improve cancer therapy. The immune system can inhibit or promote tumor progression in local tissues where pre-malignancies form. Major program themes are to elucidate, (i) how pre-malignancies create and sustain local immunologic tolerance necessary for tumor formation and, (ii) how to destroy local tolerance that protects tumors from natural and vaccine-induced anti-tumor immunity. Since loss of immune tolerance leads to autoimmune syndromes (e.g. type I diabetes, systemic lupus erythematosus, rheumatoid arthritis, colitis, multiple sclerosis), program investigators use mouse models of cancer and autoimmune progression to elucidate critical molecular and cellular pathways that either create or destroy immune tolerance. The scientific rationale for this parallel approach is that pre-malignant cells create and sustain tolerance during tumor progression, while breaking tumor-associated tolerance is necessary for successful anti-tumor treatment. Hence, program goals are to elucidate molecular and cellular pathways at sites of inflammation that promote or break immune tolerance using pre-clinical mouse models of tumor progression and autoimmune syndromes, and developing novel immunotherapies to treat these syndromes more effectively by targeting tolerance pathways. To this end, program faculty also engage in promoting pre-clinical research and early-phase clinical trials of novel vaccine adjuvants to improve cancer immunotherapy, in some cases with corporate partners. To pursue these focused research themes and scientific goals, program faculty employ many state-of-the-art techniques, facilities, and unique resources, including flow cytometric sorting and analysis, a range of molecular imaging techniques, genomic analysis, and genetically modified mouse strains. Future program development will build on existing CIT program strengths by recruiting new investigators with expertise in inflammation, immunological, and metabolic research to complement current research focused on regulation of adaptive immunity.

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reports // cit program

Esteban Celis, MD, PhD Professor

CN-4121

Research performed by the Celis laboratory, and in collaboration with investigators from various institutions, has facilitated the development of various strategies to optimize T cell therapies for cancer. Studies in various mouse cancer models treated with the immune modulator poly-IC and a blocking antibody for the checkpoint inhibitor PD-1 have shown a remarkable anti-tumor effect (Clin Cancer Res. 2014, 20(5):1223-34; Oncoimmunology. 2014, 15;3:e28440). Dr. Celis’ group observed that mutated oncogene BRAF emerges during tumor recurrences in a murine melanoma model after immunotherapy (Mol Ther. 2014, In Press). Some studies on overcoming the negative effects of myeloid derived suppressor cells (J Clin Invest. 2014, 124(6):2626-39) and deficiencies of dendritic cells caused by lipid oxidation (J Immunol. 2014, 192(6):2920-31) will facilitate the optimization of cancer immunotherapy. They also reported that posttranslational modifications of tumor protein p53 generated peptide epitopes recognized by human CD4 T cells (Cancer Immunol Immunother. 2014, 63:469-78) and that tumor derived suppressor substances (TGF-β and prostaglandin E2) decrease anti-tumor immune responses in head and neck cancers that are treated with EGFR inhibitors (J Transl Med. 2014, 12:265). Proper T cell activation is essential to develop anti-tumor immunity. It was shown that NF-κB is crucial in proximal T-cell signaling for calcium influx and NFAT activation (Eur J Immunol. 2014, 12:3741-6). Now that cancer immunotherapy has gained significant momentum and recognition by the oncology community, it becomes important to classify the major modes of immune based therapies. Together with a large number of the colleagues in this field, the Celis laboratory participated in the first effort in classifying the current cancer immunotherapies (Oncotarget. 2014, In Press).

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Yan Cui, PhD Professor

CN-4120

It is now well appreciated that tumor establishment, progression, and metastases are markedly affected by the cellular and molecular constituents surrounding tumors, the so-called tumor microenvironment (TME). During the past decade, significant progress has been made toward our understanding of the factors that dictate the antitumor versus pro-tumor function of immune cells, including T, B, NK, and myeloid cells, within the TME. However, the immunological contribution of non-hematopoietic stromal cells, including cancer associated fibroblasts (CAFs), lymphatic, and blood endothelial cells within the TME, to tumor progression has yet to be fully understood and appreciated.

The supportive role of CAFs in tumor progression has been documented previously. Until recently, the immunological contribution of CAFs to tumor progression has been largely overlooked. Recent studies from the Cui laboratory (Cancer Res. 2013, 73:1668-75) and others demonstrated that CAFs share many phenotypic and immunological properties with specialized fibroblastic reticular stromal cells (FRC) of the secondary lymphoid organs. They also demonstrated that CAFs and FRCs are strongly immunosuppressive by producing high levels of pro-inflammatory molecules and enhancing the differentiation and expansion of myeloid derived suppressor cells (MDSCs). Recently, the Cui laboratory observed that CAFs and FRCs also impose immunosuppressive effects on dendritic cells and T cells. They are currently investigating the molecular pathways involved in this specialized fibroblast-myeloid cell or fibroblast-T cell crosstalk and their immunological impacts on the TME and tumorigenesis.

The p53 tumor suppressor is the most frequently mutated/inactivated gene in tumors. It has been well accepted that the major mechanism by which p53 suppresses tumor development is by inducing apoptosis or senescence. Recently, compelling evidence suggests that p53 also suppresses tumorigenesis by regulating other crucial biological functions, including host immune responses. We recently demonstrated that p53 inactivation/ dysfunction in the TME skews the immunological landscape toward pro-inflammation. As chronic inflammation plays a vital role in tumor initiation, progression, and metastasis, p53 inactivation/dysfunction promotes tumorigenesis and tumor progression by compromising host immune surveillance and altering the tumor milieu to pro-tumor inflammation (J ImmunoTher Cancer, 2015, In Press).

Conversely, it was demonstrated by others that p53-reactivation or conversion of mutant p53 to wild type function in tumors or stromal cells resulted in tumor elimination or regression, which is at least partially mediated by senescence-induced antitumor immunity. Because many conventional therapies, such as radiotherapy and chemotherapy, induce tumor cell death through DNA damage and p53-activation, we propose and are actively investigating whether some of the observed therapeutic effects of these conventional therapies may have an immunological component due to p53-activation-induced activation of antitumor immunity. With currently available novel pharmacological p53 activators or defined radiotherapy and chemotherapy regimens, targeted activation/restoration of the p53 pathway may prove to be an excellent immune adjuvant for promoting antitumor immunity, which can be used in combination with other active immunotherapies to maximize ultimate antitumor efficacy for tumors maintaining wildtype p53, as well as those that incur p53 mutations.

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Yukai He, MD, PhD Associate Professor

CN-4150

The He laboratory has been focusing on rational vaccine design and on the development of immunotherapy approaches for liver cancer in addition to their continuing interest in tackling the effector phase of immunity to achieve more potent antitumor effect.

Using a mouse hepatocellular carcinoma (HCC) model, Dr. He’s laboratory builds on previous work to show that using the technology of epitope optimization, a highly immunogenic HCC-associated tumor antigen alpha fetoprotein (AFP) could be created. Immunization with lentivector expressing the epitope-optimized AFP, but not wild-type AFP, potently activated CD8 T cells. Critically, the activated CD8 T cells not only crossrecognized short synthetic wild-type AFP peptides, but also recognized and killed tumor cells expressing wild-type AFP protein (Hepatology.

2014, 59:1448-58). Immunization with lentivector expressing optimized AFP, but not native AFP, completely protected mice from tumor challenge and reduced the incidence of carcinogen-induced autochthonous HCC. Dr. He’s data demonstrate that epitope-optimization is required to break immune tolerance and potently activate AFP-specific CD8 T cells, generating effective antitumor effects to prevent clinically relevant carcinogeninduced autochthonous HCC in mice. This study provides a practical roadmap to develop effective human HCC vaccines that may result in an improved outcome compared to the current HCC vaccines based on wild-type AFP (Immunotherapy. 2014, 6:725-36). In addition to CD8 epitope optimization, Dr. He’s laboratory initiated collaboration with Dr. Bjoern Peters of La Jolla Institute for Allergy and Immunology to design CD4 epitope-optimized liver cancer vaccines.

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Theodore S. Johnson, MD, PhD Assistant Professor

CN-4155

Dr. Johnson’s laboratory studies the indoleamine 2,3-dioxygenase (IDO) pathway of natural immune tolerance, which is co-opted by tumors to escape immune attack. Normally, IDO functions to limit immune responses against innocuous antigens such as commensal bacteria and 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. Dr. Johnson’s investigations using a syngeneic orthotopic brain tumor model have led to the important discovery that adding an IDO-blocking drug to conventional chemo-radiotherapy elicits synergistic effects on survival and changes the nature of the tumor response, leading to widespread complement activation, intense vascular activation, and local tumor necrosis (J Immunother Cancer. 2014, 2:21).

Dr. Johnson’s 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. Thus, understanding how IDO and complement are linked to inflammation in the tumor is critical to developing optimal combination chemo-immunotherapy. In fact, these novel findings from the Johnson laboratory have already opened up important new avenues of translational research. This includes an active ongoing collaboration with the adult Phase I program at the GRU Cancer Center to develop a first-in-human Phase I/II clinical trial, which is currently open and accruing patients, using the IDO pathway inhibitor drug indoximod to treat adults and adolescents with relapsed glioblastoma tumors. Dr. Johnson and his collaborators are also developing a first-in-children Phase I trial, which is expected to open early in 2015, using indoximod with chemo-radiation therapy to treat pediatric patients with progressive brain tumors.

In addition, Dr. Johnson has considerable experience with rare pediatric hyper-immune disorders, such as hemophagocytic lymphohistiocytosis (HLH) syndrome. He recently published a study in which he and collaborators at Cincinnati Children’s Hospital (Cincinnati, OH) determined the biological mechanism by which the cytolytic drug etoposide exerts a therapeutic effect in an animal model of this disease (J Immunol. 2014, 192:84-91). HLH patients have pathological immune responses that are characterized by unusually intense activation of T cells and macrophages.

Although its therapeutic mechanism of action in treating HLH has been heretofore unknown, etoposide is a widely used chemotherapeutic drug that can inhibit topoisomerase II. Using an animal model of HLH, Dr. Johnson found that etoposide acts against HLH by deleting activated T cells, but sparing quiescent naive T cells and memory T cells. Thus, etoposide exerts a therapeutic effect in HLH treatment by selectively ablating pathologic T cells, a novel immune modulatory property that may be useful in treating a broad spectrum of immunopathologic disorders in the future.

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Samir N. Khleif, MD

Mikayel Mkrtichyan, PhD

Professor and Cancer Center Director

Instructor

CN-2101

Combinational anti-cancer immune therapies that target tumor-mediated suppressive mechanisms or enhance effector immunity are emerging as promising strategies for cancer treatment. One of the major focuses of the Khleif laboratory is the development of immune-corrective strategies that target multiple tumor-mediated suppressive mechanisms along with simultaneous enhancement of effector immunity. This also involves detailed investigation of immune and molecular mechanisms of action for multiple compounds used as single agents and within combinational immunotherapy. The main targets that are currently under investigation include OX40, IDO, GITR, PD-1, PD-L1 and the PI3K/Akt pathway.

Compounds targeting these molecules are being evaluated in combination with different vaccine formulations in different mouse models.

Another major focus of the Khleif laboratory is the investigation of the role of the PI3K/Akt pathway in different T cell subsets, with a special focus on CD8 and regulatory CD4 T cells. The aim of this in depth examination of this vital pathway is the development of strategies to selectively manipulate specific subsets to enhance immune therapies. More specifically, the Khleif group reported the use of PI3K/Akt pathway inhibitors as potent agents for the selective depletion of suppressive regulatory CD4 T cells. In addition, these inhibitors were able to enhance the antitumor immune response thus translating into therapeutic efficacy (Cancer Immunol Res. 2014, 2:1080). The importance of the Akt pathway in the regulation of the differentiation and function of different CD8 T cell subsets was further demonstrated (Oncoimmunology. 2014, In Press). Akt inhibition was found to enhance the development of more functionally potent memory CD8 T cells. Akt inhibitors are therefore promising clinical reagents for Treg depletion and CD8 enhancement and the group is currently in the process of preparing for a Phase I/II clinical trial.

Results from a clinical trial that involved the Khleif laboratory involving 32 patients with advanced cervical cancer treated with HPV16 E6 or HPV16 E7 peptide pulsed on Pre-Immature Dendritic Cells were also reported. The ability of Pre-Immature Dendritic Cells pulsed with HPV16 E6 or HPV16 E7 to induce a specific immune response against the HPV peptides despite the advanced disease was demonstrated (J Transl Med. 2014; 12:353).

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Kebin Liu, PhD Associate Professor

CN-1173

The major effort of the Liu laboratory in the last year has been devoted to investigating the dynamic interactions of tumor cells and immune cells in the tumor microenvironment. The laboratory focuses on the molecular mechanisms underlying myeloid-derived suppressor cell (MDSC) persistence in tumor-bearing mice and human colon cancer patients. MDSCs are a heterogeneous population of immature myeloid cells of various differentiation stages that are induced under various pathological conditions, including cancer. In human cancer patients and in mouse tumor models, massive accumulation of MDSCs in bone marrow, peripheral blood, lymphoid tissue, and tumor tissue is a hallmark of tumor progression.

The molecular mechanism underlying MDSC differentiation and accumulation is largely unclear. IRF8 KO mice exhibit massive accumulation of MDSCs that phenotypically and functionally resemble tumor-induced MDSCs. Similarly, tumor-induced MDSCs exhibit diminished IRF8 expression, suggesting that IRF8 silencing in MDSCs might be a key determinant of deregulated MDSC differentiation. However, the Liu laboratory found that mice with an IRF8 deficiency only in myeloid cells do not accumulate MDSCs, suggesting that IRF8 might act in a cell-extrinsic manner to regulate MDSC differentiation. Indeed, mice with an IRF8 deficiency only in T cells exhibit MDSC accumulation, and adoptive transfer of BM from IRF8 KO mice and mice with an IRF8 deficiency only in T cells to lethally irradiated mice resulted in MDSC accumulation. The Liu laboratory further determined that IRF8 represses GM-CSF expression in T cells to suppress MDSC differentiation. Therefore, they determined, for the first time, that IRF8 regulates MDSC differentiation through repressing GM-CSF expression in a cell-extrinsic mechanism (J Immunol. 2015, In Press).

Another area of study in the Liu laboratory is to elucidate the molecular mechanism underlying cancer cell resistance to cell death induction for the development of targeted chemotherapies to enhance the efficacy of T cell-based cancer immunotherapy. One of the effector mechanisms of cytotoxic T lymphocytes (CTLs) is Fas-mediated cytotoxicity. However, human cancer cells often use silencing the death receptor Fas expression as a mechanism to escape from host cancer immune surveillance. The Liu laboratory has developed several therapeutic agents, including ceramide analogs and verticillin A, to sensitize cancer cells to Fas-mediated apoptosis (BMC Cancer. 2014, 14:24).

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Santhakumar Manicassamy, PhD Assistant Professor

CN-4153

The main research focus of the Manicassamy laboratory is to understand the critical mechanisms that regulate immune and commensal homeostasis at the mucosal surfaces of the intestine. 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. Dr. Manicassamy’s interest in this area stems from 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. This problem assumes a particular importance in the intestine because of the billions of commensal microorganisms, pathogenic microbes, and dietary antigens that confront the intestinal immune system every day. At the mucosal sites, antigen-presenting cells (APCs), such as dendritic cells and macrophages, exist as distinct subsets based on their phenotype and microenvironmental localizations. However, the role of these specific APC subsets in modulating immune responses and commensal homeostasis under so-called “steady-state conditions” (i.e. in the absence of any detectable infection or overt inflammation) versus “inflammatory-conditions” (i.e. in the presence of infection or tumor or overt inflammation) is largely unexplored and undefined. This raises several fundament questions: (i) What role do distinct APC subsets play in regulating immunity versus tolerance? (ii) Are the functions and phenotypes of these cells fixed, or do they display plasticity in their function and phenotype? (iii) How are APC subsets programmed to promote tolerance or immunity? (iv) What are the signaling pathways in the APCs that are critical in promoting tolerance versus immunity? (v) What roles do the tumor environment and commensals play in shaping APC function and anti-tumor immunity? New insights regarding these basic questions will shed light on immunological processes that are critical for the maintenance of homeostasis with the microbiota and how these interactions can become dysfunctional to cause increased risk of inflammatory diseases, infection by microbial pathogens, and cancer. In this context, activation of the beta-catenin pathway in dendritic cells is critical for regulating immunity versus tolerance in the gut. Recently, we have shown that TLR2-dependent activation of beta-catenin in DCs is for limiting inflammation in the periphery and autoimmunity (J Immunol. 2014, 193:4203-13). Aberrant Wnt/ beta-catenin signaling occurs in many tumors, and the tumor microenvironment contains high levels of several Wnt ligands. In collaboration with Dr. Munn, the Manicassamy laboratory is studying the role of beta-catenin pathway in tumor induced immune suppression. In this context, our recent study has shown that beta-catenin promotes T regulatory cell responses in tumors by inducing vitamin A metabolism in dendritic cells (Cancer Res. 2015, In Press). These studies provide the pre-clinical basis for future translation studies aimed at the development of an entirely new class of agents that may have significant therapeutic impact in treating inflammatory diseases and cancer.

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Tracy McGaha, PhD Assistant Professor

CN-4143

The McGaha laboratory investigates the mechanism of immune regulation and tolerance induced by apoptotic cell death in secondary lymphoid organs. Specifically, the laboratory is interested in delineating the role that stromal (i.e. resident non-inflammatory) macrophages and dendritic cells play in initiating and propagating regulatory immunity. The recognition and processing of apoptotic cells by specialized macrophages in the marginal zone of the spleen and sub-capsular region of lymph nodes is thought to be critical for maintaining immune homeostasis and tolerance to particulate self-antigens. However, the underlying process driving the response on the cellular or molecular level remains poorly defined.

Thus, the McGaha laboratory is exploring the early innate response to apoptotic cell phagocytosis in the spleen and lymph node, examining the sequence of molecular and micro-environmental changes that are responsible for initial apoptotic cell-driven immune suppression and long-term immunologic tolerance to apoptotic cell-associated antigens. The McGaha laboratory has reported that apoptotic cell uptake by a specialized CD169+ macrophage population in the spleen drives splenic recruitment of regulatory T cells and CD103+ dendritic cells within the first few hours after phagocytosis (Proc Natl Acad Sci U S A. 2014, 111: 4215-20). This recruitment was crucial for the anti-inflammatory effect driven by apoptotic cells and, if inhibited, apoptotic cells induced inflammatory autoimmunity to DNA and other nuclear antigens. This report was the first to suggest that macrophages provide a key coordination function in the initiation of adaptive immunity and indicated preformed regulatory T cell populations are required for initiation of tolerance.

Tumor-driven suppression of antigen-specific CD8+ T cells can occur in the spleen and tumor-draining lymph node as a result of myeloid derived suppressor cell (MDSC) expansion and exosome-derived antigen cross presentation. Since marginal zone macrophages are key mechanistic components of immune tolerance in the spleen, the McGaha group surmised they may play a role in MDSC-dependent suppression. Their data suggests MDSCs are dependent on splenic macrophages for the recruitment and acquisition of suppressor function. Relatedly, they found that MDSC-driven suppression is dependent on genes associated with the integrated stress response. MDSCs genetically deficient in stress response proteins show an inability to inhibit antigen-specific CTL-mediated lysis of tumor cells in vitro or in vivo. Their interpretation of these observations is that cell stress is an integral component of MDSC expansion, differentiation, and function. Moreover, they believe there is a direct relationship between the action of macrophages in the spleen and tumor draining lymph node, initial stress responses in MDSC precursors, and ultimate expansion of immune-suppressive monocytic lineage cells. Thus, the second research interest outlined here is to understand the relationship between activation-induced stress and monocyte development and acquisition of suppressive function associated with tumor establishment and growth. Supporting this hypothesis, the McGaha laboratory reported that the stress response kinase General Control Non-derepressible 2 (GCN2) is a critical modulator of macrophage function in a nutrient-poor microenvironment (Mol Cell Biol. 2014, 34: 428-38). When GCN2 was deleted, macrophages showed aberrant NFkB signaling and altered patterns of cytokine message transcription and translation, resulting in a profound alteration of cytokine production in response to toll-like receptor ligands. Thus, it is likely that micro-environmental stress in inflamed tissue is a key second signal that is critical for proper innate responsiveness to inflammatory signals, a concept they are currently testing in models of cancer and autoimmunity.

Finally, the McGaha laboratory has a long-standing interest in systemic autoimmune disease pathophysiology. In particular, they focus on mechanisms of self-tolerance breakdown and development of target organ damage in systemic lupus erythematosus (SLE). They are investigating how defects in apoptotic cell recognition can drive lymphocyte dysfunction; the role of metabolic stress signals in inflammatory lymphocyte differentiation; and target pathology associated with lupus nephritis.

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Andrew Mellor, PhD

Lei Huang, PhD

Professor and Co-Leader, CIT Program

Research Scientist

CN-4151

The immune system prevents malignant lesions from becoming life-threatening tumors. Tumors form only when lesions create local inflammatory microenvironments that inhibit anti-tumor immunity. Specialized immune cells regulate immunity to suppress natural and vaccine-induced anti-tumor immunity. Several ‘checkpoint’ regulatory mechanisms have been identified, including dendritic cells (DCs) expressing indoleamine 2,3 dioxygenase (IDO), a mechanism first described at GRU. Checkpoint blockade reagents are under scrutiny as potential immunotherapies to stimulate effective anti-tumor immunity. DCs expressing IDO are found in different types of tumor microenvironments in mice and humans.

Research in the Mellor laboratory is focused on elucidating underlying mechanisms that induce DCs to express IDO in tumor microenvironments, and in other syndromes such as autoimmune and infectious diseases. As in cancer, inflammation associated with chronic infections inhibits host immunity. On the other hand, inflammation associated with autoimmune diseases correlates with loss of immune regulation, allowing the immune system to destroy healthy tissues, rather than protect diseased tissues as in cancer and persistent infections. Pathways that incite or inhibit immunity at sites of inflammation are poorly defined, even though they are pivotal drivers of cancer and autoimmune diseases. We are studying the role of DNA sensing pathways in regulation of immunity based on the exciting observation that DNA nanoparticles (DNPs) inhibit immunity and autoimmunity. We showed that cargo DNA is the bioactive component of DNPs sensed by cytosolic DNA sensors to activate the adaptor Stimulator of Interferon Genes (STING) and induce IDO in DCs, which then suppress autoimmunity. It has been shown that DNPs attenuate autoimmune disease progression and severity in mouse models of Rheumatoid Arthritis and experimental autoimmune encephalitis, a multiple sclerosis model (J Immunol. 2014, 192:5571-8), and autoimmune Type I Diabetes. While executing these studies, we discovered that another class of STING activating reagents, cyclic dinucleotides, also attenuated autoimmune diseases (Eur J Immunol. 2014, 44:2847-53). In ongoing studies, potential roles for cellular DNA from dying tissue or tumor cells as a source of tolerogenic DNA that inhibits autoimmunity and anti-tumor immunity are being evaluated. Other ongoing research is evaluating how IDO protects tissues from injury after exposure to ionizing radiation and how IDO impacts host immunity to retroviral infections that increase the risk of leukemia. Collectively, these studies have broad implications for elucidating fundamental pathways that modulate immunity in chronic inflammatory syndromes and for their prevention and treatment (Curr Opin Oncol. 2014, 26:92-9).

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Nagendra Singh, PhD Assistant Professor

CN-1162

Epidemiological studies have shown a correlation between dietary fiber intake and decreased incidence of intestinal inflammation and colon cancers. In the colon, dietary fiber is fermented by gut bacteria into short-chain fatty acids (SCFA): butyrate, propionate, and acetate. Among SCFA, butyrate is known for its ability to suppress intestinal inflammation and carcinogenesis. Therefore, it has been hypothesized that dietary fiber suppresses colonic inflammation and cancers by providing substrate for butyrate production. This hypothesis is further supported by evidence showing a decrease in butyrate-producing gut bacteria in the colons of human patients with ulcerative colitis and colon cancers compared with those of healthy individuals. However, molecular mechanisms underlying the protective effect of butyrate-producing bacteria or dietary fiber/ butyrate in the suppression of colonic inflammation and colon cancer are poorly understood.

The Niacin receptor 1 (Niacr1), a G protein-coupled cell surface protein, is a receptor for both niacin and butyrate. The Singh group found that Gpr109a plays an essential role in butyrate-/niacin-mediated induction of the anti-inflammatory molecules interleukin-10 (IL-10) and aldehyde dehydrogenase 1a (Aldh1a) in colonic dendritic cells and macrophages, leading to the differentiation of regulatory T cells (Tregs), the most dominant immunosuppressive cells in the colon. Consequently, mice deficient in Gpr109a (Gpr109a-/-) are hypersusceptible to the development of colonic inflammation and carcinogenesis. The Niacr1 agonist niacin, a water-soluble vitamin, replaces the role of gut microbiota and dietary fiber in the suppression of colonic inflammation and colon cancers (Immunity. 2014, 40:128-39). Thus, Gpr109a connects dietary fiber and gut microbiota to the pathways that promote wound healing and the anti-inflammatory environment in the colon, leading to the maintenance of colonic health. The Singh laboratory’s findings suggest that niacin may be helpful in the prevention and/or treatment of ulcerative colitis and colon cancers.

In collaborative work, the Singh laboratory found that Gpr109a signaling plays an important role in other biological process relevant for the promotion of human health. Studies with Dr. Thangaraju (MOB Program) showed that deletion of Gpr109a in MMTV-Neu transgenic mice stimulates early onset of tumorigenesis and promotes lung metastasis (Cancer Res. 2014, 74:1166-78). Gpr109a ligand monomethylfumarate (MMF) induces expression of Îł-globin, and thus MMF has therapeutic potential for the treatment of sickle cell anemia (Invest Ophthalmol Vis Sci. 2014, 55:5382-93).

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Gang Zhou, PhD Associate Professor

CN-4140

The Zhou laboratory studies cancer therapy-induced inflammatory monocytes and tumor relapse. Tumor recurrence remains a major problem for cancer patients. With recent advances in immune-based therapeutic strategies, there is growing interest in synergistically combining immunotherapy with conventional chemotherapy to achieve durable antitumor effects. In some cases, chemotherapy-induced myeloid suppressor cells represent a critical obstacle to this goal. Dr. Zhou’s group reported that certain standard-of-care chemotherapeutic agents, including cyclophosphamide, melphalan, and doxorubicin can induce the expansion of immunosuppressive monocytic myeloid cells. The team showed that in a mouse model of B-cell lymphoma, selective depletion of CTX-MDSCs following chemo-immunotherapy significantly improved long-term survival, providing evidence that CTX-MDSCs contribute to tumor immune evasion and relapse (Cancer Res. 2014, 74; 3441-53). Based on these findings, Dr. Zhou’s laboratory proposed that the net impact of chemotherapy on tumor immunity is a dynamic balancing act between its two opposing immunomodulatory effects. Thus, targeting therapy-induced myeloid suppressor cells will allow a robust response to immunotherapies in the post-chemotherapy window, thereby tilting the balance toward a durable therapeutic outcome (OncoImmunology. 2014 3(8):e954471).

In collaboration with Dr. Yuqing Huo at the GRU Vascular Biology Center, the Zhou laboratory participated in the study of the influence of endothelial glycolysis on angiogenesis both in vitro and in vivo. Vascular cells, particularly endothelial cells, adopt aerobic glycolysis to generate energy to support cellular functions. The effect of endothelial glycolysis on angiogenesis remains unclear. 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) is a critical enzyme for endothelial glycolysis. The study found that blockade or deletion of endothelial PFKFB3 decreases angiogenesis both in vitro and in vivo. Thus, PFKFB3 is a promising target for the reduction of endothelial glycolysis and its related pathological angiogenesis. This finding has implications for cancer treatment because the Zhou lab showed that the combination of chemotherapy and PFKFB3 blockade had enhanced antitumor effect in mouse models (Arterioscler Thromb Vasc Biol. 2014, 34:1231-9).

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MOLECULAR ONCOLOGY AND BIOMARKERS (MOB) PROGRAM

Co-Leader // Dr. J.K. Cowell Co-Leader // Dr. N. Mivechi

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molecular oncology and biomarkers program //

OVERVIEW OF THE PROGRAM

The overall goals of this program are to understand the fundamental cellular and molecular processes that contribute to cancer development and progression. The research interests of the program can be divided into three broad themes: Genetics and Epigenetics od caner development and progression, Cell stress dn metasbolism and cancer cell metastasis. Collectively these themes address important topics of tumor cell and molecular biology: • 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; • The role of transcription factors in promoting cancer progression; • 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 oncogenes and glycoconjugates in cancer cell progression; • Genome-wide analysis of epigenetic changes in cancer development as a tool to ideintfiy biomarkers for prediction of progression and prognosis; • Analysis of heat shock chaperones and other stress proteins in cancer development and as targets for cancer therapies; • 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.

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Satyanarayana Ande, PhD Assistant Professor

CN-3150

The Ande laboratory focuses on studies related to liver cancer, cancer metabolism, obesity, and the molecular links between obesity and liver cancer. In one project, they identified that the transcriptional regulator inhibitor of DNA binding 1 (Id1) is strongly expressed in both brown and white adipose tissues, and it has a completely different function in adipose tissue metabolism compared to its other family members Id2, Id3 and Id4 (Front Biosci. 2014, 19:1386-97). Specifically, it was shown that Id1 has a predominant role in brown adipose tissue (BAT) and functions as a negative regulator of the PGC1Îą/UCP1 thermogenesis pathway, and thus negatively regulates BAT-mediated thermogenesis (J Cell Physiol. 2014, 229:1901-7). Deletion of Id1 in mice leads to increased energy expenditure due to increased thermogenesis in the BAT and increased lipolysis in white adipose tissue, and the mice are protected from age- and diet-induced obesity. To further investigate the role of Id1 in adipose tissue metabolism, the laboratory generated and is analyzing adipose-specific Id1 transgenic mice.

Studies from the Ande laboratory provide unique 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 an investigation of the role of Id1 in cancer metabolism. It was shown that Id1 is strongly expressed in liver tumors and in hepatoma cells and that it promotes both glycolysis and glutaminolysis by regulating c-Myc levels and AKT activity through the MAPK/ERK pathway in hepatoma cells. Knock-down of Id1 prevented cancer cell metabolic adaptation and caused cell death. These studies are being expanded into Id1 knock-out and transgenic mouse models with the goal of determining whether Id1 functions as a molecular target to inhibit liver tumor growth by blocking cancer cell metabolic reprogramming.

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Ahmed Chadli, PhD Associate Professor

CN-3151

Hsp90 inhibitors that are in clinical trials for cancer treatment have provided proof of principal that the Hsp90 machine is a valuable therapeutic target. However, current inhibitors induce overexpression of anti-apoptotic proteins such as Hsp70 and Hsp27, which may contribute to the modest outcomes observed in the clinic. Thus, novel modulators of this machine with different mechanisms of action are urgently needed. To fill this need, the Chadli laboratory has developed a high throughput screen (HTS) based on the progesterone (PR) receptor using Rabbit Reticulocyte Lysate (RRL) or the five purified chaperones required for folding steroid receptors, i.e., Hsp90, Hsp70, Hsp40, heat shock proteins organizing protein (Hop) and p23. 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. 2014, In Press).

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 an effort to understand the biology of the Hsp90 co-chaperone UNC45A, it was shown that this protein is required for cellular proliferation of cancer cell in vitro and for tumor growth in vivo through its ability to bind and regulate the ChK1 nuclear-cytoplasmic localization. Further studies revealed that UNC45A and ChK1 co-localize to the centrosome and UNC45A is essential for ChK1 tethering to the centrosome. These findings identify a novel centrosomal function for UNC45A and its role in cell proliferation and tumorigenesis (Cancer Lett. 2015, 357:114-20).

In collaboration with Dr. Marc Cox (University of Texas, El Paso), it was shown that the small glutamine-rich tetratricopeptide repeat protein α (sgtα) regulates androgen, progesterone, and glucocorticoid receptors by antagonizing the action of fkbp52 (J Biol Chem. 2014, 289:15297-308).

In collaboration with Dr. Ahmed Elmarakbi (GRU), it was shown that inhibition of the adenosine kinase protects the kidney against streptozotocininduced diabetes (Pharmacol Res. 2014, 85:45-54).

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Justin Choi, PhD Assistant Professor

CN-2152

The Choi laboratory has developed modules and pipelines to analyze GeneChip, RNA-seq, ChIP-seq, and BS-seq, which have been applied to various projects. In collaboration with Dr. Keith Robertson, the pipeline has performed epigenetic analysis in the human embryonic carcinoma cell line NCCIT using Infinium 450K microarray to show that (1) epigenome profiling after combination depletion identifies DNMT interactions, (2) DNMT3B regulates initiation of differentiation pathways, (3) DNMT1 and DNMT3B inversely co-regulate 5mC and 5hmC at conserved loci, (4) DNMT3B promotes non-CpG methylation, and (5) DNMT3L regulates CpG versus non-CpG choice (Cell Reports. 2014, 9:1554-1566). We have also studied the role of TET proteins in hydoxymethylation by analyzing MBD-seq of NCCIT. TET1 depletion yields widespread reduction of 5hmC, while depletion of TET2 and TET3 reduces 5hmC at a subset of TET1 targets, suggesting functional co-dependence. TET2 or TET3 depletion also causes increased 5hmC, suggesting these proteins play a major role in 5hmC removal. All TETs prevent hypermethylation throughout the genome, a finding dramatically illustrated in CpG island shores, where TET depletion results in prolific hypermethylation. Surprisingly, TETs also promote methylation, as hypomethylation was associated with 5hmC reduction (Genome Biology. 2014, 15:R81).

In collaboration with Dr. Han-Fei Ding, the pipeline has been used to analyze ChIP-seq and Affymetrix GenChip to reveal an essential role of MEIS2 in the development, organogenesis, and pathogenesis of human cancer. MEIS2 is highly expressed in human neuroblastoma cell lines and is required for neuroblastoma cell survival and proliferation. Depletion of MEIS2 in neuroblastoma cells leads to M-phase arrest and mitotic catastrophe, whereas ectopic expression of MEIS2 markedly enhances neuroblastoma cell proliferation, anchorage-independent growth, and tumorigenicity (Cell Death & Disease. 2014, 5: e1417).

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John K. Cowell, PhD, DSc, FRCPath GRU Cancer Center Associate Director for Basic Science Georgia Cancer Coalition Distinguished Cancer Scholar Professor and Co-leader, MOB Program CN-2133

Mingqiang Ren, PhD

Yong Teng, PhD

Assistant Professor

Assistant Professor

The Cowell laboratory has been studying the role of the WASF3 gene in the development of invasion and metastasis. Knockdown of WASF3 in breast cancer cells leads to suppression of invasion and metastasis. In a recent study (Oncogene. 2014, 33:203-211), it was demonstrated that WASF3 exerts its effect through down regulation of the KISS1 metastasis suppressor gene. KISS1 regulates IkB suppression of NFkB, keeping this transcription factor in the cytoplasm and hence suppressing genes that normally contribute to invasion and metastasis, such as MMP9 and IL6. By down-regulating KISS1, release of the inhibition of NFkB is achieved, which activates ZEB1, a transcription factor that is involved in the epithelialmesenchyme transition, partly by suppressing e-cadherin expression. In addition, ZEB1 suppresses members of the micro-RNA 200 family, which are themselves regulators of WASF3 message levels. As a result, WASF3 levels are increased even further promoting invasion. Since activation of WASF3 can be achieved by IL6 treatment through the activation of JAK2 (JAK-STAT. 2014 3:e28086), the involvement of NFkB signaling ensures high-level WASF3 expression through a feed-forward loop involving several different mechanisms. These studies lead to the potential of targeting WASF3 function through inactivation of the gene essential for its function, as a means to suppress invasion and metastasis.

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Quansheng Du, PhD Associate Professor

CA-2010

The Du laboratory is interested in the interaction between astral microtubules and the cell cortex, which has been proposed to be important for chromosome separation. A GÎą/LGN-independent lipid- and membrane-binding domain at the C terminus of NuMA was identified. It was shown that the membrane binding of NuMA is cell cycle-regulated: it is inhibited during prophase and metaphase by CDK1-mediated phosphorylation, and only occurs after anaphase onset when CDK1 activity is down-regulated. Further studies indicate that cell cycle-regulated membrane association of NuMA underlies anaphase-specific enhancement of cortical NuMA and cytoplasmic dynein. By replacing endogenous NuMA with a membrane-binding deficient NuMA, The Du laboratory can specifically reduce the cortical accumulation of NuMA and dynein during anaphase and demonstrated, for the first time, that cortical NuMA and dynein contribute to efficient chromosome separation in mammalian cells (Mol Biol Cell.

2014, 25:606-19).

The Du laboratory is also interested in cell polarization and epithelial morphogenesis. The establishment and maintenance of cell polarity is achieved through complex protein-protein interactions between polarity proteins. Detailed mechanisms underlying polarity complex formation were largely unknown. In collaboration with Dr. Mingjie Zhang of Hong Kong University of Science and Technology, the Du laboratory solved the crystal structures of the Dlg/Lgl and Crumbs3/PALS1 complexes (Cell Res. 2014, 24:451-63; Proc Natl Acad Sci U S A. 2014, 111:17444-9). A functional analysis in 2D- and 3D-cultured cells supports the structural and biochemical analyses. These studies provide mechanistic insight into the highly specific interactions between polarity proteins.

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Zhonglin Hao, MD, PhD Assistant Professor and Co-Leader, Thoracic Oncology Program CN-2132

The Hao laboratory has been studying YM155 in combination with other anti-neoplastic drugs in the treatment of lung cancer and other malignancies. YM155 was initially developed as a survivin suppressor. Despite multiple early phase clinical trials showing YM155 was welltolerated, the drug did not pass the efficacy test. Recent studies have shown synergy between YM155 and other antineoplastic drugs. However, the drug mechanism of action remained a lingering issue with conflicting evidence suggesting that YM155 does not suppress survivin. The current thought is that YM155 triggers apoptosis by counteracting survivin. In a screen for antineoplastic drugs that synergize with the cell cycle essential kinase Plk1 inhibitor volasertib, the Hao laboratory found that YM155 did so potently in multiple lung cancer cell lines. Further studies have defined YM155 as a DNA damaging agent (Am J Cancer Res. 2014, 4:135-147). YM155 triggers cell cycle arrest and checkpoint signaling and induces apoptosis in lung cancer cells. As a result, it delays cell cycle transition from G1 to S and G2 to M and back to G1 again. During treatment, DNA damage ensues with double strand breaks. YM155 causes survivin down-regulation at higher concentrations, but is thought to be secondary to the DNA damage response. Survivin knock down did not affect the extent of DNA damage. The transition of DNA from the supercoiled state to the relaxed state is impaired in the presence of YM155. Currently, the mechanism by which YM155 causes DNA damage is being investigated in detail.

The E3 ubiquitin ligase Skp2 attaches ubiquitin to its target proteins and marks them for destruction by the 26S proteasome. This mechanism participates in a number of important cellular processes such as cell proliferation, DNA replication, V(D)J recombination, gene transcription, cellular metabolism, and senescence. Skp2 is oncogenic and is overexpressed in various solid tumors and hematological malignancies. Due to the antagonistic role Skp2 plays against p27, its overexpression is frequently associated with p27 down-regulation. Importantly, Skp2 overexpression in cancer cells is prognostic of cancer progression and overall survival. Recent studies have shown promise that Skp2 suppression might be an excellent strategy to inhibit tumorigenesis in those tumors where tumor suppressor genes such as VHL, RB, or TP53 are mutated. In collaboration with Dr. Shuang Huang, the Hao laboratory recently discussed evidence that implicates Skp2 as an attractive target in cancer therapy and efforts in the development of Skp2 inhibitors. (Front Biosci. 2015, 20:474-90).

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Lesleyann Hawthorn, PhD Associate Professor and Director of Cancer Center Shared Resources CN-2135

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally with an accompanying low 5-year survival rate (~ 60%).

However, the early-stage disease is mostly asymptomatic; hence, approximately two-thirds of patients with CRC are diagnosed at a more advanced stage. One emerging modality of cancer risk stratification is via identification of “field carcinogenesis,” a “field” of epithelium that has been preconditioned by largely unknown processes so as to be predisposed towards development of cancer. Since then, the terms “field cancerization” and “field defect” have been used to describe pre-malignant tissue in which new cancers are more likely to arise. In the colon, this field of cancerization hypothesis is the rationale for colonoscopic post-polypectomy surveillance. Aside from the adenomatous polyp, there have been a number of putative biomarkers that occur earlier in the pre-dysplastic mucosa. These include gains, amplifications, losses, deletions, and translocations that are the hallmarks of chromosomal instability observed in most tumor types. Copy number alterations (CNAs) typically seen in colorectal tumors may occur in low-grade dysplastic adenomas and are therefore proposed as major factors in tumorigenesis.

The Hawthorn laboratory compared transcript expression, copy number, and loss of heterozygosity (LOH) profiles on a series of tumors and sites distal to the tumor to determine if there was evidence of field effect cancerization. In isolated tumor cells, chromosomal abnormalities were found that had been previously reported in colorectal cancer. Epithelial cells were isolated from regions surrounding the tumor ranging from 1 to 10 cm for each of 12 patients. The number and size of the chromosomal abnormalities were greatly reduced in these cells; however, many copy number and LOH events were discernable. Interestingly, these abnormalities were not consistent across the field in the same patient samples, suggesting a field of chromosomal instability surrounding the tumor (Genomics. 2014, 103:211–221). These findings have significant relevance to tumor recurrence following surgical resection of colon cancer, since the presence of genetic abnormalities in the apparently normal tissue could indicate the possibility of recurrence.

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Anatolij Horuzsko, MD, PhD Associate Professor

CN-3154

The Horuzsko laboratory has developed a new model for studying mechanisms, potential prevention of, and management of inflammationassociated cancer. They have identified that ablation of triggering receptor expressed on myeloid cell-1 (TREM-1), a potent amplifier of inflammation, protected mice from developing dyethylnitrosamine-induced hepatocellular carcinoma. They discovered that high mobility group box1 (HMGB1) is a TREM-1 ligand that plays a role in a novel mechanism in the establishment of chronic inflammatory responses leading to carcinogenesis.

In collaboration with Dr. L. Mulloy (GRU Department of Medicine), the Horuzsko laboratory has studied the role of HLA-G in the prolongation of kidney allograft survival. They demonstrated that a high level of HLA-G dimers in the plasma and increased expression of the membrane-bound form of HLA-G on monocytes are associated with prolonged human kidney allograft survival. They also demonstrated that the presence of soluble HLA-G dimers links to lower levels of proinflammatory cytokines, suggesting a potential role of HLA-G dimers in controlling the accompanying inflammatory state. (J Immunol Res. 2014, 2014:153981).

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Shuang Huang, PhD Professor and Interim Chair, Department of Biochemistry and Molecular Biology CN-2177

An ongoing research interest in the Huang laboratory addresses the molecular mechanisms critical for cancer invasion and metastasis. Epithelialmesenchymal transition (EMT) has long been recognized as a key event for cancer metastasis. In a functional study, the Huang laboratory recently demonstrated that the expression of SHOX2 and miR-375 show an inverse correlation in breast cancer cells. SHOX2 acts as a novel EMT inducer in breast cancer cells, while miR-375 is a potent EMT suppressor. Further studies demonstrate that SHOX2 promotes EMT by acting as a transcription factor of TGFβ-receptor I gene expression, whereas miR-375 blocks EMT traits by directly targeting SHOX2 mRNA (Neoplasia. 2014, 16:279-290).

In another project, Dr. Huang’s group has uncovered the molecular mechanism through which HOXC8 facilitates breast tumor tumorigenesis. They show that HOXC8 transcriptionally promotes the expression of CDH11 in breast cancer cells and that HOXC8 regulation of breast tumorigenesis is CDH11-dependent. Analysis of a clinical dataset indicates that expression of HOXC8 and CDH11 is highly correlated in breast tumor specimens, and higher expression of both genes is associated with poor patient survival. Because CDH11 is a cell surface protein and represents an ideal therapeutic target, this study suggests that an effective anti-breast tumor modality could be developed by targeting the HOXC8-CDH11 axis (Oncotarget. 2014, 6: 2596-2607).

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Ravindra Kolhe, MBBS, PhD Clinical Assistant Professor

BAE-2575

In collaboration with Dr. DeRemer, the Kolhe laboratory is investigating obesity-associated epigenetic changes in AML patients. Genome-wide methylation (GWM) profiles of over 450,000 CpGs were analyzed using the Illumina Infinium Human Methylation 450K Beadchip (Infinium®) in cytogenetically normal AML patients (negative CKIT, CEPBA, and FLT-3, NPM1 mutation) who were to receive induction chemotherapy (anthracycline + cytarabine) (n=18). Patients were characterized by obesity status (obese, BMI ≥ 30 kg/m2) and drug response (complete remission, ≤ 5% blasts at day +14 bone marrow biopsy). A distinct hypermethylated epigenome was identified in obese AML patients who did not achieve a complete remission. These findings demonstrated that there is distinct differential methylation in obese patients who are responders versus nonresponders. This differential methylation is focused on negative regulation of an immune response including genes such as PRKCZ, KCNQ1DN, BANP, PLEKHG4B, and LYPD1. (Pharmacotherapy. 2014, 34(10):E297-E298).

Using microarray technology, the Kolhe laboratory has developed a more sensitive testing approach for cytogenetically normal AML patients. A large percentage of patients with the 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. Of AML/MDS cases analyzed, 22 were identified that had a normal karyotype. Subsequently, high-resolution SNP microarray using the CytoScanHD Microarray platform (Affymetrix, Inc.) was used to study 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 percent of cases had a gain/loss and/or mosaicism. Interestingly, all AML cases showed ROH in chromosome regions 1p34.3, 1p32.3, and 16q22.1. (Cytogenet Genome Res. 2014, 142:226-256. Doi: 10.1159/000360710).

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Hasan Korkaya, DVM, PhD Assistant Professor

CN-2136

Metastatic breast cancer is the second leading cause of cancer-related death among women in the United States. Patients with the basal-like triple negative breast cancer (TNBC) often exhibit an aggressive/metastatic disease with limited treatment options. Thus there is an urgent unmet need to develop molecularly targeted therapeutics for this patient population. Utilizing human cell lines, primary patient xenografts, and murine tumors in syngeneic mouse models, Dr. Korkaya’s laboratory aims to understand the role of the inflammation-mediated epithelial mesenchymal transition (EMT)/cancer stem cell (CSC) phenotype in the metastatic process.

The CSC hypothesis proposes that cancers are driven by a component of tumor-initiating cells that mediate metastasis, recurrence, and treatment resistance. Moreover, it has been well established that EMT induces the CSC phenotype. Dr. Korkaya’s team and others have provided evidence that activation of inflammatory cytokines in tumors is associated with an aggressive EMT/CSC phenotype (Oncogene. 2014, 34:671-80). The development of CSC-specific therapeutics in recent years underlines the clinical relevance of the CSC model in the treatment of patients. The CSC model fundamentally differs from the traditional model of carcinogenesis in which any cell may become transformed and all cells within a tumor have equal malignant potential. The CSC model suggests that tumor-initiating cells comprise only a small fraction of tumor cells and thus alterations in this population may not be reflected by changes in tumor volume. While the existence of CSCs in multiple human tumors has been firmly established, the functional and clinical significance of these cells is under ongoing investigation. The development of biomarkers to identify CSCs, as well as validation of in vitro and mouse models, has facilitated the isolation and characterization of these cells from both murine and human tumors. Dr. Korkaya’s work has provided a better understanding of the role of CSCs in trastuzumab resistance in HER2+ breast cancer.

His team recently demonstrated that activation of inflammatory cytokines in basal/triple negative tumors is due to loss of the suppressor of cytokine signaling 3 (SOCS3), and that is associated with induction of EMT/CSC phenotype.

Developmental pathways such as Notch play a pivotal role in tissue-specific stem cell self-renewal, as well as in tumor development. Utilizing the Notch reporter system, the Korkaya laboratory recently demonstrated that Notch signaling plays an important role in breast cancer stem cell selfrenewal and provides a strong rational for its therapeutic utility in breast cancer patients (Mol Cancer Ther. 2015, 14:779-87).

Although there is a wealth of current information describing the genetic and epigenetic differences between metastatic versus non-metastatic tumors, a knowledge gap exists in the understanding of early events between tumor and immune system. Dr. Korkaya’s long-term goal is to dissect the early molecular crosstalk between malignant cells and the immune system in the metastatic process and identify therapeutic targets. It is hypothesized that tumor-secreted inflammatory cytokines induce systemic expansion of myeloid progenitor cells that facilitate metastasis. The Korkaya group now provides evidence that basal/TNBCs with activated inflammatory feedback loops may convert anti-tumor immune responses into cancer-promoting inflammation. Cytokines control immune responses by controlling the Jak/Stat3/NF-kB pathway, which is negatively regulated by SOCS3 (Oncogene. 2014, 34:671-80). These ongoing studies identify that SOCS3 plays a critical role by negatively regulating the inflammatory cytokines in tumors as well as mediating the anti-tumor immune responses.

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Nahid F. Mivechi, PhD Professor and Co-leader, MOB Program

CN-3153

The Mivechi laboratory studies the function of mammalian heat shock transcription factor 1 (Hsf1) in vitro and in vivo. Hsf1 activation promotes growth of premalignant cells and HCC development by stimulating lipid biosynthesis and perpetuating chronic hepatic metabolic disease induced by carcinogens. Inactivation of Hsf1 impairs cancer progression, mitigating adverse effects of carcinogens on hepatic metabolism by enhancing insulin sensitivity and sensitizing activation of AMPK, an important regulator of energy homeostasis and inhibitor of lipid synthesis. Therefore, Hsf1 is a potential target for the control of hepatic steatosis, insulin resistance, and HCC development. In continuing efforts to examine the function of Hsf1 in reducing cancer and altering metabolism, a tissue-specific knockout of the Hsf1 gene has been generated in mice. These mice exhibit a significantly lower level of glucose production both using hepatocyte cultures and in vivo, and the underlying mechanisms is Hsf1 regulation of mitochondrial biogenesis. Additionally, specific deletion of Hsf1 from white and brown adipose tissues almost entirely regenerates the phenotype of Hsf1-/- mice (such as their resistance to obesity). Further deletion of Hsf1 specifically from hepatocytes leads to significant reduction in liver tumorigenesis, and these mice exhibit glucose hypersensitivity and reduced levels of gluconeogenesis. Removal of Hsf1 from an already established liver cancer leads to tumor regression in a mouse model where Hsf1 is under the control of a tamoxifen-induced albumin Cre promoter.

Although Hsf1 inhibition has been shown to delay tumorigenesis, the impact of Hsf1 on progression of breast cancer has remained elusive. In a recent study the Mivechi laboratory demonstrated that deletion of Hsf1 in mice overexpressing ErbB2/Neu significantly reduces mammary tumorigenesis and metastasis. Hsf1+/-ErbB2/Neu+ tumors exhibit reduced cellular proliferative and invasive properties associated with reduced activated ERK1/2 and reduced epithelial-mesenchymal transition (EMT).

Hsbp1 represses Hsf1 activity and to investigate the function of this 70 amino acid peptide in the regulation of Hsf1 activity in vivo, the Mivechi laboratory generated mice with targeted disruption of the Hsbp1 gene and also examined zebrafish embryos treated with Hsbp1-specific morpholino oligonucleotides (Developmental Biology. 2014, 386(2):448-60). This study showed that Hsbp1 is critical for the preimplantation stage of embryonic development. Meanwhile since the full in vivo function of Hsbp1 in adult tissue (s) could not be revealed using the conventional Hsbp1 mouse line, a conditional mutant mouse has been generated using the Cre LoxP system.

In related studies a protective function of heat shock proteins Hsp110 and Hsp70 following traumatic brain injury was described (J Neurochemistry.

2014, 130:626-641).

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Dimitrios Moskofidis, MD, PhD; aka Demetrius Moskophidis, MD, PhD Professor CN-3143

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 – including the major members of HSP70 and HSP90 in the endoplasmic reticulum (GRP78, GRP170, SIL1, GRP94), cytoplasm (HSP70, HSC70, HSP25), and mitochondrion (GRP75) – provides important materials for innovative research in the cancer biology field. Recently, studies on the functional characterization in situ of the stress-induced HSP70 and HSP25 chaperone proteins were reported (Dev Biol. 2014, 386:448-60; J Neurochem.

2014, 130:626-41) in collaboration with Dr. Mivechi.

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Amyn M. Rojiani, MD, PhD

Mumtaz V. Rojiani, PhD

Professor and Department Chair, Pathology Pund Distinguished Chair in Pathology CN-3111

Associate Professor

CN-3112

The Rojiani laboratory focuses on the role of the tumor microenvironment in brain metastasis. This includes the role of matrix metalloproteinases and their natural endogenous inhibitors TIMPs. In recent years TIMPs have emerged as truly multifunctional proteins with MMP-independent roles in tumor growth apoptosis, angiogenesis, invasion and metastasis. The lab’s major interest lies in understanding this multifaceted and sometimes paradoxical role of TIMP-1 in apoptosis, angiogenesis and tumor growth. TIMP-1 has been shown to be an important prognostic marker associated with poor prognosis for a number of cancers.

Further studies have examined angiogenesis at the edge of lung carcinoma metastasis to the brain, correlating it with the expression of MMP2.

Using a lung adenocarcinoma cell line the effects of TIMP-1 on tumor growth have been examined in animal studies and in vitro. TIMP-1 overexpressing cells resulted in highly aggressive, more vascularized tumors in nude mice, with increased angiogenesis, anchorage independent growth and invasiveness in vitro. The anti-apoptotic functions of TIMP-1 have also been examined. Currently, we are focusing on the downstream effects of TIMP-1 overexpression, seeking to define molecules including miRNA that interact with or affects and the signaling pathways that are induced in apoptosis and angiogenesis following TIMP-1 over-expression.

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Huidong Shi, PhD Georgia Cancer Coalition Distinguished Cancer Scholar Associate Professor CN-2138

The Shi laboratory has identified novel epigenetic biomarkers for the prediction of gastric carcinoma metastasis in an international collaboration involving researchers from four different countries. Metastasis is the leading cause of death for gastric carcinoma. An epigenetic biomarker panel for predicting gastric carcinoma metastasis could have significant clinical impact on the care of patients with gastric carcinoma. Based on results from genome-wide DNA methylation analysis between metastatic and nonmetastatic gastric carcinomas and their surgical margins (SM), the Shi laboratory has identified 73 candidate genes that were differentially methylated between metastatic and nonmetastatic gastric carcinomas. The predictive values of potential metastasis-specific DNA methylation biomarkers were validated in cohorts of patients with gastric carcinoma in China (n=330), Japan (n=129), and Korea (n=153). Significant differential methylation was validated in the CpG islands of 15 genes. These genes included BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Methylation changes of GFRA1, SRF, and ZNF382 resulted in up- or down-regulation of their transcription. Most importantly, the prevalence of GFRA1, SRF, and ZNF382 methylation alterations was consistently and coordinately associated with gastric carcinoma metastasis and the patients’ overall survival throughout discovery and validation cohorts in China, Japan, and Korea. The study’s results indicate that GFRA1, SRF, and ZNF382 may be a potential biomarker set for the prediction of gastric carcinoma metastasis. This is the first epigenetic study of this scale that focuses on metastasis in gastric cancer (Clin Cancer Res. 2014, 20:4598-612).

In another study, the Shi laboratory performed an in depth analysis of the DNA methylation landscape in glioblastoma (GBM)-derived cancer stem cells (GSCs). GBM is the most common and most aggressive brain tumor in adults. Its frequent recurrence after resection and dismal prognosis are thought to be due to a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy. To understand how epigenetics controls the molecular phenotype of GSCs, the Shi laboratory compared the genome-wide DNA methylation profiles between primary GBM tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue).

Interestingly, they identified two 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. Single base resolution analysis of these hyper- and hypo-methylated genes revealed clonal CpG methylation patterns, suggesting that these candidate genes may be epigenetic signatures of the GSC populations. Intriguingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1, and PTPRN2 in GSCs, but not in matched primary GBMs. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors, suggesting that they were not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes such as SPINT2, NEFM, and PENK that are frequently down regulated in GBMs. Forced re-expression of SPINT2 in the GBM cell line U87G reduced proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of gliomas.

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Paul M. Weinberger, MD, FACS Assistant Professor

BP-4109

The Weinberger laboratory focuses on both basic- and translational- research projects that center around new treatment options for anaplastic thyroid carcinoma (ATC) and airway reconstruction. These two themes are closely linked, since ATC almost always invades the trachea (windpipe).

While currently there are no proven treatments for these patients, as novel ATC therapies are developed it will also be necessary to have ways to rebuild these patient’s damaged airways. Many of these patients have complex ethical issues associated with their care, which the Weinberger team has helped the scientific and clinical community explore (Laryngoscope. 2014, 124:1663-7).

As part of long-standing collaboration with the NCI’s flagship Cancer Genome Atlas (TCGA) project, they have been able to support large-cohort genomic studies unraveling the changes that lead to several different cancer types, including head and neck squamous cell (Proc Natl Acad Sci. 2014, 111:15544-9), urothelial bladder carcinoma (Nature. 2014 507:315-322), and more closely linked to the Weinberger lab’s own research efforts, papillary thyroid carcinoma (Cell. 2014, 159:676-90).

The Weinberger laboratory has been developing expertise in a challenging but useful orthotopic xenograft animal model for ATC. Leveraging collaborations with both Moffitt Cancer Center (Tampa, FL) and Mayo Clinic – Jacksonville (FL), the Weinberger laboratory has recently uncovered a novel potential driver in a subset of fast-growing and aggressive ATC patients. This oncogene, when inhibited by RNA-interference “knockdown”, results in near-total growth arrest of ATC cells. ATC cell lines with high levels of this protein demonstrate rapid tumor formation, local invasion, lung metastases and death in the orthotopic xenograft model, while ATC cell lines with low levels of the protein do not. These studies may eventually lead to a novel therapy for ATC.

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Daqing Wu, PhD Associate Professor

CN-2153

Prostate cancer is a leading cause of cancer-related death in the United States and the State of Georgia. In 2014, 233,000 new cases will be diagnosed and 29,480 patients will die, mostly from metastatic castration-resistant disease (mCRPC). The Wu laboratory has been developing novel therapeutic strategies with small-molecule drugs and natural compounds. Recently (Prostate. 2014, 74:497-508), POMx, a pomegranate extraclyt preparation (POM Wonderful LLC), was shown to exhibit potent in vivo toxicity in mCRPC cells. They identified survivin as a novel molecular target that may mediate the anti-cancer activity of POMx, presumably through a Stat3-dependent signaling pathway. The in vivo administration of POMx treatment effectively inhibited survivin, induced apoptosis, retarded C4-2 tumor growth in mouse bone, and significantly enhanced the efficacy of docetaxel, the first-line chemotherapy for mCRPC. These findings provide a rationale to evaluate pomegranate extracts in improving clinical outcomes in patients with mCRPC and receiving standard chemotherapy.

The Wu laboratory further developed a pomegranate-derived formulation (ProFine) consisting of naturally-occurring flavonoids, and evaluated its in vitro and in vivo efficacy in targeting mCRPC in pre-clinical models. A major mechanism of action of ProFine was shown to involve dual-inhibition of AKT and androgen receptor signaling. An oil-based formulation of ProFine has now been developed that will be tested as a nutraceutical to enhance the efficacy of androgen-deprivation therapy.

The Wu laboratory also established a cell-based drug screening system that can be used to discover new anti-cancer compounds for therapeuticresistant cancer. In collaboration with University of Colorado, LG1980, an aminobisphosphonate-derived compound, was developed as a smallmolecule lead compound that selectively induces apoptosis in prostate cancer stem cells. In collaboration with the Emory University Chemical Biology Discovery Center, a pilot screening of ~3,200 compounds was performed. With a hit rate of ~2.8%, 36 compounds/drugs were identified as potential inhibitors of prostate cancer stem cells that can be tested in pre-clinical models. These findings validated the application of their novel screening platform in cancer drug discovery and provided lead candidates for further pre-clinical and clinical development.

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Chunhong Yan, PhD Associate Professor

CN-2134

The Yan laboratory studies transcription programs in cancer initiation and progression. One of their major research areas involves the transcription factor ATF3, which is frequently aberrantly expressed in a wide range of human cancers. While ATF3 has been demonstrated to be a critical p53 activator in the DNA damage response, the role of ATF3 in cancer remains largely unknown. Emerging evidence suggests that it is likely that ATF3 regulates tumor growth and cancer progression in a context-dependent manner. In a recent report, Dr. Yan and colleagues discovered that down-regulation of ATF3 expression is a reliable diagnostic marker for metastasis of lung cancers harboring p53 mutations (J Biol Chem. 2014, 289(13):8947-59). Occurring in the majority of lung cancers, p53 mutations not only diminish normal p53 tumor suppressor function but also confer new oncogenic functions, including promoting drug resistance, cancer cell invasion and metastasis. Consistent with the observations that ATF3 expression is lower in p53-mutated cancer, the Yan laboratory demonstrated that ATF3 directly binds mutant p53 proteins, and subsequently counteracts drug resistance and suppresses cell migration and invasion driven by the mutant p53 proteins. Mutant p53 proteins mainly exert their oncogenic activities through interacting with the p53 family member p63, which in turn regulates expression of pro-migratory and pro-invasive genes. Not surprisingly, ATF3 prevents mutant p53 proteins from interacting with p63 and therefore counteracts the oncogenic activity of mutant p53. These findings shed light on the understanding of mechanisms by which the gain-of-function of mutant p53 is regulated in cancer and indicate the potential of ATF3-targeted therapeutic strategy in treating p53-mutated lung cancer.

The Yan laboratory is also interested in developing novel cancer therapeutic agents targeting various oncogenic pathways, including pathways that involve Hsp90, HIF-1, eIF4E, Skp2, and the androgen receptor. In a recent study (PLoS One. 2014, 9: e99584), the Yan laboratory and their collaborators in the Chinese Academy of Medical Sciences employed a reporter gene-based drug-screening platform to identify therapeutic agents targeting hypoxia-inducible factor 1 (HIF-1). As the master regulator of the cellular hypoxia response, HIF-1 activity is crucial for cancer cells to adapt to hypoxic environments for sustaining growth and survival. The researchers identified a synthetic manassantin-A derivative that can inhibit HIF-1 nuclear accumulation induced by hypoxia and inhibit the growth of a wide range of cancer cells as a consequence of cell cycle arrest. They further demonstrated that oral administration of this novel HIF-1 inhibitor can inhibit growth of breast, lung, and pancreatic tumors implanted in nude mice. These results warrant further development of this novel HIF-1 inhibitor into a new class of anti-cancer drugs.

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TUMOR SIGNALING AND ANGIOGENESIS (TSA) PROGRAM

Co-Leader // Dr. V. Ganapathy

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tumor signaling and angiogenesis program //

OVERVIEW OF THE PROGRAM

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: • A variety of kinase targets involved in cancer cell proliferation and progression; • The basic undelying 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 regualtors of apoptosis.

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.

The GRU medical school has a strong history in the basic underlying mechanisms of vascular biology, which is an important aspect of neovascularization in developing tumors. To complement this expertise, the GRU Cancer Center is in the process of developing a tumor microenvironment theme within the signaling program with one emphasis on angiogenesis. This will build on the expertise in the basic biology of the vascular biology group to devise ways of understanding the mechanisms of tumor vascularization and how this is affected by the microenvironment and how novel targets for intervention can be designed and used as anti-cancer therapies. In this area, the biology of tumor angiogenesis in gliomas is a special focus, particularly as it relates to hypoxia, with a view to targeting critical molecules essential for endothelial cell function in animal models. Tumor neovascularization in these models is visualized in vivo using imaging approaches such as MRI and SPECT.

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Ali Arbab, MD, PhD Professor CN-3141

Dr. Arbab’s laboratory is involved in identifying the cause of failure of antiangiogenic treatments in glioblastoma (GBM) and other cancers. Dr. Arbab uses magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and optical imaging to determine the effect of different treatments on the vascular parameters in tumors determined by MRI, expression of pro-angiogenic and pro-growth factors determined by SPECT and protein array, and migration of bone marrow progenitor cells (BMPC) by optical imaging. Different antiangiogenic agents (such as vatalanib, sunitinib and CXCR4 antagonist) were used in an orthotopic GBM model in rats and, MRI and in vitro analysis were performed.

DCE-MRI showed a significant increase in tumor size after vatalanib treatment. The AMD3100-treated group showed a significant decrease in a number of vascular parameters determined by DCE-MRI. AMD3100 significantly decreased the expression of different angiogenic factors compared to sunitinib or vatalanib; however, there were no significant changes in vascular density among the groups. Sunitinib-treated animals showed significantly higher migration of invasive cells, whereas in both vatalanib- and AMD3100-treated animals, the invasive cell migration distance was significantly lower compared to that of control. Vatalanib and sunitinib resulted in suboptimal therapeutic effects, but AMD3100 treatment resulted in a significant reduction in tumor growth, permeability, interstitial space volume, and invasion of tumor cells in an animal model of GBM (Transl Oncol. 2013, 6:660–9). These antiangiogenic agents as well as other receptor tyrosine kinase inhibitors were used in a chimeric mouse model of human GBM, and there was significantly increased mobilization of BMPC to the tumors and indication of drug resistance due to Bone Marrow Derived Myeloid Cells. In collaboration with Dr. James Ewing of the Henry Ford Health System, DCE-MRI parameters have been optimized in a rat model of GBM using two different MRI contrast agents (J Magn Reson Imaging. 2014, 40:1223-9).

Dr. Arbab is also working with a newer drug, HET0016, which is an inhibitor of 20-HETE synthase and blocks proliferation and migration of endothelial progenitor cells. In collaboration with a group in Faculty of Medicine of São José do Rio Preto FAMERP, Brazil, HET0016 has been shown to have an effect on triple negative breast cancer, although resistance to treatment was observed after 21 days (PLoS One. 2014, 9:e116247).

In collaboration with a group in New Medical College, Valhalla, NY, it was shown that EPC increased angiogenesis in vivo by ~3.6 fold using the Matrigel plug angiogenesis assay, and these increases were markedly reduced by the local inhibition of 20-HETE system. These results strengthened the notion that 20-HETE regulates the angiogenic functions of EPC in vitro and EPC-mediated angiogenesis in vivo (J Pharmacol Exp Ther. 2014, 348:442-51.) When HET0016 was administered intraperitoneally, the effect on GBM was not significant, although many pro-angiogenic factors were altered in the tumor and in the serum. An intravenous formulation has been prepared and the inhibitory effect on tumor growth is dramatic.

Radiation therapy is one of the main treatment strategies for GBM. However, recurrence occurs, and it is shown that sub-curative radiation is in fact detrimental. Dr. Arbab, in collaboration with Dr. Sanath Kumar (Henry Ford Hospital), created a model of sub-curative radiation therapy in glioma stem cell derived GBM, and showed that sub-curative radiation significantly increased proliferation, invasion, and migration of primary GBM cells.

The study provides insights into possible mechanisms of treatment resistance following radiation therapy for GBM (Chin J Cancer. 2014, 33:148-58).

In collaboration with a group in Faculty of Medicine of São José do Rio Preto FAMERP, Brazil, Dr. Arbab showed the effect of melatonin on triple negative breast cancers and showed that both melatonin and curcumin can inhibit pro-angiogenic factors in breast cancer and inhibit angiogenesis.

Inhibition of angiogenesis was detected by SPECT studies (PLoS One. 2014, 9:e85311, Eur J Cancer. 2014, 50:169-70). In collaboration with Dr. Gautam in Henry Ford Hospital, it was shown that the medicinal plant product pristimerin can be anti-proliferative and an apoptosis inducing agent in ovarian cancer (J Exp Ther Oncol. 2014, 10:275-83).

Finally, Dr. Arbab’s group is actively involved in stem cell-based therapeutic projects and in exploiting umbilical cord-derived progenitor cells, especially endothelial progenitor cells (EPCs) in brain injury, stroke, and arthritis models. In collaboration with different groups in USA and India, it is shown that stem cells can be used as both therapeutic and imaging probes (Arthritis Res Ther. 2014, 16:R68; J Stem Cell Res Ther. 2014, 4:202; Nucl Med Biol. 2014, 41:744-8). // 55

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Erhard Bieberich, PhD

Guanghu Wang, PhD

Professor

Assistant Professor

CA-4012

CA-4054A

The Bieberich laboratory, in conjunction with Dr. Guanghu Wang, is interested in the function of lipids, in particular sphingolipids and bile acids, for cell signaling in cancer cells. Dr. Bieberich’s research focus is on the design of lipid-based drug regimens that utilize the sphingolipid ceramide and its interaction with bile acid metabolism for the induction of apoptosis in breast cancer cells. Dr. Wang’s research interest is in the function of sphingosine-1-phosphate (S1P), a ceramide derivative, for tumor progression of non-small cell lung cancer.

Research in the Bieberich laboratory is based on the original discovery that secondary bile acids, cholesterol derivatives synthesized by intestinal bacteria and taken up into the blood stream, induce migration and promote survival of breast cancer stem-like cells. The Bieberich laboratory has found that this pro-survival effect is caused by reducing ceramide levels in cancer stem-like cells. It was shown that secondary bile acids are enriched in bone tissue, suggesting that there is a novel “gut-to-bone” connection that is involved in the induction of breast cancer cell migration and metastasis to the bone. The Bieberich laboratory is now investigating the mechanism by which bile acids reduce ceramide and how this can be reversed to elevate ceramide and kill cancer (stem) cells. New data suggests that antagonists of the nuclear bile acid receptor such as the plant sterol guggulsterone are important drugs to achieve this goal. Currently, the Bieberich laboratory is testing various combinations of ceramideelevating drugs for the treatment of breast cancer. In addition, Dr. Bieberich is involved in several collaborative projects with Drs. Liu and Schoenlein to utilize ceramide-induced apoptosis for treatment of other cancers (BMC Cancer. 2014, 14:24).

Dr. Wang’s research is based on the original discovery that down-regulation of the S1P transporter, Spns2, increases migration of non-small lung cancer cells, most likely due to elevation of intracellular S1P expression. Consistent with this observation, new data show that Spns2 expression is reduced in lung cancer patients. Dr. Wang’s research identifies down-regulation of Spns2 as a potential risk factor for lung cancer as well as a potential drug target (PLOS One. 2014,9:e110119).

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Wendy B. Bollag, PhD, FAHA Professor

CA-1008

The Bollag laboratory has been examining the roles of two signaling pathways that regulate keratinocyte growth and differentiation and which are abnormal in non-melanoma skin cancer. PKD (or PKD1) is a serine/threonine protein kinase that plays a role in a variety of cellular processes, although its function in the skin has not been fully investigated. The balance between proliferation and differentiation processes in keratinocytes, the predominant cells of the epidermis, is essential for normal skin function. To investigate the effect of PKD1 deficiency on the proliferation and differentiation of epidermal keratinocytes, a floxed PKD1 mouse model was used to demonstrate a significant decrease in PKD1 mRNA and protein levels following Cre recombinase expression in keratinocytes (J Dermatol Sci. 2014, 76:186-195). Deficiency of PKD1 resulted in significantly increased expression of differentiation markers such as loricrin, involucrin, and keratin 10, either basally and/or upon stimulation of differentiation.

PKD1-deficient keratinocytes also showed an increase in transglutaminase expression and activity, indicating an anti-differentiative role of PKD1.

Furthermore, the PKD1-deficient keratinocytes exhibited decreased proliferation. However, PKD1 loss had no effect on stem cell marker expression.

In another project, the role of the phospholipase D2/aquaporin-3 (AQP3) in regulating keratinocyte growth and differentiation was investigated.

AQP3 is an integral membrane water and glycerol channel expressed in epidermal keratinocytes. Despite many studies, controversy remains about the role of AQP3 in keratinocyte differentiation. Previously, the Bollag laboratory showed co-localization of AQP3 and phospholipase D2 (PLD2) in caveolin-rich membrane microdomains, suggesting that AQP3 increases glycerol transport and “funnels” this primary alcohol to PLD2 to form a pro-differentiative signal, such that the action of AQP3 to induce differentiation should require PLD2. Re-expression of PLD2 in AQP3-null mouse keratinocytes led to increased [3H]glycerol uptake, and induction of epidermal differentiation markers such as keratin 1, keratin 10 and loricrin (J Invest Dermatol. 2015, 135:499-507). Re-expression of AQP3 had no effect on the expression of proliferation markers such as keratin 5 and cyclin D1. Furthermore, a selective inhibitor of PLD2, CAY10594, and a lipase-dead PLD2 mutant significantly inhibited AQP3 re-expression-induced differentiation marker expression with calcium elevation, suggesting a role for PLD2 in this process. Thus, AQP3 appears to have a pro-differentiative role in epidermal keratinocytes, and PLD2 activity is necessary for this effect. This dependence on PLD2 is likely related to the formation of phosphatidylglycerol (PG), which can inhibit the proliferation and promote the differentiation of rapidly dividing keratinocytes, and stimulate the growth of slowly proliferating epidermal cells. To determine the species of PG most effective at modulating keratinocyte proliferation, primary mouse keratinocytes were treated with different PG species, and proliferation was measured. PG species containing polyunsaturated fatty acids were effective at inhibiting rapidly proliferating keratinocytes, whereas PG species with monounsaturated fatty acids were effective at promoting proliferation in slowly dividing cells. Thus, palmitoyl-arachidonyl-PG (16:0/20:4), palmitoyl-linoleoyl-PG (16:0/18:2), dilinoleoyl-PG (18:2/18:2), and soy PG (a PG mixture with a large percentage of polyunsaturated fatty acids) were particularly effective at inhibiting proliferation in rapidly dividing keratinocytes. Conversely, palmitoyl-oleoyl-PG (16:0/18:1) and dioleoyl-PG (18:1/18:1) were especially effective proproliferative PG species (PLoS One. 2014, 9:e107119). Thus, different PG species may be useful for treating skin diseases characterized by excessive or insufficient proliferation.

In another project, the Bollag laboratory examined the effect of the antipsoriatic agent monomethylfumarate (MMF), used to treat hyperproliferative skin disorders, on keratinocyte growth and differentiation (J Pharm Exp Ther. 2015, 352:90-97). MMF significantly increased the protein levels of the early keratinocyte differentiation marker, keratin 10, as well as transglutaminase activity, a late differentiation marker. These results are consistent with an ability of MMF to promote keratinocyte differentiation and inhibit proliferation, thereby improving psoriatic lesions. In 12-O-tetradecanoylphorbol-13-acetate (TPA)-activated keratinocytes, MMF significantly inhibited the mRNA expression of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα), interleukin-6, and interleukin-1α, as well as the protein production of TNFα. Since inflammation in often associated with cancer development, this result suggests the possible utility of MMF in the treatment or prevention of cancer.

The Bollag laboratory also has other ongoing independent and collaborative projects, which resulted in publications in 2014. Thus, Dr. Bollag published a collaborative article on mitochondrial fusion in prostate cancer with Dr. Vijay Kumar (Int J Oncol. 2014, 44:1767-1773), as well as articles examining mesenchymal stem cell and osteoclast biology with Dr. Carlos Isales (PLoS One. 2014, 9:e91108 and Calcif Tissue Int. 2014, 95:174-182).

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Darren D. Browning, PhD Associate Professor

CN-1164

The Browning laboratory seeks to exploit cGMP signaling in the colon mucosa for the treatment of inflammatory bowel disease and the prevention of colon cancer.

Type 2 cGMP-dependent protein kinase was shown to regulate homeostasis by blocking c-Jun N-terminal kinase in the colon epithelium (Cell Death Differ. 2014, 21:427-437). This work describes the first evidence to directly demonstrate that activation of cGMP signaling in the colon epithelium of normal (wild-type) mice is barrier-protective. More importantly, they showed that clinically available erectile dysfunction drugs are able to activate this pathway and could block experimental colitis in mice. The mechanism was shown to involve PKG2-dependent inhibition of stress signaling through the JNK pathway. Using VIAGRA速 (sildenafil citrate) in mice, the laboratory continues to build upon previous finding that cGMP/PKG2 activation by erectile dysfunction drugs can protect the lining of the colon from damage. They have demonstrated that cGMP/PKG2 can activate the tumor-suppressor protein FoxO3a. This transcription factor activates protective antioxidant gene expression, and it was shown that cGMP signaling protects the colon epithelium from oxidative damage.

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Han-Fei Ding, PhD Georgia Cancer Coalition Distinguished Cancer Scholar Professor CN-2134

The Ding laboratory investigates molecular mechanisms underlying cancer cell proliferation, survival, and differentiation, with the focus on neuroblastoma, a common pediatric cancer of the sympathetic nervous system.

MEIS2 has an important role in development and organogenesis and is implicated in the pathogenesis of human cancer. The molecular basis of MEIS2 action in tumorigenesis is not clear. In a recently published study (Cell Death Dis. 2014, 5:e1417), the Ding laboratory reports that MEIS2 is highly expressed in human neuroblastoma cell lines and is required for neuroblastoma cell survival and proliferation. Depletion of MEIS2 in neuroblastoma cells leads to M phase arrest and mitotic catastrophe, whereas ectopic expression of MEIS2 markedly enhances neuroblastoma cell proliferation, anchorage-independent growth, and tumorigenicity. Gene expression profiling reveals an essential role of MEIS2 in maintaining the expression of a large number of late cell cycle genes, including those required for DNA replication, G2-M checkpoint control, and M phase progression. Moreover, the study shows that MEIS2 is a transcription activator of the MuvB-BMYB-FOXM1 complex that functions as a master regulator of cell cycle gene expression. These findings link a developmentally important gene to the control of cell proliferation and suggest that high MEIS2 expression is a molecular mechanism for high expression of mitotic genes that is frequently observed in cancers of poor prognosis.

Induction of differentiation is a therapeutic strategy in neuroblastoma. The homeobox protein HOXC9 is a key regulator of neuroblastoma differentiation. The Ding laboratory recently reported (Genomics Data. 2014, 2:50-52) that HOXC9-induced differentiation is associated with a marked reduction in cellular metabolism, as a result of global downregulation of genes involved in the biosynthesis of nucleotides, sterol, and amino acids. This finding sheds new light on the interplay between metabolic reprogramming and cancer cell differentiation, and suggests that reprogramming cellular metabolism may represent a promising strategy for promoting cancer cell differentiation.

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Vadivel Ganapathy, PhD Chair, Department of Biochemistry and Molecular Biology Regents’ Professor of Biochemistry and Molecular Biology Professor CN-1177A

Butyrate functions as an anti-inflammatory and anticancer agent in the colon: The Ganapathy laboratory in collaboration with Dr. Nagendra Singh, has demonstrated that butyrate, produced by colonic bacteria, functions as an anti-inflammatory and anticancer agent in the colon by serving as an agonist for the G-protein-coupled receptor GPR109A (Immunity. 2014, 40:128-39). This is an important finding because it provides a molecular mechanism for the biological effects of butyrate, linking colonic bacteria to colonic health. Deletion of Gpr109a in mice increases the risk for colitis and colon cancer in experimental models. Oral administration of butyrate in the form of tributyrin effectively reduces antibiotic-induced intestinal injury. While butyrate is the physiologic agonist for GPR109A, the B-complex vitamin niacin is a pharmacologic agonist. Oral administration of niacin to mice suppresses colonic inflammation and colon cancer in experimental models. This vitamin also reduces antibiotic-induced diarrhea (J Parenter Enteral Nutr. 2013, 37:763-74).

Butyrate also functions as an inhibitor of histone deacetylases 1 and 3: The bacterial metabolite butyrate also functions as an inhibitor of histone deacetylases 1 and 3. This represents an intracellular action of the compound. The plasma membrane transporter SLC5A8 is critical to mediating the entry of this metabolite from the colonic lumen into colonic epithelial cells. Deletion of Slc5a8 in mice increases the risk for colon cancer in experimental models. The effect is even higher when mice are fed a low-fiber diet. This is because Slc5a8 is a high-affinity transporter for butyrate. With a normal fiber diet, butyrate levels in colonic lumen are very high, and the metabolite can enter colonic epithelial cells even without Slc5a8 via diffusion. In contrast, with low-fiber diets, butyrate levels in the colonic lumen are markedly reduced. Under these conditions, the high-affinity transporter Slc5a8 becomes obligatory for entry of butyrate into colonic epithelial cells. Butyrate also has marked effects on the mucosal immune system. This bacterial metabolite effectively alters the biological phenotype of the dentritic cells in that after exposure to butyrate, dendritic cells acquire the ability to convert naïve T cells into immunosuppressive Tregs. This does not occur in dendritic cells isolated from Slc5a8-null mice, indicating that inhibition of histone deacetylases might be critical for this phenomenon.

Dr. Ganapathy’s laboratory also observed that SLC5A8 elicits biological effects independent of its transport function. This is a surprising finding because there is no precedence for this phenomenon. SLC5A8 interacts with survivin and sequesters this anti-apoptotic protein in the plasma membrane. In breast cancer cells, SLC5a8 is silenced. When the transporter is expressed ectopically in breast cancer cells, survivin moves to the plasma membrane, thus reducing the intracellular and nuclear levels of this protein. This suppresses the growth of breast cancer cells (Biochem J. 2013, 450:169-78; Curr Opin Pharmacol. 2013, 13:869-74).

Plasma membrane transporter xCT and cancer: The plasma membrane transporter xCT is gaining increasing attention in the field of cancer biology. This transporter mediates the cellular entry of the amino acid cystine and thereby increases cellular levels of the antioxidant molecule glutathione. This transporter is upregulated in a wide variety of cancers. The prevailing notion is that this transporter is critical for tumor cell proliferation and protection against oxidative stress. It is believed that that is why tumor cells upregulate this transporter. xCT is an exchanger that mediates the entry of cystine into cells coupled with efflux of glutamate out of the cells. Therefore, intracellular levels of glutamate control the activity of xCT. Dr. Ganapathy’s team has shown that intracellular levels of glutamate are controlled by glutamine transporters in the plasma membrane. They are focusing on two selective glutamine transporters, namely SLC6A14 and SLC38A5. They have shown that SLC6A14 is upregulated in estrogen receptor-positive breast cancer, colon cancer, cervical cancer, and pancreatic cancer, whereas SLC38A5 is upregulated in Triple-negative breast cancer. Therefore, the function of xCT is coupled to that of SLC6A14 in certain cancers but to that of SLC38A5 in certain other cancers. The laboratory is currently testing a hypothesis that simultaneous blockade of xCT and the glutamine transporters would be effective in preventing tumor growth (Antioxid Redox Signal. 2013, 18:522-55).

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Nita Maihle, PhD GRU Cancer Center Associate Director for Education Professor CN-3114

Dr. Maihle’s research program focuses on how to best target the right drug to the right patient at the right time. The Maihle laboratory also investigates how cancer cells become resistant to these new drugs, and how this resistance can be overcome. Progress was made in 2014 on three major projects: 1) Dr. Maihle’s group identified a novel soluble isoform of the human HER3 oncogene, p85 sHER3, as a binding partner for the extracellular matrix protein tenascin C. While tenascin C expression has been known to be associated with poor patient prognosis for cancers such as melanoma and breast cancer, its precise role in tumor cell growth and progression has been elusive. In recent studies (Cancer Res. 2014, 74(19 Suppl):Abstract nr 1164), sHER3 was shown to bind to tenascin C to regulate both cancer cell survival and migration, providing a potential explanation for the antiadhesive phenotype associated with tenascin C expression. These studies also provide further support for the concept that the naturally occurring soluble HER receptors may function as matricellular proteins – by moderating interactions between the extracellular matrix and cell surface EGFR/ HER receptors. Since EGFR and HER3 are clinically validated therapeutic targets in cancer patients, studies that improve the understanding of the role of alternate HER receptor isoforms in cancer cell signaling may one day allow more precise targeting of the critical growth regulatory pathways stimulated by these receptors.

2) Supportive of a role for sHERs as matricellular proteins is a discovery made by Dr. Maihle’s team while studying another soluble EGFR isoform, p110 sEGFR. EGFR, the prototypic HER receptor family member, has been shown to play a critical role in to the process of trophoblast differentiation in human placenta. Maihle and her collaborator (Dr. R. Armant – Wayne State University) have shown that EGFR signaling is dysregulated in human preeclamptic placental tissues and that this dysregulation correlates with p110 sEGFR expression, which may contribute to the impaired trophoblast development seen in preeclampsia (Placenta. 2015, 36:270-8). Since the process of placentation, which includes trophoblast invasion, has been compared to that of cancer cell invasion and metastasis, a similar disruption in EGFR signaling by p110 sEGFR in cancer cells may contribute to the development of metastasis.

3) In collaboration with the GRU Vascular Biology Center (I. Kim) and other Cancer Center members, Dr. Maihle’s group identified endothelin-1/ endothelin A receptor (ETAR)-mediated biased signaling in human ovarian cancer. This novel finding is based on the observation that G proteincoupled receptor (GPCR) signaling elicits multiple pathways with disparate effects. While the overexpression of the ETAR GPCR in ovarian tumors is associated with both late-stage disease and the activation of metastasis genes, clinical trials attempting to target ETAR in ovarian cancer patients have been unsuccessful. In this new collaboration, Dr. Maihle and her colleagues demonstrated that activation of ETAR in human metastatic ovarian cancer cell lines generated both tumor suppressive and oncogenic signals: signaling through the Gαs subunit/cAMP/ PKA pathway was shown to be tumor suppressive, whereas signaling through the Gαq subunit/PKC and b-arrestin pathways was shown to be oncogenic. Interrogating the Cancer Genome Atlas data base revealed a positive correlation between Gαs overexpression and overall survival in ovarian cancer patients. The investigators further showed that ETAR/b-arrestin signaling activates two genes (Calcrl and Icam2) with known metastatic/angiogenic functions – and that this activation is blocked by the Gαs subunit/cAMP/PKA pathway. Together, these results suggest that more precise targeting of ETAR/b-arrestin signaling for ovarian cancer patient treatment may be possible through the development of selective ETAR antagonists (Cell Signal. 2014, 26:2885-95).

Dr. Maihle also is extensively involved with innovative activities that bring about transformational change to education and biomedical research, to increase the effectiveness of learning organizations and ultimately to improve human health. Toward this end, she was a recent contributing author in the development of a novel anticancer strategy (BMC Cancer. 2014, 14:186).

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reports // tsa program

Daitoku Sakamuro, PhD Associate Professor

CN-1176

The E2F1 transcription factor induces apoptosis under stress conditions, including DNA damage and serum starvation. In response to DNA damage, E2F1 is phosphorylated by ataxia telangiectasia mutated (ATM) kinase to promote apoptosis, but the precise mechanism by which serum starvation enhances E2F1-induced apoptosis remained unclear. Dr. Sakamuro’s group recently discovered that 1) E2F1 is poly(ADP-ribosyl) ated by PARP1 in optimal conditions, 2) poly(ADP-ribosyl)ated E2F1 physically interacts with BIN1 (a pro-apoptotic tumor suppressor), and thus 3) serum starvation (or PARP inhibitors) reduces E2F1 poly(ADP-ribosyl)ation, thereby liberating BIN1 from E2F1. They concluded that a release of BIN1 from hypo-poly(ADP-ribosyl)ated E2F1 is a mechanism by which serum starvation (or PARP1 inhibition) induces apoptosis in cancer cells.

(Cell Death Differ. 2014, In Press) Cancer cells ultimately acquire resistance to conventional chemotherapeutic agents, such as cisplatin. In contrast, many tumor suppressors are proapoptotic after treatments with DNA-damaging agents. Therefore, it would be clinically relevant to increase cancer chemo- and radiationsensitivities by combining standard anticancer treatments with agents that can restore the activity of silenced tumor suppressors, such as BIN1, TP53, and RB1. Dr. Sakamuro’s group recently reported the discovery of small molecule inhibitors that increase or stabilize these tumor suppressors, thereby reversing the transforming activities of HPV E6 and E7. (Mol Cell Oncol. 2014, In Press).

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tsa program // reports

Muthusamy Thangaraju, PhD Associate Professor

CN-1161

The main focus of the Thangaraju laboratory is to explore the tumor suppressor function of GPR109A, a G protein-coupled receptor for niacin and butyrate, in breast cancer. Upon activation in colonocytes, GPR109A potentiates anti-inflammatory pathways, induces apoptosis, and protects against inflammation-induced colon cancer. In contrast, GPR109A activation in keratinocytes induces flushing by activating Cox-2-dependent inflammatory signaling, and the receptor expression is upregulated in human epidermoid carcinoma. Thus, depending on the cellular context and tissue, GPR109A functions either as a tumor suppressor or a tumor promoter. The Thangaraju laboratory has recently shown that GPR109A is expressed in normal mammary tissue and, irrespective of the hormone receptor status, its expression is silenced in human primary breast tumor tissues, breast cancer cell lines, and in tumor tissues of three different murine mammary tumor models. Functional expression of this receptor in human breast cancer cell lines decreases cAMP production, induces apoptosis, and blocks colony formation and mammary tumor growth.

Transcriptome analysis revealed that GPR109A activation inhibits genes that are involved in cell survival and anti-apoptotic signaling in human breast cancer cells. In addition, deletion of Gpr109a in mice increased tumor incidence and triggered early onset of mammary tumorigenesis with increased lung metastasis in the MMTV-Neu mouse model of spontaneous breast cancer (Cancer Res. 2014, 74:1166-78). These findings suggest that GPR109A is a tumor suppressor in the mammary gland and that pharmacological induction of this gene in tumor tissues followed by its activation with agonists could be an effective therapeutic strategy to treat breast cancer.

Mammary stem and progenitor cells are key drivers of self-renewal and regeneration of the mammary epithelium, which undergoes multiple rounds of proliferation, differentiation, and apoptosis during pregnancy and involution. In self-renewing mammalian epithelial tissues, DNA methyltransferase 1 (DNMT1) plays a key role in stem and progenitor cell maintenance wherein its enrichment in undifferentiated cells enables them to retain their regenerative capacity. However, the role of DNMT1 in the regulation of stem/progenitor cells in constantly replenishing tissues like the mammary gland is not well understood. The Thangaraju laboratory has now shown that Dnmt1 is required for mammary gland outgrowth and terminal end bud development and that mammary gland-specific Dnmt1 deletion in mice leads to significant reduction in mammary stem/ progenitor cell formation (Nature Communications, in press). Interestingly, Dnmt1 deletion almost completely abolishes Neu-Tg- and C3(1)SV40-Tg- driven mammary tumor formation and metastasis. This phenomenon is associated with significant reduction in cancer stem cell (CSC) formation. Similar observations were also recapitulated using pharmacological inhibitors of Dnmts in Neu-Tg mice. Through genome-wide methylation studies of normal and cancer stem cells, Dr. Thangaraju’s group found that ISL1, an endogenous inhibitor of the estrogen receptor, is hypermethylated and is a direct target of DNMT1 in CSCs. ISL1 is hypermethylated and silenced in most human breast cancers, and functional re-expression in breast cancer cells reduces cell growth and CSC formation. Overall, this laboratory’s findings provide the first in vivo evidence that DNMT1 plays a key role in mammary stem/progenitor and CSC maintenance and identify ISL1 as a novel target for breast cancer treatment.

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reports // tsa program

Guangyu Wu, PhD Professor

CB-3528

G protein-coupled receptors (GPCRs) constitute the largest superfamily of cell surface receptors and regulate cellular responses to a broad spectrum of extracellular signals. However, the molecular mechanisms underlying the transport of GPCRs to the cell surface, which is the functional destination, remain poorly understood. We have used the α2B-adrenergic receptor (α2B-AR) as a model GPCR to determine the role of Golgi-localized, gamma-adaptin ear domain homology, ADP ribosylation factor-binding proteins (GGAs). GGAs are a family of multidomain clathrin adaptor proteins that sort cargo proteins at the trans-Golgi network (TGN) to the endosome/lysosome pathway. We have demonstrated that the normal function of GGA1, GGA2, and GGA3 is required for the maximal cell surface expression of inducibly expressed and endogenous α2B-AR, as well as receptor-mediated signaling. GGAs likely control α2B-AR export en route from the TGN. Interestingly, all three GGAs interact with α2BAR. These data reveal a novel function of the GGA family proteins in post-Golgi export trafficking of α2B-AR. We have also studied the role of Rab small GTPases in the trafficking of the channel protein KCa3.1 (PLoS ONE. 2014, 9:e92013).

Another major project in the Wu Laboratory is to define novel signaling molecules involved in tumorigenesis. In collaboration with Dr. Il-man Kim (GRU Vascular Biology Center), the Wu Laboratory has studied the endothelin-1/endothelin A receptor-mediated biased signaling in modulating human ovarian cancer cell tumorigenesis (Cell Signal. 2014, 26:2885-95).

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GRU CANCER CENTER SHARED RESOURCES

Biorepository and Central Source for the Biorepository Alliance of Georgia-Oncology (BRAG-ONC) Core Imaging Facility for Small Animals Flow Cytometry Resource Integrated Genomics Microarray

Next-Gen Sequencing Microscopy Imaging Core Proteomics and Metabolomics Facility Bioinformatics and Biostatistics

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BIOREPOSITORY AND CENTRAL SOURCE FOR THE BRAG-ONC

Director // Roni Bollag, MD

Website // www.gru.edu/cancer/research/shared/tumor

Our Mission The repository (tumor tissue and serum) was established to provide a centralized service for biospecimen procurement and distribution to support basic and translational research. The repository collects and stores specimens under standardized conditions with accompanying clinical and demographic information. The collection is supported by a web-accessible database for inventory management and annotation, and a long-term storage facility with backups of cryopreserved specimens. In addition to serving the GRU research community, the repository serves as the central coordinating center for the statewide network. BRAG-Onc was established with funds from the Georgia Cancer Coalition to represent the diversity of the cancer patient population in Georgia and to enhance cancer research in the state.

A Collaborative Effort The collection of specimens, coordinated by the tumor bank, requires the collaboration of many individuals, such as surgical oncologists, surgery staff, and pathologists. Most important in this process are the patients who donate specimens for future research. It is an opportunity for patients to contribute to science that may lead to better and earlier cancer detection and treatments. And donating makes use of tissue or other material that is not needed for diagnosis and that would otherwise be discarded.

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 collect are considered for specific studies.

• Tissues are maintained at -150oC to -190oC liquid nitrogen vapor phase; blood derivatives and biofluids are maintained at -50 oC 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 TissueMetrix biorepository management system for tracking procurement and distribution of samples with annotated clinical information.

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CORE IMAGING FACILITY FOR SMALL ANIMALS

Director // Nathan Yanasek, PhD Manager // Christopher Middleton, MBA

Website // www.gru.edu/cancer/research/shared/smallanimal

Our Mission The Core Imaging Facility for Small Animals (CIFSA), commissioned to provide MRI and optical imaging resources of small animals, provides a mechanism for studying animal models in vivo and ex vivo samples for the GRU Cancer Center research community. In particular with regard to MRI, the core facilities mirror clinical imaging capabilities on campus in order to advance the translation of clinical and biomedical sciences. Efforts of the CIFSA are focused on elucidating the pathophysiology of disease and on providing a better evaluation of the efficacy of pharmaceutical interventions in the battle of those diseases.

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 role non-invasive whole body magnetic resonance, bioluminescent, and fluorescent imaging can play in achieving research objectives.

Equipment Bruker Biospin 7T horizontal bore scanner • Bore diameter of 30 cm • Gradient strength of 200 mT/m and Max slew rate of 640 T/m/s • ParaVision® software package provides a framework for multi-dimensional MRI/ MRS data acquisition, reconstruction, analysis and visualization • Two gradients are available to accommodate both small and large rodents • Numerous ready-to-use MRI methods and sequences available • Small animal anesthesia and monitor system available

Infusion & Animal Prep Station Useful for control of animal anesthesia and minimal surgical preparation, if necessary.

Perkin Elmer IVIS 100 The Perkin Elmer IVIS 100 optical imaging device is capable of in vivo bioluminescence and fluorescence imaging in mice and rats. The system includes animal handling features such as a heated sample shelf and a full gas anesthesia system. It is highly automated with all hardware motor movement, imaging parameters, and image analysis controlled via Living Image ® software.

• Adjustable field of view of 10-25 cm • 25 mm (1.0 inch) square back-thinned, back-illuminated, cooled CCD camera • Signals detectable from 500-900 nm • Extremely light-tight, low background imaging chamber can be used in standard lab lighting environments

In-House Data Analysis Packages • Imagei • Paravision

• Matlab • Amira

• MRIcro • Spin

• Bioimage Suite • Andor Solis

• Itk-Snap • Volview // 71

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FLOW CYTOMETRY RESOURCE

Manager // William King

Website // www.gru.edu/cancer/research/shared/flow

Equipment The Cancer Center Flow Cytometry Core Facility is equipped with 5 flow cytometers that are categorized into 3 types: • Four analyzer flow cytometers that are typically operated by investigators themselves • A state-of-the-art imaging flow cytometer that is typically operated by investigators themselves.

• A cell sorter flow cytometer that is typically provided as a service to investigators. In order to select the best fluorophores for use in a specific application on a particular flow cytometer, it is necessary to know the laser configuration of the cytometer and its optical configuration and detectors. The facility’s lasers are summarized in the following table. Each cytometer’s configuration is detailed in the section specific to the cytometer on the website. The facility is able to accommodate the majority of flow cytometry protocols.

Software FlowJo v10 and v9 ModFit LT v4 IDEAS v6 (for ImageStream× data file analysis)

Cyflogic v1.2.1 Flowing Software v2.5

Flow Cytometers And Laser Lines ANALYZER FLOW CYTOMETERS (Becton Dickson) Laser

Accuri C6

FACSCanto

LSR II SORP

IMAGING FLOW CYTOMETER

CELL SORTER FLOW CYTOMETER

LSR II SORP w/ HTS

Amnis ImageStream

Becton Dickson FACSAria II SORP

UV (355 nm)

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Violet (405 nm)

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Cyan (457 nm) Blue (488 nm)

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Green (514-532 nm) Yellow (561 nm) Orange (592 nm) Red (633/640/658 nm) Infrared (780 nm) 72 //

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gru cancer center shared resources //

INTEGRATED GENOMICS: MICROARRAY

Director // Eiko Kitamura, PhD

Website // www.gru.edu/cancer/research/shared/genomics

Scope Gene expression profiling, genotyping, cytogenetics, and epigenetic analysis using microarray technologies.

Equipment • Affymetrix GeneChip Scanner 3000 7G Plus • Affymetrix Hybridization Oven 640 • Affymetrix Fulidics Station 450 • Agilent Microarray Scanner • Agilent Hybridization Oven • Agilent 2100 Bioanalyzer • Agilent 2200 TapeStation • Applied Biosystems GeneAmp 9700 Thermocycler • Applied Biosystems StepOnePlus Real-Time PCR system • NanoDrop 1000 • Pyrosequencer, Qiagen PyroMark MD / PyroMark Q96 workstation

Services GeneChip Human Gene 2.0 ST GeneChip miRNA 3.0 Array Other Arrays • GeneChip Human Exon 1.0 ST Array • GeneChip Mouse Exon 1.0 ST Array • GeneChip Rat Gene 2.0 ST Array • GeneChip Rat Exon 2.0 ST Array • Mode and applied research organisms Gene 1.0 ST Array • Arabidopsis Gene 1.0 ST Array • Bovine Gene 1.0 ST Array • C. elegans Gene 1.0 ST Array • Canine Gene 1.0 ST Array • Chicken Gene 1.0 ST Array • Drosophila (melanogaster) Gene 1.0 ST Array • Guinea Pig Gene 1.0 Gene 1.0 ST Array • Genome-Wide Human SNP Array

Software • Affymetrix Expression Console • Partek Genomics Suite 6.6 • Partek Pathway anaysis • Ingenuity Pathway Analysis (IPA) • Gene Set Enrichment Analysis (GSEA) • Pyromark

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INTEGRATED GENOMICS: NEXT-GEN SEQUENCING

Manager // Chang-Sheng

(Sam) Chang, PhD

Website // www.gru.edu/cancer/research/shared/genomics

With the addition of the Illumina HiSeq 2500, this integrated genomics resource offers single read, paired-end, and multiplex sequencing. It also offers library preparation services for DNA-seq, RNA-seq, Chip-seq, and other standard sequencing libraries.

Rapid mode provides users a faster turn-around time. A two-lane flow cell for rapid mode processes approximately 30 GB per lane, whereas an eight-lane flow cell for hithroughput mode processes around 36 GB per lane. Miseq instrumentation specializes in handling small genome species and targeted-region DNA and RNA projects such as microbiome sequencing and small RNA sequencing.

The Ion Proton instrument will perform Exome, RNA-Seq, or ChIP- Seq with faster turnaround times but somewhat reduced coverage. There are also many panels or custom designed panels for cancer and other diseases available for this system, as well as custom-designed panels that can be used to validate findings.

Equipment/Infrastructure • Illumina HiSeq 2500 (Rapid & Hi-Throughput Modes) • Illumina Miseq • cBot Cluster Generation System • Ion Proton and automated Ion Chef • Agilent ® 2100 Bioanalyzer • Agilent ® 2200 TapeStation • NanoDrop 1000 • QuBit Fluorometer • cBot Cluster Generation System • Applied Biosystems GeneAmp 9700 Thermocycler • Pyrosequencer (Qiagen PyroMark MD/PyroMark Q96 workstation)

Applications • DNA Sequencing • Gene Regulation Analysis • Sequencing-Based Transcriptome Analysis • SNP Discovery and Structural Variation Analysis • Cytogenetic Analysis • DNA-Protein Interaction Analysis (ChIP-Seq) • Sequencing-Based Methylation Analysis 74 //

Data Analysis • CASAVA (Eland Alignment & SNP calling) • Partek Genomics Suite • TrueSeqEnrichment Analysis Tool • BowTie Alignment • BWA • GATK2 (dbSNP137) • Annovar • VarScan2 • Tophat2 & Cufflinks • GSNAP & GMAP • RSEM • ExomeCNV • FusionMap • Tools for DNA-Seq, RNA-Seq and Chip-Seq analyses • IPA Pathway Analysis

gru cancer center shared resources //

MICROSCOPY IMAGING CORE

Director // Jeane Silva, PhD

Website // www.gru.edu/cancer/research/shared/microscopy

Services • Confocal Microscopy • Fluorescence Microscopy • Digital Imaging scanner • Imaging processing

Equipment • Scanning confocal microscope: Zeiss LSM 510 meta-inverted microscope • Sub-resolution fluorescence microscope: Zeiss AxioObserver.D1 • Digital slide scanning system: Ariol DM6000 B Digital Slide Scanner • Two image analysis workstations

Software • Zen 2009 Imaging acquisition and analysis • Digital Imaging Hub – Slide Path software

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PROTEOMICS AND METABOLOMICS FACILITY

Manager // Lambert Ngoka, PhD

Website // www.gru.edu/cancer/research/shared/proteomics

Instrumentation Three LC/MS systems Proteomics • Thermo Scientific Orbitrap Velos Pro Hybrid Mass Spectrometer/plus a new Nanospray Flex Ion Source ES071 • Thermo Scientific-Dionex UltiMate 3000 RSLCnano+(TBPLFC)+(MSTHM)+(nAO2D) • Agilent 1200 Series Nanoflow/capillary LC System for MS Discovery Metabolomics • Agilent 6520 Accurate-Mass Quadrupole Time-of-Flight MS • Agilent 1200 Series Binary LC System Targeted Metabolomics • Agilent 6410 Triple Quad LC/MS System • Agilent 1200 Series Binary LC System

Services Proteomics • Protein extraction from cell lines, tissue and biofluids • Co-immunoprecipitation • Trypsin digestion • Nano-LC/MS/MS • Protein identification • Detection and characterization of posttranslational modifications of proteins– structural characterization of modified proteins, lipids and DNA in disease–e.g. the identification and quantification of oxidative damage to proteins, lipids and DNA • Screening for genetic mutations in proteins Metabolomics • Sample extraction and purification for metabolomics • Metabolome profiling • LC/MS analysis of the different sample sets (i.e. disease vs. matched controls) • XCMS differential analysis of the LC/MS analyses.

• Provide XCMS output (m/z and RT) highlighting the ions that differed the most in intensity between data sets.

• Provide tentative identification based on accurate mass and molecules available in the METLIN database.

• Provide more firm identification based on comparative MS/MS and high accuracy analysis of ‘unknown’ with a standard provided by the client.

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Software Thermo Scientific LTQ Orbitrap Discovery™ Hybrid FT MS • Agilent ChemStation for LC systems Rev. B.04.01 SP1 (647) (*.M; *.S) • Thermo Fisher Xcalibur™ 2.0.7 (*.RAW) • Thermo Fisher Proteome Discoverer 1.4 v1.4.0.288 (*.MSF) • Thermo Fisher BioWorks™ Rev.3.3.1 SP1 (*.SRF) • Proteome Software Scaffold 3.6.5 (*.Sf3) Agilent 6410 Triple Quad LC/MS System • Agilent MassHunter Workstation Software, Qualitative Analysis, Version B.01.03; Build 1.3.157.0; Patch 2 • Agilent MassHunter Workstation Software, Data Acquisition for 6400 Series Triple Quadrupole, Version B.01.04 • Agilent MassHunter Workstation Software, Quantitative Analysis, Version B.01.04 Software for Agilent 6520 Accurate-Mass Quadrupole Time-of-Flight MS • Agilent MassHunter Workstation Software, LC/MS Data Acquisition Version B.02.00, for 6200 Series TOF & 6500 Series Q-TOFBuild 1.3.157.0; Patch 2 • Agilent MassHunter Workstation Software, Qualitative Analysis, Version B.03.01; Build 3.1.346.6; Serv. Pack 2 • Agilent MassHunter Workstation Software, Quantitative Analysis; Version B.01.04 Independently Licensed Software • Proteome Discoverer 1.2 (Thermo Fisher scientific) • Bioworks 3.3.1 SR1 (Thermo Fisher scientific) • Scaffold 3.6.5 (Proteome Software, Inc.) • Scaffold PTM 1.0 (Proteome Software, Inc.) • G3835-64000 Mass Profiler Professional B.02.01.

Rev. B.02.01 G3835-6003 USK0183590 (Agilent Technologies) • G6825AA Personal METLIN Metabolite Database (Agilent Technologies)

gru cancer center shared resources //

BIOINFORMATICS AND BIOSTATISTICS

Manager // Justin Choi, PhD – Bioinformatices Website // www.gru.edu/cancer/research/shared/bioinformatics

Manager // Ramses F. Sadek, PhD – Biostatistics, Clinical Trials Website // www.gru.edu/cancer/research/shared/biostatistics

Services Bioinformatics is an interdisciplinary scientific field that develops methods for storing, retrieving, organizing and analyzing biological data.

A major activity in bioinformatics is to develop software tools to generate useful biological knowledge. 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 success of the analysis.

Statistical Software • SAS •R • Partek • NCSS/PASS

In addition to conducting independently sponsored research in statistical analysis and quantitative methods to develop novel methodologies, the Bioinformatics and Biostatistics Core provides: • Expertise for the planning, conducting, analysis, and reporting of data related to clinical trials, as well as epidemiologic- and population-based studies in areas such as cancer biology and genetic susceptibility • Database design and management of clinical research data for the Quality Assurance Office for Clinical Trials (QACT) and the Office for Protection of Research Subjects (OPRS) • Microarray data analysis • NGS data analysis • Design and monitor clinical trials, experimental design, power, and sample size calculation • Collaborative research support throughout all phases of grant proposal preparations and funded research • Education in the areas of study design, data collection, computerization, and statistical methods for laboratory, clinical, and population based studies • Methodological research in quantitative methods

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2014 GRU CANCER CENTER PUBLICATIONS

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2014 gru cancer center publications

Abu Eid R, Friedman KM, Mkrtichyan M, Walens A, King W, John Janik J, Khleif SN. Akt 1 and 2 Inhibition Diminishes Terminal Differentiation and Enhances Central Memory CD8 T Cell Proliferation and Survival. Oncoimmunology. Epub 2015 Feb 3.

Abu-Eid R, Samara RN, Ozbun L, Abdalla MY, Berzofsky JA, Friedman KM, Mkrtichyan M, Khleif SN. Selective Inhibition of Regulatory T Cells by Targeting the PI3K-Akt Pathway. Cancer Immunol Res. 2014 Nov;2(11):1080-9.

Achyut BR, Varma NR, Arbab AS. Application of Umbilical Cord Blood Derived Stem Cells in Diseases of the Nervous System. J Stem Cell Res Ther. 2014;4. pii: 1000202.

Ali MM, Kumar S, Shankar A, Varma NR, Iskander AS, Janic B, Chwang WB, Jain R, Babajeni-Feremi A, Borin TF, Bagher-Ebadian H, Brown SL, Ewing JR, Arbab AS. Effects of tyrosine kinase inhibitors and CXCR4 antagonist on tumor growth and angiogenesis in rat glioma model: MRI and protein analysis study. Transl Oncol. 2013 Dec 1;6(6):660-9. eCollection 2013 Dec 1.

Allott EH, Howard LE, Cooperberg MR, Kane CJ, Aronson WJ, Terris MK, Amling CL, Freedland SJ. Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

BJU Int. 2014 Nov;114(5):661-6.

Allott EH, Howard LE, Cooperberg MR, Kane CJ, Aronson WJ, Terris MK, Amling CL, Freedland SJ. Serum Lipid Profile and Risk of Prostate Cancer Recurrence: Results from the SEARCH Database. Cancer Epidemiol Biomarkers Prev. 2014 Nov;23(11):2349-56.

Ananth S, Gnana-Prakasam JP, Bhutia YD, Veeranan-Karmegam R, Martin PM, Smith SB, Ganapathy V. Regulation of the cholesterol efflux transporters ABCA1 and ABCG1 in retina in hemochromatosis and by the endogenous siderophore 2,5-dihydroxybenzoic acid. Biochim Biophys Acta. 2014 Apr;1842(4):603-12. Epub 2014 Jan 23.

Andrews JO, Mueller M, Newman SD, Magwood G, Ahluwalia JS, White K, Tingen MS. The Association of Individual and Neighborhood Social Cohesion, Stressors, and Crime on Smoking Status Among African-American Women in Southeastern US Subsidized Housing Neighborhoods. J Urban Health. 2014 Dec;91(6):1158-74.

Arthur ME, Odo N, Parker W, Weinberger PM, Patel VS. CASE 9-2014: Supracarinal Tracheal Tear After Atraumatic Endotracheal Intubation: Anesthetic Considerations for Surgical Repair. J Cardiothorac Vasc Anesth. 2014 Aug;28(4):1149-57.

Bailey LJ, Choudhary V, Merai P, Bollag WB. Preparation of primary cultures of mouse epidermal keratinocytes and the measurement of phospholipase D activity. Methods Mol Biol. 2014;1195:111-31.

Barik A, Lu Y, Sathyamurthy A, Bowman A, Shen C, Li L, Xiong WC, Mei L. LRP4 Is Critical for Neuromuscular Junction Maintenance. J Neurosci.

2014 Oct 15;34(42):13892-905.

Barik A, Zhang B, Sohal GS, Xiong WC, Mei L. Interaction between Agrin and Wnt signalings in development of vertebrate neuromuscular junction.

Dev Neurobiol. 2014 May 17. [Epub ahead of print] No abstract available.

Barman SA, Chen F, Su Y, Dimitropoulou C, Wang Y, Catravas JD, Han W, Orfi L, Szantai-Kis C, Keri G, Szabadkai I, Barabutis N, Rafikova O, Rafikov R, Black SM, Jonigk D, Giannis A, Asmis R, Stepp DW, Ramesh G, Fulton DJ. NADPH Oxidase 4 Is Expressed in Pulmonary Artery Adventitia and Contributes to Hypertensive Vascular Remodeling. Arterioscler Thromb Vasc Biol. 2014 Jun 19. [Epub ahead of print] Bashyam MD, Kotapalli V, Raman R, Chaudhary AK, Yadav BK, Gowrishankar S, Uppin SG, Kongara R, Sastry RA, Vamsy M, Patnaik S, Rao S, Dsouza S, Desai D, Tester A. Evidence for presence of mismatch repair gene expression positive Lynch syndrome cases in India. Mol Carcinog.

2014 Nov 24. doi: 10.1002/mc.22244. [Epub ahead of print] Bean JC, Lin TW, Sathyamurthy A, Liu F, Yin DM, Xiong WC, Mei L. Genetic Labeling Reveals Novel Cellular Targets of Schizophrenia Susceptibility Gene: Distribution of GABA and Non-GABA ErbB4-Positive Cells in Adult Mouse Brain. J Neurosci. 2014 Oct 1;34(40):13549-66.

Berger PK, Principe JL, Laing EM, Henley EC, Pollock NK, Taylor RG, Blair RM, Baile CA, Hall DB, Lewis RD. Weight gain in college females is not prevented by isoflavone-rich soy protein: a randomized controlled trial. Nutr Res. 2014 Jan;34(1):66-73.

Berkowitz JL, Janik JE, Stewart DM, Jaffe ES, Stetler-Stevenson M, Shih JH, Fleisher TA, Turner M, Urquhart NE, Wharfe GH, Figg WD, Peer CJ, Goldman CK, Waldmann TA, Morris JC. Safety, efficacy, and pharmacokinetics/pharmacodynamics of daclizumab (anti-CD25) in patients with adult T-cell leukemia/lymphoma. Clin Immunol. 2014 Dec;155(2):176-87.

Bertuccio CA, Lee SL, Wu G, Butterworth MB, Hamilton KL, Devor DC. Anterograde trafficking of KCa3.1 in polarized epithelia is Rab1- and Rab8dependent and recycling endosome-independent. PLoS One. 2014 Mar 14;9(3):e92013. eCollection 2014.

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2014 gru cancer center publications

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. 2014 Dec 23. doi: 10.1038/ajg.2014.396. [Epub ahead of print] Review.

Bharucha AE, Rao SS. An update on anorectal disorders for gastroenterologists. Gastroenterology. 2014 Jan;146(1):37-45.e2.

Bi LL, Sun XD, Zhang J, Lu YS, Chen YH, Wang J, Liu F, Zhang M, Geng F, Liu JH, Mei L, Gao TM. Amygdala NRG1-ErbB4 is Critical For the Modulation of Anxiety-Like Behaviors. Neuropsychopharmacology. 2014 Oct 13. doi: 10.1038/npp.2014.274. [Epub ahead of print] Bieberich E. Synthesis, Processing, and Function of N-glycans in N-glycoproteins. Adv Neurobiol. 2014;9:47-70.

Blackburn AR 2nd, Hamrick MW, Chutkan N, Sangani R, Waller JL, Corpe R, Prasad PD, Isales CM, Ganapathy V, Fulzele S. Comparative analysis of sodium coupled vitamin C transporter 2 in human osteoarthritis grade 1 and grade 3 tissues. BMC Musculoskelet Disord. 2014 Jan 8;15:9.

Blanco VM, Chu Z, Vallabhapurapu SD, Sulaiman MK, Kendler A, Rixe O, Warnick RE, Franco RS, Qi X. Phosphatidylserine-selective targeting and anticancer effects of SapC-DOPS nanovesicles on brain tumors. Oncotarget. 2014 Jul 14. [Epub ahead of print] Bollag WB. Regulation of aldosterone synthesis and secretion. Compr Physiol. 2014 Jul 1;4(3):1017-55. Epub 2014 Jun 12.

Borin T, Arbab AS, Ferreira LC, Botaro GB, Maschio LB, Moschetta GM, Gonçalves NN, Martins GR, Zuccari DAPC. Evaluation of the efficacy of melatonin in breast cancer metastasis mediated by ROCK-1. Eur J Cancer. 2014 Jan 11;50:169-70.

Borin TF, Zuccari DA, Jardim-Perassi BV, Ferreira LC, Iskander AS, Varma NR, Shankar A, Guo AM, Scicli G, Arbab AS. HET0016, a Selective Inhibitor of 20-HETE Synthesis, Decreases Pro-Angiogenic Factors and Inhibits Growth of Triple Negative Breast Cancer in Mice. PLoS One. 2014 Dec 30;9(12):e116247.

Bourgault AM, Heath J, Hooper V, Sole ML, Waller JL, Nesmith EG. Factors influencing critical care nurses’ adoption of the AACN practice alert on verification of feeding tube placement. Am J Crit Care. 2014 Mar;23(2):134-44.

Bozec A, Zaiss MM, Kagwiria R, Voll R, Rauh M, Chen Z, Mueller-Schmucker S, Kroczek RA, Heinzerling L, Moser M, Mellor AL, David JP, Schett G. T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway. Sci Transl Med. 2014 May 7;6(235):235ra60.

Bradley E, Dasgupta S, Jiang X, Zhao X, Zhu G, He Q, Dinkins M, Bieberich E, Wang G. Critical role of spns2, a sphingosine-1-phosphate transporter, in lung cancer cell survival and migration. PLoS One. 2014 Oct 20;9(10):e110119. doi: 10.1371/journal.pone.0110119. eCollection 2014.

Bradley E, Zhao X, Wang R, Brann D, Bieberich E, Wang G. Low dose Hsp90 inhibitor 17AAG protects neural progenitor cells from ischemia induced death. J Cell Commun Signal. 2014 Dec;8(4):353-62.

Bronk CC, Yoder S, Hopewell EL, Yang S, Celis E, Yu XZ, Beg AA. NF-κB is crucial in proximal T-cell signaling for calcium influx and NFAT activation. Eur J Immunol. 2014 Dec;44(12):3741-6.

Brücher BL, Lyman G, van Hillegersberg R, Pollock RE, Lordick F, Yang HK, Ushijima T, Yeoh KG, Skricka T, Polkowski W, Wallner G, Verwaal V, Garofalo A, D’Ugo D, Roviello F, Steinau HU, Wallace TJ, Daumer M, Maihle N, Reid TJ 3rd, Ducreux M, Kitagawa Y, Knuth A, Zilberstein B, Steele SR, Jamall IS. Imagine a world without cancer. BMC Cancer. 2014 Mar 14;14(1):186.

Buckley KM, Hess DL, Sazonova IY, Periyasamy-Thandavan S, Barrett JR, Kirks R, Grace H, Kondrikova G, Johnson MH, Hess DC, Schoenlein PV, Hoda MN, Hill WD. Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke. Exp Transl Stroke Med. 2014 Jun 21;6:8. eCollection 2014.

Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014 Mar 20;507(7492):315-22.

Cancer Genome Atlas Research Network. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014 Oct 23;159(3):676-90.

Cao Q, Wang X, Jia L, Mondal AK, Diallo A, Hawkins GA, Das SK, Parks JS, Yu L, Shi H, Shi H, Xue B. Inhibiting DNA Methylation by 5-Aza-2’deoxycytidine Ameliorates Atherosclerosis Through Suppressing Macrophage Inflammation. Endocrinology. 2014 Dec;155(12):4925-38.

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2014 gru cancer center publications

Cao W, Ramakrishnan R, Tuyrin VA, Veglia F, Condamine T, Amoscato A, Mohammadyani D, Johnson JJ, Min Zhang L, Klein-Seetharaman J, Celis E, Kagan VE, Gabrilovich DI. Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J Immunol. 2014 Mar 15;192(6):2920-31.

Cassuto J, Dou H, Czikora I, Szabo A, Patel VS, Kamath V, Belin de Chantemele E, Feher A, Romero MJ, Bagi Z. Peroxynitrite disrupts endothelial caveolae leading to eNOS uncoupling and diminished flow-mediated dilation in coronary arterioles of diabetic patients. Diabetes. 2014 Apr;63(4):1381-93. Epub 2013 Dec 18.

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.

Chen L, Ackerman R, Saleh M, Gotlinger KH, Kessler M, Mendelowitz LG, Falck JR, Arbab AS, Scicli AG, Schwartzman ML, Yang J, Guo AM. 20-HETE regulates the angiogenic functions of human endothelial progenitor cells and contributes to angiogenesis in vivo. J Pharmacol Exp Ther.

2014 Mar;348(3):442-51.

Chen X, Wang X, Ruan A, Han W, Zhao Y, Lu X, Xiao P, Shi H, Wang R, Chen L, Chen S, Du Q, Yang H, Zhang X. miR-141 is A Key Regulator of Renal Cell Carcinoma Proliferation and Metastasis by Controlling EphA2 Expression. Clin Cancer Res. 2014 Mar 19. [Epub ahead of print] Chen Z, Ozbun L, Chong N, Wallecha A, Berzofsky JA, Khleif SN. Episomal Expression of Truncated Listeriolysin O in LmddA-LLO-E7 Vaccine Enhances Antitumor Efficacy by Preferentially Inducing Expansions of CD4+FoxP3- and CD8+ T Cells. Cancer Immunol Res. 2014 Sep;2(9):91122.

Choudhary V, Gullotto M, Sato L, Bollag W. MicroRNAs in the development and progression of skin cancer. In: MicroRNA in Development and in the Progression of Cancer. SR Singh & P Rameshwar, eds. Springer, New York, 2014. (Invited review) Choudhary V, Kaddour-Djebbar I, Alaisami R, Kumar MV, Bollag WB. Mitofusin 1 degradation is induced by a disruptor of mitochondrial calcium homeostasis, CGP37157: A role in apoptosis in prostate cancer cells. Int J Oncol. 2014 May;44(5):1767-73.

Choudhary V, Olala LO, Kaddour-Djebbar I, Helwa I, Bollag WB. Protein kinase D1 deficiency promotes differentiation in epidermal keratinocytes. J Dermatol Sci. 2014 Dec;76(3):186-95.

Choudhary V, Olala LO, Qin H, Helwa I, Pan ZQ, Tsai YY, Frohman MA, Kaddour-Djebbar I, Bollag WB. Aquaporin-3 Re-Expression Induces Differentiation in a Phospholipase D2-Dependent Manner in Aquaporin-3 Knockout Mouse Keratinocytes. J Invest Dermatol. 2015 135:499-507.

[Epub 2014 Sep 18] Chwang WB, Jain R, Bagher-Ebadian H, Nejad-Davarani SP, Iskander AS, VanSlooten A, Schultz L, Arbab AS, Ewing JR. Measurement of rat brain tumor kinetics using an intravascular MR contrast agent and DCE-MRI nested model selection. J Magn Reson Imaging. 2014 Nov;40(5):12239.

Clark SP, Bollag WB, Westlund KN, Ma F, Falls G, Xie D, Johnson M, Isales CM, Bhattacharyya MH. Pine oil effects on chemical and thermal injury in mice and cultured mouse dorsal root ganglion neurons.

Phytother Res. 2014 Feb;28(2):252-60.

Condamine T, Kumar V, Ramachandran IR, Youn JI, Celis E, Finnberg N, El-Deiry WS, Winograd R, Vonderheide RH, English NR, Knight SC, Yagita H, McCaffrey JC, Antonia S, Hockstein N, Witt R, Masters G, Bauer T, Gabrilovich DI. ER stress regulates myeloid-derived suppressor cell fate through TRAIL-R-mediated apoptosis. J Clin Invest. 2014 Jun 2;124(6):2626-39. Epub 2014 May 1.

Coss-Adame E, Erdogan A, Rao SS. Treatment of esophageal (noncardiac) chest pain: an expert review. Clin Gastroenterol Hepatol. 2014 Aug;12(8):1224-45.

Coss-Adame E, Rao SS. Brain and gut interactions in irritable bowel syndrome: new paradigms and new understandings. Curr Gastroenterol Rep. 2014 Apr;16(4):379.

Cronin P, Rawson JV, Heilbrun ME, Lee JM, Kelly AM, Sanelli PC, Bresnahan BW, Paladin AM. How to critically appraise the clinical literature.

Acad Radiol. 2014 Sep;21(9):1117-28.

Cronin P, Rawson JV, Heilbrun ME, Lee JM, Kelly AM, Sanelli PC, Bresnahan BW, Paladin AM. How to report a research study. Acad Radiol. 2014 Sep;21(9):1088-116.

Cui Y. In silico mapping of polymorphic miRNA-mRNA interactions in autoimmune thyroid diseases. Autoimmunity. 2014 Mar 10. [Epub ahead of print] 82 //

2014 gru cancer center publications

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. 2014 Oct 30. pii: S1879-8500(14)00119-2. doi: 10.1016/j.prro.2014.05.005. [Epub ahead of print] 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 Lines Identifies a Subset of Cells with Stem Cell Activity. Mol Cancer Ther.

2015 Feb 11 [Epub ahead of print] doi:10.1158/1535-7163.MCT-14-0228 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. [Epub 2014 Aug 19] Ding ZC, Lu X, Yu M, Lemos H, Huang L, Chandler P, Liu K, Walters M, Krasinski A, Mack M, Blazar BR, Mellor AL, Munn DH, Zhou G. Immunosuppressive Myeloid Cells Induced by Chemotherapy Attenuate Antitumor CD4+ T-Cell Responses through the PD-1-PD-L1 Axis. Cancer Res. 2014 Jul 1;74(13):3441-53. Epub 2014 Apr 29.

Ding ZC, Munn DH, Zhou G. Chemotherapy-induced myeloid suppressor cells and antitumor immunity: The Janus face of chemotherapy in immunomodulation. Oncoimmunology. 2014 Aug 3;3(8):e954471. eCollection 2014.

Dinkins MB, Dasgupta S, Wang G, Zhu G, Bieberich E. Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging. 2014 Aug;35(8):1792-800.

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. 2014 Nov 26:ajprenal.00629.2014. doi: 10.1152/ajprenal.00629.2014. [Epub ahead of print] Dubovsky JA, Flynn R, Du J, Harrington BK, Zhong Y, Kaffenberger B, Yang C, Towns WH, Lehman A, Johnson AJ, Muthusamy N, Devine SM, Jaglowski S, Serody JS, Murphy WJ, Munn DH, Luznik L, Hill GR, Wong HK, MacDonald KK, Maillard I, Koreth J, Elias L, Cutler C, Soiffer RJ, Antin JH, Ritz J, Panoskaltsis-Mortari A, Byrd JC, Blazar BR. Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest.

2014 Nov 3;124(11):4867-76.

Duke WS, Bush CM, Singer MC, Haskins AD, Waller JL, Terris DJ. Incision Planning in Thyroid Compartment Surgery: Getting it Perfect. Endocr Pract. 2014 Aug 22:1-27. [Epub ahead of print] Duke WS, Chaung K, Terris DJ. Contemporary Surgical Techniques. Otolaryngol Clin North Am. 2014 Aug;47(4):529-544. Review.

Duke WS, Terris DJ. Alternative Approaches to the Thyroid Gland. Endocrinol Metab Clin North Am. 2014 Jun;43(2):459-474. Review.

Duke WS, White JR, Waller JL, Terris DJ. Endoscopic Thyroidectomy is Safe in Patients with a High Body Mass Index. Thyroid. 2014 Jul;24(7):1146-50. Epub 2014 Mar 31.

Einstein MH, Smith KM, Davis TE, Schmeler KM, Ferris DG, Savage AH, Gray JE, Stoler MH, Wright TC Jr, Ferenczy A, Castle PE. Clinical Evaluation of the Cartridge-Based GeneXpert Human Papillomavirus Assay in Women Referred for Colposcopy. J Clin Microbiol. 2014 Jun;52(6):2089-95. Epub 2014 Apr 9.

Elding Larsson H, Vehik K, Gesualdo P, Akolkar B, Hagopian W, Krischer J, Lernmark Å, Rewers M, Simell O, She JX, Ziegler A, Haller MJ; TEDDY Study Group. Children followed in the TEDDY study are diagnosed with type 1 diabetes at an early stage of disease. Pediatr Diabetes. 2014 Mar;15(2):118-26.

El Refaey M, Zhong Q, Hill WD, Shi XM, Hamrick MW, Bailey L, Johnson M, Xu J, Bollag WB, Chutkan N, Isales CM. Aromatic amino Acid activation of signaling pathways in bone marrow mesenchymal stem cells depends on oxygen tension. PLoS One. 2014 Apr 11;9(4):e91108. eCollection 2014.

Elangovan S, Pathania R, Ramachandran S, Ananth S, Padia RN, Lan L, Singh N, Martin PM, Hawthorn L, Prasad PD, Ganapathy V, Thangaraju M. The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival. Cancer Res. 2014 Feb 15;74(4):1166-78.

Epub 2013 Dec 26.

Erdogan A, Adame EC, Yu S, Rattanakovit K, Rao SS. Optimal Testing for Diagnosis of Fructose Intolerance: Over-dosage Leads to False Positive Intolerance Test. J Neurogastroenterol Motil. 2014 Oct 30;20(4):560.

Erion JR, Wosiski-Kuhn M, Dey A, Hao S, Davis CL, Pollock NK, Stranahan AM. Obesity elicits interleukin 1-mediated deficits in hippocampal synaptic plasticity. J Neurosci. 2014 Feb 12;34(7):2618-31. // 83

2014 gru cancer center publications

Eroglu B, Kimbler DE, Pang J, Choi J, Moskophidis D, Yanasak N, Dhandapani KM, Mivechi NF. Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury. J Neurochem. 2014 Sep;130(5):626-41.

Eroglu B, Min JN, Zhang Y, Szurek E, Moskophidis D, Eroglu A, Mivechi NF. An essential role for heat shock transcription factor binding protein 1 (HSBP1) during early embryonic development. Dev Biol. 2014 Feb 15;386(2):448-60. Epub 2013 Dec 28.

Ezeakile M, Portik-Dobos V, Wu J, Horuzsko DD, Kapoor R, Jagadeesan M, Mulloy LL, Horuzsko A. HLA-G dimers in the prolongation of kidney allograft survival. J Immunol Res. 2014;2014:153981. Epub 2014 Mar 30.

Fahmy CE, Carrau R, Kirsch C, Meeks D, de Lara D, Solares CA, Otto BA, Prevedello DM. Volumetric analysis of endoscopic and traditional surgical approaches to the infratemporal fossa. Laryngoscope. 2014 May;124(5):1090-6.

Fizazi K, Delva R, Caty A, Chevreau C, Kerbrat P, Rolland F, Priou F, Geoffrois L, Rixe O, Beuzeboc P, Malhaire JP, Culine S, Aubelle MS, Laplanche A. A risk-adapted study of cisplatin and etoposide, with or without ifosfamide, in patients with metastatic seminoma: results of the GETUG S99 multicenter prospective study. Eur Urol. 2014 Feb;65(2):381-6.

Flynn R, Du J, Veenstra RG, Reichenbach DK, Panoskaltsis-Mortari A, Taylor PA, Freeman GJ, Serody JS, Murphy WJ, Munn DH, Sarantopoulos S, Luznik L, Maillard I, Koreth J, Cutler C, Soiffer RJ, Antin JH, Ritz J, Dubovsky JA, Byrd JC, MacDonald KP, Hill GR, Blazar BR. Increased T follicular helper cells and germinal center B cells are required for cGVHD and bronchiolitis obliterans. Blood. 2014 Jun 19;123(25):3988-98.

Galluzzi L, Vacchelli E, Bravo-San Pedro JM, Buqué A, Senovilla L, Baracco EE, Bloy N, Castoldi F, Abastado JP, Agostinis P, Apte RN, Aranda F, Ayyoub M, Beckhove P, Blay JY, Bracci L, Caignard A, Castelli C, Cavallo F, Celis E, Cerundolo V, Clayton A, Colombo MP, Coussens L, Dhodapkar MV, Eggermont AM, Fearon DT, Fridman WH, Fučíková J, Gabrilovich DI, Galon J, Garg A, Ghiringhelli F, Giaccone G, Gilboa E, Gnjatic S, Hoos A, Hosmalin A, Jäger D, Kalinski P, Kärre K, Kepp O, Kiessling R, Kirkwood JM, Klein E, Knuth A, Lewis CE, Liblau R, Lotze MT, Lugli E, Mach JP, Mattei F, Mavilio D, Melero I, Melief CJ, Mittendorf EA, Moretta L, Odunsi A, Okada H, Palucka AK, Peter ME, Pienta KJ, Porgador A, Prendergast GC, Rabinovich GA, Restifo NP, Rizvi N, Sautès-Fridman C, Schreiber H, Seliger B, Shiku H, Silva- Santos B, Smyth MJ, Speiser DE, Spisek R, Srivastava PK, Talmadge JE, Tartour E, Van Der Burg SH, Van Den Eynde BJ, Vile R, Wagner H, Weber JS, L. Whiteside TL, Wolchok JD, Zitvogel L, Zou W, Kroemer G. Classification of current anticancer immunotherapies. Oncotarget. 2014, 5(24) Dec 18 [Epub ahead of print] Gao X, Liu Y, Deeb D, Arbab AS, Gautam SC. Anticancer activity of pristimerin in ovarian carcinoma cells is mediated through the inhibition of prosurvival Akt/NF-κB/mTOR signaling. J Exp Ther Oncol. 2014;10(4):275-83.

Gao XP, Feng F, Zhang XQ, Liu XX, Wang YB, She JX, He ZH, He MF. Toxicity assessment of 7 anticancer compounds in zebrafish. Int J Toxicol.

2014 Mar-Apr;33(2):98-105. Epub 2014 Feb 20.

Geem D, Medina-Contreras O, McBride M, Newberry RD, Koni, PA, Denning TL. Specific Microbiota-Induced Intestinal Th17 Differentiation Requires MHC Class II but Not GALT and Mesenteric Lymph Nodes. J Immunol. 2014 Jul 1;193(1):431-8. Epub 2014 Jun 4.

Ghuman MS, Woodall MN, Alleyne CH Jr. Teaching NeuroImages: Microvascular decompression of the optic nerve. Neurology. 2014 May 20;82(20):1847.

Gonzales JN, Kim KM, Zemskova MA, Rafikov R, Heeke B, Varn MN, Black S, Kennedy TP, Verin AD, Zemskov EA. Low anticoagulant heparin blocks thrombin-induced endothelial permeability in a PAR-dependent manner. Vascul Pharmacol. 2014 Aug;62(2):63-71. Epub 2014 Jan 25.

Gnana-Prakasam JP, Baldowski RB, Ananth S, Martin PM, Smith SB, Ganapathy V. Retinal expression of the serine protease matriptase-2 (Tmprss6) and its role in retinal iron homeostasis. Mol Vis. 2014 Apr 26;20:561-74. eCollection 2014.

Griffin KL, Fischer BM, Kummarapurugu AB, Zheng S, Kennedy TP, Rao NV, Foster WM, Voynow JA. 2-O, 3-O-Desulfated Heparin Inhibits Neutrophil Elastase-Induced HMGB-1 Secretion and Airway Inflammation. Am J Respir Cell Mol Biol. 2014 Apr;50(4):684-9.

Guo G, Marrero L, Rodriguez P, Del Valle L, Ochoa A, Cui Y. Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network. Cancer Res. 2013 Mar 15;73(6):1668-75.

Ha Y, Shanmugam AK, Markand S, Zorrilla E, Ganapathy V, Smith SB. Sigma receptor 1 modulates ER stress and Bcl2 in murine retina. Cell Tissue Res. 2014 Apr;356(1):15-27. Epub 2014 Jan 28.

Han CB, Wang WL, Quint L, Xue JX, Matuszak M, Ten Haken R, Kong FM. Pulmonary artery invasion, high-dose radiation, and overall survival in patients with non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014 Jun 1;89(2):313-21. Epub 2014 Mar 28.

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.

84 //

2014 gru cancer center publications

Hawkins CM, Duszak R, Rawson JV. Social Media in Radiology: Early Trends in Twitter Microblogging at Radiology’s Largest International Meeting. J Am Coll Radiol. 2014 Apr;11(4):387-90.

Hawthorn L, Lan L, Mojica W. Evidence for Field Effect Cancerization in Colorectal Cancer. Genomics. 2014 103:211-21.

He MF, Gao XP, Li SC, He ZH, Chen N, Wang YB, She JX. Anti-angiogenic effect of auranofin on HUVECs in vitro and zebrafish in vivo. Eur J Pharmacol. 2014 Oct 5;740:240-7.

He Q, Wang G, Wakade S, Dasgupta S, Dinkins M, Kong JN, Spassieva SD, Bieberich E. Primary cilia in stem cells and neural progenitors are regulated by neutral sphingomyelinase 2 and ceramide. Mol Biol Cell. 2014 Jun 1;25(11):1715-29.

He Y, Hong Y, Mizejewski GJ. Engineering α-fetoprotein-based gene vaccines to prevent and treat hepatocellular carcinoma: review and future prospects. Immunotherapy. 2014 Jun;6(6):725-36.

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.

Ho B, Jang DW, Van Rompaey J, Figueroa R, Brown JJ, Carrau RL, Solares CA. Landmarks for endoscopic approach to the parapharyngeal internal carotid artery: A radiographic and cadaveric study. Laryngoscope. 2014 Sep;124(9):1995-2001.

Hoda MN, Fagan SC, Khan MB, Vaibhav K, Chaudhary A, Wang P, Dhandapani KM, Waller JL, Hess DC. A 2 × 2 factorial design for the combination therapy of minocycline and remote ischemic perconditioning: efficacy in a preclinical trial in murine thromboembolic stroke model. Exp Transl Stroke Med. 2014 Oct 9;6:10. doi: 10.1186/2040-7378-6-10. eCollection 2014.

Hong M, Ren M, Silva J, Kennedy T, Choi J, Cowell JK, Hao Z. Sepantronium is a DNA damaging agent that synergizes with PLK1 inhibitor volasertib. Am J Cancer Res. 2014 Mar 1;4(2):135-47. eCollection 2014.

Hong S, Noh H, Teng Y, Shao J, Rehmani H, Ding HF, Dong Z, Su SB, Shi H, Kim J, Huang S. SHOX2 is a direct miR-375 target and a novel epithelial-to-mesenchymal transition inducer in breast cancer cells. Neoplasia. 2014 Apr;16(4):279-90.e1-5.

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 Jan 7. [Epub ahead of print] Hong Y, Peng Y, Guo ZS, Guevara-Patino J, Pang J, Butterfield LH, Mivechi NF, Munn DH, Bartlett DL, He Y. Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. Hepatology. 2014 Apr;59(4):1448-58. Epub 2014 Feb 18.

Howell RJ, Solowski NL, Belafsky PC, Courey MC, Merati AL, Rosen CA, Weinberger PM, Postma GN. Microdebrider complications in laryngologic and airway surgery. Laryngoscope. 2014 Nov;124(11):2579-82.

Huang L, Mellor AL. Metabolic control of tumour progression and antitumour immunity. Curr Opin Oncol. 2014 Jan;26(1):92-9. Review.

Ibilibor C, Wells J, Kavuri S, Moses KA. A 55-Year-Old Man with Stage IV Squamous Cell Carcinoma of the Right Groin after External Beam Radiation for Testicular Cancer. Case Rep Urol. 2014;2014:346247. Epub 2014 Jun 15.

Isales CM, Bollag WB. Physiology of the Parathyroid Glands. In: Thyroid and Parathyroid Diseases: Medical and Surgical Management, Second edition. DJ Terris and CG Gourin, eds. Thieme, New York, In press.

Isozaki T, Amin MA, Arbab AS, Koch AE, Ha CM, Edhayan G, Haines GK, Ruth JH. Inhibitor of DNA binding 1 as a secreted angiogenic transcription factor in rheumatoid arthritis. Arthritis Res Ther. 2014 Mar 13;16(2):R68.

Itokazu Y, Yu RK. Amyloid β-Peptide 1-42 Modulates the Proliferation of Mouse Neural Stem Cells: Upregulation of Fucosyltransferase IX and Notch Signaling. Mol Neurobiol. 2014 Jan 17. [Epub ahead of print] Jayakumar C, Nauta FL, Bakker SJ, Bilo H, Gansevoort RT, Johnson MH, Ramesh G. Netrin-1, a urinary proximal tubular injury marker, is elevated early in the time course of human diabetes. J Nephrol. 2014 Apr;27(2):151-7. Epub 2014 Feb 8.

Jaja C, Patel N, Scott SA, Gibson R, Kutlar A. CYP2C9 Allelic Variants and Frequencies in a Pediatric Sickle Cell Disease Cohort: Implications for NSAIDs Pharmacotherapy. Clin Transl Sci. 2014 May 29. [Epub ahead of print] // 85

2014 gru cancer center publications

Janes K, Little JW, Li C, Bryant L, Chen C, Chen Z, Kamocki K, Doyle T, Snider A, Esposito E, Cuzzocrea S, Bieberich E, Obeid L, Petrache I, Nicol G, Neumann WL, Salvemini D. The Development and Maintenance of Paclitaxel-Induced Neuropathic Pain Requires Activation of the Sphingosine 1-Phosphate Receptor Subtype 1. J Biol Chem. 2014 May 29. [Epub ahead of print] Jardim-Perassi BV, Arbab AS, Ferreira LC, Borin TF, Varma NR, Iskander AS, Shankar A, Ali MM, de Campos Zuccari DA. Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer. PLoS One. 2014 Jan 9;9(1):e85311.

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.

Jha V, Workman CJ, McGaha TL, Li L, Vas J, Vignali DA, Monestier M. Lymphocyte Activation Gene-3 (LAG-3) Negatively Regulates Environmentally-Induced Autoimmunity. PLoS One. 2014 Aug 14;9(8):e104484. eCollection 2014.

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 C, Jeon Y, Kleven DT, Pollock JS, White JJ, Pollock DM. Combined endothelin a blockade and chlorthalidone treatment in a rat model of metabolic syndrome. J Pharmacol Exp Ther. 2014 Nov;351(2):467-73.

Jin C, O’Boyle S, Kleven DT, Pollock JS, Pollock DM, White JJ. Anti-hypertensive and anti-inflammatory actions of combined azilsartan and chlorthalidone in Dahl salt-sensitive rats on a high-fat, high-salt diet. Clin Exp Pharmacol Physiol. 2014 May 6. [Epub ahead of print] Jin Y, Sharma A, Bai S, Davis C, Liu H, Hopkins D, Barriga K, Rewers M, She JX. Risk of type 1 diabetes progression in islet autoantibody-positive children can be further stratified using expression patterns of multiple genes implicated in peripheral blood lymphocyte activation and function.

Diabetes. 2014 Jul;63(7):2506-15. Epub 2014 Mar 4.

Johnson TS, Terrell CE, Millen SH, Katz JD, Hildeman DA, Jordan MB. Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. J Immunol. 2014 Jan 1;192(1):84-91.

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. [Epub 2014 Aug 5] Jones MC, Rueggeberg FA, Faircloth HA, Cunningham AJ, Bush CM, Prosser JD, Waller JL, Postma GN, Weinberger PM. Defining the biomechanical properties of the rabbit trachea. Laryngoscope. 2014 Oct;124(10):2352-8.

Joshi AD, Dimitropoulou C, Thangjam G, Snead C, Feldman S, Barabutis N, Fulton D, Hou Y, Kumar S, Patel V, Gorshkov B, Verin AD, Black SM, Catravas JD. Heat shock protein 90 inhibitors prevent LPS-induced endothelial barrier dysfunction by disrupting RhoA signaling. Am J Respir Cell Mol Biol. 2014 Jan;50(1):170-9.

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. 2014 Oct 10. pii: 0003489414549154. [Epub ahead of print] Kassing P, Mulaik MW, Rawson J. Pricing radiology bundled CPT codes accurately: 2014. Radiol Manage. 2014 Mar-Apr;36(2):9-19.

Kazi AA, Flowers WJ, Barrett JM, O’Rourke AK, Postma GN, Weinberger PM. Ethical issues in laryngology: tracheal stenting as palliative care.

Laryngoscope. 2014 Jul;124(7):1663-7. Epub 2014 Jan 15. Review.

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 A, Hagopian W, She JX, Krischer JP, Akolkar B, Schatz DA, Atkinson MA, Triplett EW; for the TEDDY Study Group. Early Childhood Gut Microbiomes Show Strong Geographic Differences Among Subjects at High Risk for Type 1 Diabetes. Diabetes Care. 2014 Dec 17. pii: DC_140850. [Epub ahead of print] Keto CJ, Aronson WJ, Terris MK, Presti JC, Kane CJ, Amling CL, Freedland SJ. Detectable prostate-specific antigen Nadir during androgendeprivation therapy predicts adverse prostate cancer-specific outcomes: results from the SEARCH database. Eur Urol. 2014 Mar;65(3):620-7.

Epub 2012 Dec 6.

86 //

2014 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. 2014 Oct 29. [Epub ahead of print] 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):671-80. doi: 10.1038/onc.2014.4. Epub 2014 Feb 17.

King MD, Whitaker-Lea WA, Campbell JM, Alleyne CH Jr, Dhandapani KM. Necrostatin-1 reduces neurovascular injury after intracerebral hemorrhage. Int J Cell Biol. 2014;2014:495817. Epub 2014 Mar 6.

Klaassen Z, Cleveland C, McCraw CO, Burnette JO, Franken A, Wilhelm S, Kavuri SK, Biddinger PW, Terris MK, Moses KA. Clear Cell Adenocarcinoma of the Prostate: A Rare Oncologic Entity in a 42-Year-Old African American Man. Urology. 2014 Sep 9. pii: S00904295(14)00690-6. doi: 10.1016/j.urology.2014.06.042. [Epub ahead of print] No abstract available.

Klaassen Z, DiBianco JM, Li Q, Terris MK. Re: Risk Factors for Renal Cell Carcinoma in the VITAL Study. Eur Urol. 2014 Oct;66(4):784-5. doi: 10.1016/j.eururo.2014.07.047. No abstract available.

Klaassen Z, Huang J, Tatem AJ, Terris MK. Words of wisdom. Re: Prognostic influence of the third Gleason grade in prostatectomy specimens. Eur Urol. 2014 Feb;65(2):498-9.

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. 2014 Dec 9. doi: 10.1002/cncr.29147. [Epub ahead of print] Kong FM, Cuneo KC, Wang L, Bonner JA, Gaspar LE, Komaki R, Sun A, Morris DE, Sandler HM, Movsas B. Patterns of practice in radiation therapy for non-small cell lung cancer among members of the American Society for Radiation Oncology. Pract Radiat Oncol. 2014 MarApr;4(2):e133-41. Epub 2013 Jun 12.

Kong FM, Zhao J, Wang J, Faivre-Finn C. Radiation dose effect in locally advanced non-small cell lung cancer. J Thorac Dis. 2014 Apr;6(4):336347. Review.

Krafft CE, Schaeffer DJ, Schwarz NF, Chi L, Weinberger AL, Pierce JE, Rodrigue AL, Allison JD, Yanasak NE, Liu T, Davis CL, McDowell JE. Improved frontoparietal white matter integrity in overweight children is associated with attendance at an after-school exercise program. Dev Neurosci. 2014;36(1):1-9. Epub 2014 Jan 21.

Krafft CE, Schwarz NF, Chi L, Weinberger AL, Schaeffer DJ, Pierce JE, Rodrigue AL, Yanasak NE, Miller PH, Tomporowski PD, Davis CL, McDowell JE. An 8-month randomized controlled exercise trial alters brain activation during cognitive tasks in overweight children. Obesity (Silver Spring). 2014 Jan;22(1):232-42.

Kuczma M, Kurczewska A, Kraj P. Modulation of bone morphogenic protein signaling in T-cells for cancer immunotherapy. J Immunotoxicol. 2014 Oct;11(4):319-27.

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.

Kumai T, Ishibashi K, Oikawa K, Matsuda Y, Aoki N, Kimura S, Hayashi S, Kitada M, Harabuchi Y, Celis E, Kobayashi H. Induction of tumor-reactive T helper responses by a posttranslational modified epitope from tumor protein p53. Cancer Immunol Immunother. 2014 May;63(5):469-78. Epub 2014 Mar 15.

Kumai T, Oikawa K, Aoki N, Kimura S, Harabuchi Y, Celis E, Kobayashi H. Tumor-derived TGF-ß and prostaglandin E2 attenuate anti-tumor immune responses in head and neck squamous cell carcinoma treated with EGFR inhibitor. J Transl Med. 2014 Sep 21;12(1):265. [Epub ahead of print] Kutlar A, Embury SH. Cellular adhesion and the endothelium: P-selectin. Hematol Oncol Clin North Am. 2014 Apr;28(2):323-39. Epub 2014 Jan 17.

Kutlar F, Unguru Y, Dixon N, Patel N, Bailey L, Zhuang L, Carmichael H, Kutlar A. Two new hemoglobin variants: Hb Tallahassee [α3(A1)Ser→Tyr; HBA2: c.11C>A] and Hb madison-NC [β119(GH2)Gly→Ser; HBB: c.358G>A]. Hemoglobin. 2014;38(3):207-10. Epub 2014 Jan 29.

Lang L, Liu X, Li Y, Zhou Q, Xie P, Yan C, Chen X. A synthetic manassantin a derivative inhibits hypoxia-inducible factor 1 and tumor growth. PLoS One. 2014 Jun 12;9(6):e99584. eCollection 2014. // 87

2014 gru cancer center publications

Lee HS, Burkhardt BR, McLeod W, Smith S, Eberhard C, Lynch K, Hadley D, Rewers M, Simell O, She JX, Hagopian B, Lernmark A, Akolkar B, Ziegler AG, Krischer JP; TEDDY study group. Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Diabetes Metab Res Rev. 2014 Jul;30(5):424-34.

Lee JH, Choi SS, Kim HW, Xiong WC, Min CK, Lee SJ. Neogenin as a receptor for early cell fate determination in preimplantation mouse embryos.

PLoS One. 2014 Jul 11;9(7):e101989. eCollection 2014.

Lee YY, Erdogan A, Rao SS. How to assess regional and whole gut transit time with wireless motility capsule. J Neurogastroenterol Motil. 2014 Apr 30;20(2):265-70.

Lee YY, Erdogan A, Rao SS. How to perform and assess colonic manometry and barostat study in chronic constipation. J Neurogastroenterol Motil.

2014 Oct 30;20(4):547-52.

Lee YY, Gangireddy V, Khurana S, Rao SS. Are We Ready for Combination Therapy in Moderate-to-Severe Ulcerative Colitis? Gastroenterology.

2014 Aug;147(2):544.

Lee YY, Yu S, Khurana S, Rao SS. Dietary fiber and risk of inflammatory bowel disease: fact or hype? Gastroenterology. 2014 Apr;146(4):1133-4.

Epub 2014 Feb 24.

Lemos H, Huang L, Chandler PR, Mohamed E, Souza GR, Li L, Pacholczyk G, Barber GN, Hayakawa Y, Munn DH, Mellor AL. Activation of the STING Adaptor Attenuates Experimental Autoimmune Encephalitis. J Immunol. 2014 Jun 15;192(12):5571-8. Epub 2014 May 5.

Lemos H, Huang L, McGaha TL, Mellor AL. Cytosolic DNA sensing via the stimulator of interferon genes adaptor: Yin and Yang of immune responses to DNA. Eur J Immunol. 2014 Oct;44(10):2847-53.

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.

Lewandowska L, Matuszkiewicz-Rowińska J, Jayakumar C, Oldakowska-Jedynak U, Looney S, Galas M, Dutkiewicz M, Krawczyk M, Ramesh G. Netrin-1 and Semaphorin 3A Predict the Development of Acute Kidney Injury in Liver Transplant Patients. PLoS One. 2014 Oct 7;9(10):e107898. doi: 10.1371/journal.pone.0107898. eCollection 2014.

Li B, Ding L, Yang C, Kang B, Liu L, Story MD, Pace BS. Characterization of Transcription Factor Networks Involved in Umbilical Cord Blood CD34+ Stem Cells-Derived Erythropoiesis. PLoS One. 2014 Sep 11;9(9):e107133. doi: 10.1371/journal.pone.0107133. eCollection 2014.

Li M, Bolduc AR, Hoda MN, Gamble DN, Dolisca SB, Bolduc AK, Hoang K, Ashley C, McCall D, Rojiani AM, Maria BL, Rixe O, MacDonald TJ, Heeger PS, Mellor AL, Munn DH, Johnson TS. The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J Immunother Cancer. 2014 Jul 7;2:21. eCollection 2014.

Li N, Chen M, Truong S, Yan C, Buttyan R. Determinants of Gli2 co-activation of wildtype and naturally truncated androgen receptors. Prostate.

2014 Oct;74(14):1400-10.

Li Y, Chao F, Huang B, Liu D, Kim J, Huang S. HOXC8 promotes breast tumorigenesis by transcriptionally facilitating cadherin-11 expression.

Oncotarget. 2014 May 15;5(9):2596-607.

Li Y, Wei Z, Yan Y, Wan Q, Du Q, Zhang M. Structure of Crumbs tail in complex with the PALS1 PDZ-SH3-GK tandem reveals a highly specific assembly mechanism for the apical Crumbs complex. Proc Natl Acad Sci U S A. 2014 Dec 9;111(49):17444-9.

Lilenbaum R, Samuels M, Wang X, Kong FM, Jänne 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. 2014 Nov 7. [Epub ahead of print] Liu H, Huang L, Bradley J, Liu K, Bardhan K, Ron D, Mellor AL, Munn DH, McGaha TL. GCN2-dependent metabolic stress is essential for endotoxemic cytokine induction and pathology. Mol Cell Biol. 2014 Feb;34(3):428-38. Epub 2013 Nov 18.

Liu H, Lu S, Gu L, Gao Y, Wang T, Zhao J, Rao J, Chen J, Hao X, Tang SC. Modulation of BAG-1 expression alters the sensitivity of breast cancer cells to tamoxifen. Cell Physiol Biochem. 2014;33(2):365-74. Epub 2014 Feb 6.

88 //

2014 gru cancer center publications

Liu Z, Zhang J, Gao Y, Pei L, Zhou J, Gu L, Zhang L, Zhu B, Hattori N, Ji J, Yuasa Y, Kim W, Ushijima T, Shi H, Deng D. Large-Scale Characterization of DNA Methylation Changes in Human Gastric Carcinomas with and without Metastasis. Clin Cancer Res. 2014 Sep 1;20(17):4598-612.

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. 2014 Oct 2. [Epub ahead of print] Manicassamy S, Manoharan I. Mouse models of acute and chronic colitis. Methods Mol Biol. 2014;1194:437-48.

Manoharan I, Hong Y, Suryawanshi A, Angus-Hill ML, Sun Z, Mellor AL, Munn DH, Manicassamy S. TLR2-Dependent Activation of β-Catenin Pathway in Dendritic Cells Induces Regulatory Responses and Attenuates Autoimmune Inflammation. J Immunol. 2014 Oct 15;193(8):4203-13.

Mansour J, Fields B, Macomson S, Rixe O. Significant anti-tumor effect of bevacizumab in treatment of pineal gland glioblastoma multiforme.

Target Oncol. 2014 Dec;9(4):395-8.

Maria BL. Mitochondrial disease: current understanding and future directions. J Child Neurol. 2014 Sep;29(9):1177-8.

Mason E, Gurrola J 2nd, Reyes C, Brown JJ, Figueroa R, Solares CA. Analysis of the petrous portion of the internal carotid artery: Landmarks for an endoscopic endonasal approach. Laryngoscope. 2014 Sep;124(9):1988-94.

Mei L, Nave KA. Neuregulin-ERBB Signaling in the Nervous System and Neuropsychiatric Diseases. Neuron. 2014 Jul 2;83(1):27-49. Review.

Meng X, Frey K, Matuszak M, Paul S, Ten Haken R, Yu J, Kong FM. Changes in functional lung regions during the course of radiation therapy and their potential impact on lung dosimetry for non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2014 May 1;89(1):145-51.

Menzel S, Rooks H, Zelenika D, Mtatiro SN, Gnanakulasekaran A, Drasar E, Cox S, Liu L, Masood M, Silver N, Garner C, Vasavda N, Howard J, Makani J, Adekile A, Pace B, Spector T, Farrall M, Lathrop M, Thein SL. Global Genetic Architecture of an Erythroid Quantitative Trait Locus, HMIP2. Ann Hum Genet. 2014 Jul 29. [Epub ahead of print] Merchen TD, Boesen EI, Gardner JR, Harbarger R, Kitamura E, Mellor A, Pollock DM, Ghaffari A, Podolsky R, Nahman NS Jr. Indoleamine 2,3-dioxygenase inhibition alters the non-coding RNA transcriptome following renal ischemia-reperfusion injury. Transpl Immunol. 2014 May;30(4):140-4. Epub 2014 Apr 18.

Metz R, Smith C, DuHadaway JB, Chandler P, Baban B, Merlo LM, Pigott E, Keough MP, Rust S, Mellor AL, Mandik-Nayak L, Muller AJ, Prendergast GC. IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant function in inflammation. Int Immunol. 2014 Jul;26(7):357-67. Epub 2014 Jan 8.

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. 2014 Dec 24. pii: S0889-1591(14)00568-6. doi: 10.1016/j.bbi.2014.12.005.

[Epub ahead of print] Mohamed R, Ranganathan P, Jayakumar C, Nauta FL, Gansevoort RT, Weintraub NL, Brands M, Ramesh G. Urinary semaphorin 3A correlates with diabetic proteinuria and mediates diabetic nephropathy and associated inflammation in mice. J Mol Med (Berl). 2014 Dec;92(12):1245-56.

Moreira DM, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Boffetta P, Freedland SJ. Cigarette smoking is associated with an increased risk of biochemical disease recurrence, metastasis, castration-resistant prostate cancer, and mortality after radical prostatectomy: results from the SEARCH database. Cancer. 2014 Jan 15;120(2):197-204.

Murphy M, Krothapalli S, Cuellar J, Kanjanauthai S, Heeke B, Gomadam PS, Guha A, Barnes VA, Litwin SE, Sharma GK. Prognostic value of normal stress echocardiography in obese patients. J Obes. 2014;2014:419724.

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. [Epub 2014 Nov 7] 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. [Epub 2014 Aug 5] Nagato T, Celis E. A novel combinatorial cancer immunotherapy: poly-IC and blockade of the PD-1/PD-L1 pathway. Oncoimmunology. 2014 May 15;3:e28440. eCollection 2014. // 89

2014 gru cancer center publications

Nagato T, Lee YR, Harabuchi Y, Celis E. Combinatorial immunotherapy of polyinosinic-polycytidylic acid and blockade of programmed deathligand 1 induce effective CD8 T-cell responses against established tumors. Clin Cancer Res. 2014 Mar 1;20(5):1223-34. Epub 2014 Jan 3.

Oh JS, Bhalla VK, Needham L, Sharma S, Pipkin WL, Hatley RM, Howell CG. M端llerian-type, cutaneous ciliated cyst in the gluteal cleft mimicking a pilonidal cyst. Pediatr Surg Int. 2014 May;30(5):545-8.

Olala LO, Choudhary V, Johnson M, Bollag WB. Angiotensin II-Induced Protein Kinase D Activates the ATF/CREB Family of Transcription Factors and Promotes StAR mRNA Expression. Endocrinology. 2014 Jul;155(7):2524-33. Epub 2014 Apr 7.

Olala LO, Shapiro BA, Merchen TC, Wynn JJ, Bollag WB. Protein kinase C and Src family kinases mediate angiotensin II-induced protein kinase D activation and acute aldosterone production. Mol Cell Endocrinol. 2014 Jul 5;392(1-2):173-81. Epub 2014 May 22.

Orme-Johnson DW, Barnes VA. Effects of the transcendental meditation technique on trait anxiety: a meta-analysis of randomized controlled trials.

J Altern Complement Med. 2014 May;20(5):330-41.

Pan G, Cao J, Yang N, Ding K, Fan C, Xiong WC, Hamrick M, Isales CM, Shi XM. Role of Glucocorticoid-Induced Leucine Zipper (GILZ) in Bone Acquisition. J Biol Chem. 2014 May 23. [Epub ahead of print] Pan ZQ, Xie D, Choudhary V, Seremwe M, Tsai YY, Olala L, Chen X, Bollag WB. The effect of pioglitazone on aldosterone and cortisol production in HAC15 human adrenocortical carcinoma cells. Mol Cell Endocrinol. 2014 Aug 25;394(1-2):119-28.

Panizza B, Warren TA, Solares CA, Boyle GM, Lambie D, Brown I. Histopathological features of clinical perineural invasion of cutaneous squamous cell carcinoma of the head and neck and the potential implications for treatment. Head Neck. 2014 Nov;36(11):1611-8.

Pantin J, Tian X, Geller N, Ramos C, Cook L, Cho E, Scheinberg P, Vasu S, Khuu H, Stroncek D, Barrett J, Young NS, Donohue T, Childs RW. Long-term outcome of fludarabine-based reduced-intensity allogeneic hematopoietic cell transplantation for debilitating paroxysmal nocturnal hemoglobinuria. Biol Blood Marrow Transplant. 2014 Sep;20(9):1435-9.

Papiez J, Rojiani MV, Rojiani AM. Vascular alterations in schwannoma. Int J Clin Exp Pathol. 2014 Jun 15;7(7):4032-8. eCollection 2014.

Parfenov M, Pedamallu CS, Gehlenborg N, Freeman SS, Danilova L, Bristow CA, Lee S, Hadjipanayis AG, Ivanova EV, Wilkerson MD, Protopopov A, Yang L, Seth S, Song X, Tang J, Ren X, Zhang J, Pantazi A, Santoso N, Xu AW, Mahadeshwar H, Wheeler DA, Haddad RI, Jung J, Ojesina AI, Issaeva N, Yarbrough WG, Hayes DN, Grandis JR, El-Naggar AK, Meyerson M, Park PJ, Chin L, Seidman JG, Hammerman PS, Kucherlapati R; Cancer Genome Atlas Network. Characterization of HPV and host genome interactions in primary head and neck cancers. Proc Natl Acad Sci U S A. 2014 Oct 28;111(43):15544-9.

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 Feb 2. pii: 1402412. [Epub ahead of print] Paschall AV, Zimmerman MA, Torres CM, Yang D, Chen MR, Li X, Bieberich E, Bai A, Bielawski J, Bielawska A, Liu K. Ceramide targets xIAP and cIAP1 to sensitize metastatic colon and breast cancer cells to apoptosis induction to suppress tumor progression. BMC Cancer. 2014 Jan 15;14:24.

Patil M, Sharma BK, Satyanarayana A. Id transcriptional regulators in adipogenesis and adipose tissue metabolism. Front Biosci (Landmark Ed).

2014 Jun 1;19:1386-97.

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. 2014 Sep 2. pii: 1087057114549147. [Epub ahead of print] Paul A, Garcia YA, Zierer B, Patwardhan C, Gutierrez O, Hildenbrand Z, Harris DC, Balsiger HA, Sivils JC, Johnson JL, Buchner J, Chadli A, Cox MB. The Cochaperone SGTA (Small Glutamine-rich Tetratricopeptide Repeat-containing Protein Alpha) Demonstrates Regulatory Specificity for the Androgen, Glucocorticoid, and Progesterone Receptors. J Biol Chem. 2014 May 30;289(22):15297-15308. Epub 2014 Apr 21.

Penwell-Waines L, Wilson CK, Macapagal KR, Valvano AK, Waller JL, West LM, Stepleman LM. Student perspectives on sexual health: implications for interprofessional education. J Interprof Care. 2014 Jul;28(4):317-22. Epub 2014 Feb 18.

Perrine SP, Pace BS, Faller DV. Targeted fetal hemoglobin induction for treatment of beta hemoglobinopathies. Hematol Oncol Clin North Am. 2014 Apr;28(2):233-48.

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2014 gru cancer center publications

Peterson KR, Costa FC, Fedosyuk H, Neades RY, Chazelle AM, Zelenchuk L, Fonteles AH, Dalal P, Roy A, Chaguturu R, Li B, Pace BS. A cell-based high-throughput screen for novel chemical inducers of fetal hemoglobin for treatment of hemoglobinopathies. PLoS One. 2014 Sep 16;9(9):e107006. doi: 10.1371/journal.pone.0107006. eCollection 2014.

Pherson M, Yon JR, Wilhelm S, Toscano MP, Kruse EJ. Mantle cell lymphoma metastasis to the gallbladder. Am Surg. 2014 Jul;80(7):198-9.

Pimentel M, Chang C, Chua KS, Mirocha J, Dibaise J, Rao S, Amichai M. Antibiotic Treatment of Constipation-Predominant Irritable Bowel Syndrome. Dig Dis Sci. 2014 May 1. [Epub ahead of print] Promsote W, Makala L, Li B, Smith SB, Singh N, Ganapathy V, Pace BS, Martin PM. Monomethylfumarate Induces Fetal Hemoglobin Production in Cultured Human Retinal Pigment Epithelial (RPE) and Erythroid Cells, and in Intact Retina. Invest Ophthalmol Vis Sci. 2014 55(8):5382-93.

Promsote W, Veeranan-Karmegam R, Ananth S, Shen D, Chan CC, Lambert NA, Ganapathy V, Martin PM. L-2-oxothiazolidine-4-carboxylic acid attenuates oxidative stress and inflammation in retinal pigment epithelium. Mol Vis. 2014 Jan 7;20:73-88. eCollection 2014.

Prosser JD, Bush CM, Postma GN, Weinberger PM. Thyroid ala perichondrial flaps for subglottic reconstruction. Laryngoscope. 2014 Oct;124(10):2368-70.

Putiri EL, Tiedemann RL, Thompson JJ, Liu C, Ho T, Choi JH, Robertson KD. Distinct and overlapping control of 5-methylcytosine and 5-hydroxymethylcytosine by the TET proteins in human cancer cells. Genome Biol. 2014 Jun 23;15(6):R81.

Pye C, Elsherbiny NM, Ibrahim AS, Liou GI, Chadli A, Al-Shabrawey M, Elmarakby AA. Adenosine Kinase Inhibition Protects The Kidney Against Streptozotocin-Induced Diabetes Through Anti-inflammatory and Anti-oxidant Mechanisms. Pharmacol Res. 2014 Jul;85:45-54. Epub 2014 May 16.

Rafikov R, Dimitropoulou C, Aggarwal S, Kangath A, Gross C, Pardo D, Sharma S, Jezierska-Drutel A, Patel V, Snead C, Lucas R, Verin A, Fulton D, Catravas JD, Black SM. Lipopolysaccharide-induced lung injury involves the nitration-mediated activation of RhoA. J Biol Chem. 2014 Feb 21;289(8):4710-22. Epub 2014 Jan 7.

Rahma OE, Gammoh E, Simon RM, Khleif SN. Is the “3+3� dose-escalation phase I clinical trial design suitable for therapeutic cancer vaccine development? A recommendation for alternative design. Clin Cancer Res. 2014 Sep 15;20(18):4758-67.

Rahma OE, Hamilton JM, Wojtowicz M, Dakheel O, Bernstein S, Liewehr DJ, Steinberg SM, Khleif SN. The immunological and clinical effects of mutated ras peptide vaccine in combination with IL-2, GM-CSF, or both in patients with solid tumors. J Transl Med. 2014 Feb 24;12:55.

Rahma OE, Herrin VE, Ibrahim RA, Toubaji A, Bernstein S, Dakheel O, Steinberg SM, Abu Eid R, Mkrtichyan M, Berzofsky JA, Khleif SN. Preimmature dendritic cells (PIDC) pulsed with HPV16 E6 or E7 peptide are capable of eliciting specific immune response in patients with advanced cervical cancer. J Transl Med. 2014 Dec 16;12:353.

Ramesh G, Ranganathan P. Mouse Models and Methods for Studying Human Disease, Acute Kidney Injury (AKI). Methods Mol Biol.

2014;1194:421-36.

Ramakrishnan R, Tyurin VA, Veglia F, Condamine T, Amoscato A, Mohammadyani D, Johnson JJ, Zhang LM, Klein-Seetharaman J, Celis E, Kagan VE, Gabrilovich DI. Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J Immunol. 2014 Mar 15;192(6):2920-31. Epub 2014 Feb 19. Erratum in: J Immunol. 2014 May 15;192(10):4935. Tuyrin, Vladimir A [corrected to Tyurin, Vladimir A]; Cao, Wei [removed].

Ranganathan P, Jayakumar C, Li DY, Ramesh G. UNC5B receptor deletion exacerbates DSS-induced colitis in mice by increasing epithelial cell apoptosis. J Cell Mol Med. 2014 Apr 10. d [Epub ahead of print] Ranganathan P, Jayakumar C, Mohamed R, Weintraub NL, Ramesh G. Semaphorin 3A inactivation suppresses ischemia/reperfusion-induced inflammation and acute kidney injury. Am J Physiol Renal Physiol. 2014 May 14. [Epub ahead of print] Ranganathan P, Mohamed R, Jayakumar C, Ramesh G. Guidance cue netrin-1 and the regulation of inflammation in acute and chronic kidney disease. Mediators Inflamm. 2014;2014:525891. Epub 2014 Jun 3.

Rao SS. Current and emerging treatment options for fecal incontinence. J Clin Gastroenterol. 2014 Oct;48(9):752-64.

Rao SS, Coss-Adame E, Tantiphlachiva K, Attaluri A, Remes-Troche J. Translumbar and transsacral magnetic neurostimulation for the assessment of neuropathy in fecal incontinence. Dis Colon Rectum. 2014 May;57(5):645-52. // 91

2014 gru cancer center publications

Rao SS, Quigley EM, Shiff SJ, Lavins BJ, Kurtz CB, Macdougall JE, Currie MG, Johnston JM. Effect of linaclotide on severe abdominal symptoms in patients with irritable bowel syndrome with constipation. Clin Gastroenterol Hepatol. 2014 Apr;12(4):616-23.

Ravishankar B, Shinde R, Liu H, Chaudhary K, Bradley J, Lemos HP, Chandler P, Tanaka M, Munn DH, Mellor AL, McGaha TL. Marginal zone CD169+ macrophages coordinate apoptotic cell-driven cellular recruitment and tolerance. Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):4215-20.

Epub 2014 Mar 3.

Rawson JV. Why academic radiologists should use social media. Acad Radiol. 2014 Dec;21(12):1499-500.

Rawson JV, Cronin P. Decision support: the super highway between health services research and change in clinical practice. Acad Radiol. 2014 Sep;21(9):1081-2.

Refaey ME, Zhong Q, Ding KH, Shi XM, Xu J, Bollag WB, Hill WD, Chutkan N, Robbins R, Nadeau H, Johnson M, Hamrick MW, Isales CM. Impact of dietary aromatic amino acids on osteoclastic activity. Calcif Tissue Int. 2014 Aug;95(2):174-82.

Rege J, Nakamura Y, Wang T, Merchen TD, Sasano H, Rainey WE. Transcriptome profiling reveals differentially expressed transcripts between the human adrenal zona fasciculata and zona reticularis. J Clin Endocrinol Metab. 2014 Mar;99(3):E518-27. Epub 2013 Jan 1.

Reid ME, El Beshlawy A, Inati A, Kutlar A, Abboud MR, Haynes J Jr, Ward R, Sharon B, Taher AT, Smith W, Manwani D, Ghalie RG. A double-blind, placebo-controlled phase II study of the efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease.

Am J Hematol. 2014 Jul;89(7):709-13. Epub 2014 Mar 28.

Ruble K, Davis CL, Han HR. Endothelial Health in Childhood Acute Lymphoid Leukemia Survivors: Pilot Evaluation With Peripheral Artery Tonometry. J Pediatr Hematol Oncol. 2014 Feb 26. [Epub ahead of print] Sage LK, Fox JM, Mellor AL, Tompkins SM, Tripp RA. Indoleamine 2,3-Dioxygenase (IDO) Activity During the Primary Immune Response to Influenza Infection Modifies the Memory T Cell Response to Influenza Challenge. Viral Immunol. 2014 Apr;27(3):112-23. Epub 2014 Apr 4.

Sarantopoulos J, Mita AC, Wade JL, Morris JC, Rixe O, Mita MM, Dedieu JF, Wack C, Kassalow L, Craig Lockhart A. Phase I study of cabazitaxel plus cisplatin in patients with advanced solid tumors: study to evaluate the impact of cytochrome P450 3A inhibitors (aprepitant, ketoconazole) or inducers (rifampin) on the pharmacokinetics of cabazitaxel. Cancer Chemother Pharmacol. 2014 Dec;74(6):1113-24.

Schaeffer DJ, Krafft CE, Schwarz NF, Chi L, Rodrigue AL, Pierce JE, Allison JD, Yanasak NE, Liu T, Davis CL, McDowell JE. An 8-month exercise intervention alters frontotemporal white matter integrity in overweight children. Psychophysiology. 2014 May 5. [Epub ahead of print] Schaeffer DJ, Krafft CE, Schwarz NF, Chi L, Rodrigue AL, Pierce JE, Allison JD, Yanasak NE, Liu T, Davis CL, McDowell JE. The relationship between uncinate fasciculus white matter integrity and verbal memory proficiency in children. Neuroreport. 2014 Jun 19. [Epub ahead of print] Schipper MJ, Taylor JM, TenHaken R, Matuzak MM, Kong FM, Lawrence TS. Personalized dose selection in radiation therapy using statistical models for toxicity and efficacy with dose and biomarkers as covariates. Stat Med. 2014 Dec 30;33(30):5330-9.

Shankar A, Kumar S, Iskander AS, Varma NR, Janic B, deCarvalho A, Mikkelsen T, Frank JA, Ali MM, Knight RA, Brown S, Arbab AS. Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo. Chin J Cancer. 2014 Mar;33(3):148-58.

Sharma BK, Patil M, Satyanarayana A. Negative Regulators of Brown Adipose Tissue (BAT)-Mediated Thermogenesis. J Cell Physiol. 2014 Dec;229(12):1901-7.

Shen C, Xiong WC, Mei L. Caspase-3, shears for synapse pruning. Dev Cell. 2014 Mar 31;28(6):604-6.

Shull AY, Noonepalle SK, Lee EJ, Choi JH, Shi H. Sequencing the cancer methylome. Methods Mol Biol. 2015;1238:627-51.

Sierra RA, Thevenot P, Raber PL, Cui Y, Parsons C, Ochoa AC, Trillo-Tinoco J, Valle LD, Rodriguez PC. Rescue of Notch-1 Signaling in AntigenSpecific CD8+ T Cells Overcomes Tumor-Induced T-cell Suppression and Enhances Immunotherapy in Cancer. Cancer Immunol Res. 2014 Aug;2(8):800-11.

Silva J, Sharma S, Cowell JK. Homozygous Deletion of the Lgi1 Gene in Mice Leads to Developmental Abnormalities Resulting in Cortical Dysplasia. Brain Pathol. 2014 Oct 26. doi: 10.1111/bpa.12225. [Epub ahead of print] Singer MC, Heffernan A, Terris DJ. Defining anatomical landmarks for robotic facelift thyroidectomy. World J Surg. 2014 Jan;38(1):92-5.

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2014 gru cancer center publications

Singer MC, Terris DJ. Robotic Facelift Thyroidectomy. Otolaryngol Clin North Am. 2014 Jun;47(3):425-431. Review.

Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, Lee JR, Offermanns S, Ganapathy V. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 2014 Jan 16;40(1):128-39. Epub 2014 Jan 9.

Son CO, Mott FE. Pemetrexed and communicating hydrocephalus. Ochsner J. 2014 Summer;14(2):292-4.

Takemori T, Kaji T, Takahashi Y, Shimoda M, Rajewsky K. Generation of memory B cells inside and outside germinal centers. Eur J Immunol. 2014 May;44(5):1258-64. Epub 2014 Apr 10.

Tao Y, Shen C, Luo S, Traoré W, Marchetto S, Santoni MJ, Xu L, Wu B, Shi C, Mei J, Bates R, Liu X, Zhao K, Xiong WC, Borg JP, Mei L. Role of Erbin in ErbB2-dependent breast tumor growth. Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4429-38.

Tawfik A, Gnana-Prakasam JP, Smith SB, Ganapathy V. Deletion of Hemojuvelin, an Iron-regulatory Protein, in Mice Results in Abnormal Angiogenesis and Vasculogenesis in Retina along with Reactive Gliosis. Invest Ophthalmol Vis Sci. 2014 May 8. [Epub ahead of print] Tawfik A, Markand S, Al-Shabrawey M, Mayo JN, Reynolds J, Bearden SE, Ganapathy V, Smith SB. Alterations of retinal vasculature in cystathionine-β-synthase heterozygous mice: a model of mild to moderate hyperhomocysteinemia. Am J Pathol. 2014 Sep;184(9):2573-85.

Teng Y, Mei Y, Hawthorn L, Cowell JK. WASF3 regulates miR-200 inactivation by ZEB1 through suppression of KISS1 leading to increased invasiveness in breast cancer cells. Oncogene. 2014 Jan 9;33(2):203-11.

Teng Y, Ross JL, Cowell JK. The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. JAKSTAT. 2014 Jan 1;3(1):e28086. Epub 2014 Feb 20. Review.

Teoh JP, Park KM, Wang Y, Hu Q, Kim S, Wu G, Huang S, Maihle N, Kim IM. Endothelin-1/Endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis. Cell Signal. 2014 Dec;26(12):2885-95.

Terry AV Jr, Callahan PM, Beck WD, Vandenhuerk L, Sinha S, Bouchard K, Schade R, Waller JL. Repeated exposures to diisopropylfluorophosphate result in impairments of sustained attention and persistent alterations of inhibitory response control in rats.

Neurotoxicol Teratol. 2014 May 10. [Epub ahead of print] Thakur P, Lamoke F, Chaffin JM, Bartoli M, Lee JR, Duncan MB. Dysplastic hepatocytes develop nuclear inclusions in a mouse model of viral hepatitis. PLoS One. 2014 Jun 16;9(6):e99872. eCollection 2014.

Thangjam GS, Dimitropoulou C, Joshi AD, Barabutis N, Shaw MC, Kovalenkov Y, Wallace CM, Fulton DJ, Patel V, Catravas JD. Novel Mechanism of Attenuation of LPS-Induced NF-κB Activation by the Heat Shock Protein 90 Inhibitor, 17-N-allylamino-17-demethoxygeldanamycin, in Human Lung Microvascular Endothelial Cells. Am J Respir Cell Mol Biol. 2014 May;50(5):942-52.

Thevenot PT, Sierra RA, Raber PL, Al-Khami AA, Trillo-Tinoco J, Zarreii P, Ochoa AC, Cui Y, Del Valle L, Rodriguez PC. The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors. Immunity. 2014 Sep 18;41(3):389-401.

Thornton B, Cohen B, Copeland W, Maria BL. Mitochondrial disease: clinical aspects, molecular mechanisms, translational science, and clinical frontiers. J Child Neurol. 2014 Sep;29(9):1179-207.

Tiedemann RL, Putiri EL, Lee JH, Hlady RA, Kashiwagi K, Ordog T, Zhang Z, Liu C, Choi JH, Robertson KD. Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome. Cell Rep. 2014 Nov 20;9(4):1554-66.

Törn C, Hadley D, Lee HS, Hagopian W, Lernmark A, Simell O, Rewers M, Ziegler A, Schatz D, Akolkar B, Onengut-Gumuscu S, Chen WM, Toppari J, Mykkänen J, Ilonen J, Rich SS, She JX, Steck AK, Krischer J; the TEDDY Study Group. Role of Type 1 diabetes associated SNPs on risk of autoantibody positivity in the TEDDY Study. Diabetes. 2014 Nov 24. pii: DB_141497. [Epub ahead of print] Tsai YY, Rainey WE, Pan ZQ, Frohman MA, Choudhary V, Bollag WB. Phospholipase D Activity Underlies Very-Low-Density Lipoprotein (VLDL)induced Aldosterone Production in Adrenal Glomerulosa Cells. Endocrinology. 2014 Sep;155(9):3550-60.

Tsai YT, Yu RK. Epigenetic activation of mouse ganglioside synthase genes: implications for neurogenesis. J Neurochem. 2014 Jan;128(1):101-10.

// 93

2014 gru cancer center publications

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 decision-making guide for the thyroid cancer care collaborative. Head Neck. 2014 Jan 17. [Epub ahead of print] Usuki S, O’Brien D, Rivner MH, Yu RK. A new approach to ELISA-based anti-glycolipid antibody evaluation of highly adhesive serum samples. J Immunol Methods. 2014 May 23. [Epub ahead of print] Van Rompaey J, Bush C, Solares CA. Anatomic analysis specific for the endoscopic approach to the inferior, medial and lateral orbit. Orbit. 2014 Apr;33(2):115-23. Epub 2013 Dec 19.

Van Rompaey J, Suruliraj A, Carrau R, Panizza B, Solares CA. Meckel’s cave access: anatomic study comparing the endoscopic transantral and endonasal approaches. Eur Arch Otorhinolaryngol. 2014 Apr;271(4):787-94. Epub 2013 Jun 15.

Verma VK, Beevi SS, Tabassum A, Kumaresan K, Kamaraju RS, Arbab AS, Chelluri LK. In vitro assessment of cytotoxicity and labeling efficiency of 99mTc-HMPAO with stromal vascular fraction of adipose tissue. Nucl Med Biol. 2014 Oct;41(9):744-8.

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. 2014 Apr 23. [Epub ahead of print] Viers A, Smith J, Alleyne CH Jr, Allen MB Jr. Neurosurgery at Medical College of Georgia, Georgia Regents University in Augusta (1956-2013).

Neurosurgery. 2014 Sep;75(3):295-305; discussion 304-5. doi: 10.1227/NEU.0000000000000421.

Vricella GJ, Klaassen Z, Terris MK, Madi R. Retrograde robotic radical prostatectomy: description of a new technique and early perioperative outcomes. ISRN Urol. 2014 Mar 10;2014:945604. eCollection 2014.

Wang J, Cheng A, Wakade C, Yu RK. Ganglioside GD3 Is Required for Neurogenesis and Long-Term Maintenance of Neural Stem Cells in the Postnatal Mouse Brain. J Neurosci. 2014 Oct 8;34(41):13790-800.

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.

Wang T, Li YQ, Liu H, Fu XL, Tang SC. Bifocal juvenile papillomatosis as a marker of breast cancer: A case report and review of the literature. Oncol Lett. 2014 Dec;8(6):2587-2590.

Wang X, Yang L, Choi JH, Kitamura E, Chang CS, Ding J, Lee EJ, Cui H, Ding HF. Genome-wide analysis of HOXC9-induced neuronal differentiation of neuroblastoma cells. Genom Data. 2014 Dec 1;2:50-52.

Wang Y, Kim S, Kim IM. Regulation of Metastasis by microRNAs in Ovarian Cancer. Front Oncol. 2014 Jun 10;4:143. eCollection 2014. Review.

Wang Y, Zhang S, Iqbal S, Chen Z, Wang X, Wang YA, Liu D, Bai K, Ritenour C, Kucuk O, Wu D. Pomegranate extract inhibits the bone metastatic growth of human prostate cancer cells and enhances the in vivo efficacy of docetaxel chemotherapy. Prostate. 2014 May;74(5):497-508. [Epub 2013 Dec 23] 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. 2014 Dec 12. doi: 10.1002/ hep.27660. [Epub ahead of print] Wei S, Wang H, Lu C, Malmut S, Zhang J, Ren S, Yu G, Wang W, Tang DD, Yan C. The activating transcription factor 3 protein suppresses the oncogenic function of mutant p53 proteins. J Biol Chem. 2014 Mar 28;289(13):8947-59. Epub 2014 Feb 19.

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. 2014 Oct 21. doi: 10.1038/ ajg.2014.303. [Epub ahead of print] Review.

Woodall MN, McGettigan M, Figueroa R, Gossage JR, Alleyne CH Jr. Cerebral vascular malformations in hereditary hemorrhagic telangiectasia. J Neurosurg. 2014 Jan;120(1):87-92. Epub 2013 Nov 15.

Xie D, Seremwe M, Edwards JG, Podolsky R, Bollag WB. Distinct effects of different phosphatidylglycerol species on mouse keratinocyte proliferation. PLoS One. 2014 Sep 18;9(9):e107119. doi: 10.1371/journal.pone.0107119. eCollection 2014.

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2014 gru cancer center publications

Xu H, Tian YN, Dun BY, Liu HT, Dong GK, Wang JH, Lu SS, Chen B, She JX. A novel monoclonal antibody induces cancer cell apoptosis and enhances the activity of chemotherapeutic drugs. Asian Pac J Cancer Prev. 2014;15(11):4423-8.

Xu Y, An X, Guo X, Habtetsion TG, Wang Y, Xu X, Kandala S, Li Q, Li H, Zhang C, Caldwell RB, Fulton DJ, Su Y, Hoda MN, Zhou G, Wu C, Huo Y. Endothelial 6-Phosphofructo-2-Kinase/Fructose-2, 6-Bisphosphatase, Isoform 3 Plays a Critical Role in Angiogenesis. Arterioscler Thromb Vasc Biol. 2014 34(6):1231-9.

Yamaguchi M, Zhu S, Zhang S, Wu D, Moore TM, Snyder JP, Shoji M. Curcumin analogue UBS109 prevents bone loss in breast cancer bone metastasis mouse model: involvement in osteoblastogenesis and osteoclastogenesis. Cell Tissue Res. 2014 Jul;357(1):245-52. Epub 2014 Apr 11.

Yang AX, Chong N, Jiang Y, Catalano J, Puri RK, Khleif SN. Molecular characterization of antigen-peptide pulsed dendritic cells: immature dendritic cells develop a distinct molecular profile when pulsed with antigen peptide. PLoS One. 2014 Jan 27;9(1):e86306. eCollection 2014.

Yang H, Chen X, Wang X, Li Y, Chen S, Qian X, Wang R, Chen L, Han W, Ruan A, Du Q, Olumi AF, Zhang X. Inhibition of PP2A activity confers a TRAIL-sensitive phenotype during malignant transformation. Mol Cancer Res. 2014 Feb;12(2):217-27.

Yao S, Zheng P, Wu H, Song L, Ying X, Xing C, Li Y, Xiao Z, Zhou X, Shen T, Chen L, Liu Y, Lai M, Mei L, Gao T, Li J. 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. 2014 Dec 17. doi: 10.1002/path.4502. [Epub ahead of print] Yu B, Shah A, Nagarajan VK, Ferris DG. Diffuse reflectance spectroscopy of epithelial tissue with a smart fiber-optic probe. Biomed Opt Express.

2014 Feb 10;5(3):675-89. eCollection 2014 Mar 1.

Yu RK, Itokazu Y. Glycolipid and glycoprotein expression during neural development. Adv Neurobiol. 2014;9:185-222.

Yu SW, Rao SS. Advances in the management of constipation-predominant irritable bowel syndrome: the role of linaclotide. Therap Adv Gastroenterol. 2014 Sep;7(5):193-205. Review.

Yu SW, Rao SS. Anorectal physiology and pathophysiology in the elderly. Clin Geriatr Med. 2014 Feb;30(1):95-106. Review.

Yuan ST, Brown RK, Zhao L, ten Haken RK, Gross M, Cease KB, Schipper M, Stanton P, Yu J, Kong FM. Timing and intensity of changes in FDG uptake with symptomatic esophagitis during radiotherapy or chemo-radiotherapy. Radiat Oncol. 2014 Jan 27;9(1):37.

Zaidi S, Blanchard M, Shim K, Llett 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. 2014 Dec 29. doi: 10.1038/mt.2014.253. [Epub ahead of print] Zakharia Y, Rahma O, Khleif SN. Ovarian cancer from an immune perspective. Radiat Res. 2014 Aug;182(2):239-51.

Zha Y, Xia Y, Ding J, Choi JH, Yang L, Dong Z, Yan C, Huang S, Ding HF. MEIS2 is essential for neuroblastoma cell survival and proliferation by transcriptional control of M-phase progression. Cell Death Dis. 2014 Sep 11;5:e1417.

Zhang B, Shen C, Bealmear B, Ragheb S, Xiong WC, Lewis RA, Lisak RP, Mei L. Autoantibodies to agrin in myasthenia gravis patients. PLoS One. 2014 Mar 14;9(3):e91816.

Zhang D, Liu Y, Wei Q, Huo Y, Liu K, Liu F, Dong Z. Tubular p53 Regulates Multiple Genes to Mediate AKI. J Am Soc Nephrol. 2014 Oct;25(10):2278-89.

Zheng X, Zhang X, Ding L, Lee JR, Weinberger PM, Dynan WS. Synergistic Effect of High Charge and Energy Particle Radiation and Chronological Age on Biomarkers of Oxidative Stress and Tissue Degeneration: A Ground-Based Study Using the Vertebrate Laboratory Model Organism Oryzias latipes. PLoS One. 2014 Nov 6;9(11):e111362. doi: 10.1371/journal.pone.0111362. eCollection 2014.

Zheng Z, Wan Q, Meixiong G, Du Q. Cell cycle-regulated membrane binding of NuMA contributes to efficient anaphase chromosome separation.

Mol Biol Cell. 2014 Mar;25(5):606-19.

Zhi W, Ferris D, Sharma A, Purohit S, Santos C, He M, Ghamande S, She JX. Twelve Serum Proteins Progressively Increase With Disease Stage in Squamous Cell Cervical Cancer Patients. Int J Gynecol Cancer. 2014 Jul;24(6):1085-92. Epub 2014 Jun 5.

Zhu H, Pollock NK, Kotak I, Gutin B, Wang X, Bhagatwala J, Parikh S, Harshfield GA, Dong Y. Dietary sodium, adiposity, and inflammation in healthy adolescents. Pediatrics. 2014 Mar;133(3):e635-42. Epub 2014 Feb 2. // 95

2014 gru cancer center publications

Zhu J, Shang Y, Wan Q, Xia Y, Chen J, Du Q, Zhang M. Phosphorylation-dependent interaction between tumor suppressors Dlg and Lgl. Cell Res. 2014 Apr;24(4):451-63. Epub 2014 Feb 11.

Ziauddin MF, Hua D, Tang SC. Emerging strategies to overcome resistance to endocrine therapy for breast cancer. Cancer Metastasis Rev. 2014 Sep;33(2-3):791-807.

96 //

GRU CANCER CENTER BASIC SCIENCE PROGRAM RESEARCHERS

// 97

index of program researchers

Ande, Satyanarayana, PhD Arbab, Ali, MD, PhD Bieberich, Erhard, PhD Bollag, Wendy B., PhD, FAHA Browning, Darren D., PhD Celis, Esteban, MD, PhD Chadli, Ahmed, PhD Choi, Justin, PhD Cowell, John K., PhD, DSc, FRCPath Cui, Yan, PhD Ding, Han-Fei, PhD Du, Quansheng, PhD Ganapathy, Vadivel, PhD Hao, Zhonglin, MD, PhD Hawthorn, Lesleyann, PhD He, Yukai, MD, PhD Horuzsko, Anatolij, MD, PhD Huang, Lei, PhD Huang, Shuang, PhD Johnson, Theodore S., MD, PhD Khleif, Samir N., MD Kolhe, Ravindra, MBBS, PhD Korkaya, Hasan, DVM, PhD Liu, Kebin, PhD

98 //

// 28 // 55 (80, 81, 82, 84, 85, 86, 92, 94) // 57 (81, 83, 85, 86, 90) // 58, 62 (80, 81, 82, 83, 85, 90, 92, 93, 94) // 59 (94) // 11 (81, 82, 84, 87, 89, 90, 91, 95) // 29 (86, 90, 91) // 31 (84, 85, 91, 92, 93, 94, 95) // 06, 32 (85, 92, 93) // 12 (82, 83, 84, 92, 93) // 61 (83, 85, 94, 95) // 34 (82, 88, 95, 96) // 62 (80, 81, 83, 84, 91, 93) // 35 (84, 85) // 36 (83, 85, 93) // 13 (85) // 38 (84) // 21 (83, 85, 88) // 39 (83, 84, 85, 88, 93, 95) // 14 (86, 88) // 06, 16 (80, 82, 91, 95) // 40 // 42 (83, 87) // 17, 57 (83, 88, 90, 94, 95)

index of program researchers

Maihle, Nita, PhD // 06, 63 (81, 93) // 19 (85, 89, 93) Manicassamy, Santhakumar, PhD // 20 (86, 88, 90, 92) McGaha, Tracy, PhD // 21 (81, 83, 85, 88, 89, 90, 92) Mellor, Andrew, PhD // 43, 45 (84, 85) Mivechi, Nahid F., PhD // 16 (80, 91) Mkrtichyan, Mikayel, PhD // 45 (84) Moskofidis, Dimitrios, MD, PhD // 32 (85) Ren, Mingqiang, PhD // 46 (88, 90) Rojiani, Amyn, MD, PhD // 46 (90) Rojiani, Mumtaz V., PhD // 65 (87) Sakamuro, Daitoku, PhD // 48 (81, 82, 85, 89, 92, 93) Shi, Huidong, PhD // 22, 62 (83, 91, 93, 94) Singh, Nagendra, PhD // 32 (85, 93) Teng, Yong, PhD // 22, 66 (83, 93) Thangaraju, Muthusamy, PhD // 57 (81, 83, 85) Wang, Guanghu, PhD // 49 (80, 85, 86, 89, 91, 95) Weinberger, Paul, MD, FACS // 50 (94, 95) Wu, Daqing, PhD // 67 (80, 93) Wu, Guangyu, PhD // 51 (87, 88, 94, 95) Yan, Chunhong, PhD // 23 (83, 90, 94, 95) Zhou, Gang, PhD

// 99