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Ivan M. Lang, DVM, PhD Professor of Medicine Division of Gastroenterology and Hepatology Medical College of Wisconsin
I graduated with BS in mathematics from University of Pittsburgh, MS and PhD in Physiology and Biophysics from Temple University, and DVM from University of Wisconsin. After the PhD, I obtained an NIH Postdoctoral Fellowship in the study of the Central Neural Control of the Cardiovascular System at Texas Tech University Medical School. I then came to MCW in 1982 as a Research Associate in the Department of Surgery to study the neurophysiology of the digestive tract, transferred to the Division of Gastroenterology and Hepatology in 1992, and became full Professor in the Department of Medicine in 2008. My research objective, i.e. study of the neurophysiology of the digestive tract, has not changed since coming to MCW, but currently my interest is centered on the esophagus.
“The Effect of Body Position on Esophageal Reflexes in Cats: A Possible Mechanism of SIDS?” Lang IM, Medda BK, Shaker R, Jadcherla S. Pediatric Research. 2018;83(3):731-738. It has been hypothesized that sudden infant death syndrome (SIDS) is caused by supra-esophageal reflux (SER) of gastric contents which activates laryngeal chemoreflex-stimulated apnea. In addition, placing infants supine decreases the risk of SIDS. The aim of this study was to determine whether body position affects esophageal reflexes that control SER. We investigated the effects of body position on various esophageal reflexes in cats. We found that the only reflex that was significantly more sensitive in the supine vs prone position was the esophagusstimulated pharyngeal swallow reflex (ESPR). The EPSR occurs in babies and animals, but not adult humans. We hypothesize that the lack of EPSR may contribute to the etiology of SIDS and/or the sensitization of EPSR, by placement of babies in the prone position, may help prevent SIDS. Figure 1. Types of stimuli applied and possible responses.
The possible responses to balloon and air stimulation of the esophagus and water stimulation of the nasopharynx are illustrated. The balloon stimulations were in the form of a ramp, slow square wave, or rapid square wave. The ramp stimulus activated esophago-UES contractile reflex and EPSR. The slow square wave stimulus activated upper esophageal sphincter and secondary peristalsis. The rapid square wave stimulus activated esophago-UES relaxation reflex and EPSR. The air pulse stimulation activated esophago-UES relaxation reflex and EPSR. The nasopharyngeal stimulation activated PS. TH, thyrohyoideus; TP, thyropharyngeus; CP, cricopharyngeus; EMG, electromyography; E#, esophagus #cm from the CP; Mano, manometry; prox, proximal; dist, distal; Stim, stimulus artifact; EPSR, esophagus stimulated pharyngeal swallow response; PS, pharyngeal swallow; SP, secondary peristalsis; EUCR, esophago-UES contractile response; EURR, esophago–UES relaxation response; UES, upper esophageal sphincter.
Figure 5. Effects of body position on the proportion of stimuli activating the EPSR at different esophageal locations using ramp (a), slow square wave (b) and rapid square wave (c) balloon distension, and air pulse (d) stimulation.
Activation of EPSR by all stimuli and at all regions of the esophagus was significantly (P < 0.05) affected by body position. The supine position caused over a 100% increase in the proportion of stimuli that activated EPSR. EPSR, esophagus-stimulated pharyngeal swallow response. See Figure 1 for definition of symbols.
Caitlin R. Patten, MD Assistant Professor of Surgery Division of Surgical Oncology Medical College of Wisconsin
I am fellowship-trained Breast Surgical Oncologist. I completed my General Surgery residency at MCW in 2015 before going to the Carolinas Medical Center in Charlotte, North Carolina to complete my breast fellowship. I returned to MCW in 2016 to join the faculty in the Department of Surgery as an Assistant Professor. While in my fellowship, I became interested in reducing margin re-excision rates for close margins when patients undergo a lumpectomy for early stage breast cancer. Before starting my research project, The Society of Surgical Oncology and The American Society for Radiation Oncology (SSO/ASTRO) developed a consensus guideline that changed the definition of what constituted a positive margin for women undergoing a lumpectomy.
“Changes in Margin Re-excision Rates: Experience Incorporating the “No Ink on Tumor" Guideline into Practice” Patten CR, Walsh K, Sarantou T, et al. Journal of Surgical Oncology. 2017;116(8):1040-1045. In 2014, the SS0/ASTRO consensus guideline changed the definition of a positive margin to “no ink on tumor” for women undergoing a lumpectomy for early stage breast cancer. Prior to the guideline, the definition of a negative margin was 2 mm and women had a 20% chance of having a margin re-excision after a lumpectomy at a single institution. This retrospective review sought to determine if following the guideline led to significant decreases in positive margins and re-excision rates. The implementation of the “no ink on tumor” guideline at a single institution has resulted in a significant decrease in positive margin rates and a numerical decrease in margin re-excisions. Surgeons also continue to use individual patient and histologic factors to decide for or against a margin re-excision. Figure 1. Positive margin and re-excision rates
Michael A. James, PhD Assistant Professor of Surgery Division of Research Medical College of Wisconsin
The goal of research in my lab is to understand key tumor cell survival and therapy resistance mechanisms and exploit them for better cancer therapy. Broadly, my expertise lies in molecular and cellular pathobiology of cancer. I apply this expertise to the functional evaluation of novel tumor-associated proteins. The application of murine modeling, cell biology and molecular biology techniques has allowed me to elucidate CLPTM1L/CRR9 as an anti-apoptotic oncology target that is necessary for oncogene-induced transformation and tumorigenesis. I have developed diseaserepresentative, patient-derived, 3D organoid models of pancreatic cancer in collaboration with Drs. Evans and Tsai, who have established a surgical biorepository for pancreatic cancer tissues and blood at MCW. I have utilized these personalized models in the study of stromal and immune interaction with pancreatic tumor tissues.
“Development of Primary Human Pancreatic Cancer Organoids, Matched Stromal and Immune Cells and 3D Tumor Microenvironment Models” James MA, Tsai S, McOlash L, et al. BMC Cancer. 2018;18(1):335. Personalized models of cancer are increasingly important in an era of targeted medicine. Primary tumor organoids are emergent but have not yet been broadly implemented. Complex organotypic models of pancreatic tumors using organoids, stromal and immune cellular components of the tumor microenvironment (TME) are currently being established. Our objective was to develop and characterize pancreatic cancer organoids and multi-cell type organotypic co-culture models to demonstrate their applicability to the study of pancreatic cancer. We provide the first report of diseaserelevant 3D in-vitro models representing pancreatic tumor, stromal, and immune components using primary tissues, and demonstrate organoid-dependent T-cell infiltration in these models. Organoid TME models promise to facilitate the study of tumor-stroma and tumor-immune interaction and may be valuable for the assessment of immunotherapeutic effects on T-cell infiltration and activation. Figure 1. Organoid Tumor Microenvironment (TME) Models.
Figure 2. TME Model Schematic
A) Primary tumor organoids and cancer-associated fibroblasts (CAFs). B) Micrographs and immunofluorescence for the indicated markers on co-cultured primary tumor organoids and fibroblasts. C) IF staining of Laminin α5 in sections of 3D spheroids and organoids. Bars, 100 µM. D) IF staining of CK19 in tumor tissues and αSMA in stromal fibroblasts. Arrows indicate CK19 positive tumor tissue surrounded by αSMA positive fibroblasts. E) Micrographs of T-lymphocytes in co-culture with organoids or empty matrigel domes at the matrigel boundary. F) Micrographs of fixed cells and immunofluorescence using anti-CD3 and DAPI staining of T-lymphocytes in co-culture with organoids or empty matrigel domes at the matrigel boundary. Dotted lines represent matrigel boundaries. Bars, 100 μM.
Cynthiane Morgenweck, MD, MA Associate Professor Center for Bioethics & Medical Humanities Institute for Health & Equity Medical College of Wisconsin
My focus at the Medical College of Wisconsin is service and education. I am one of the Clinical Ethicists at the Center for Bioethics and Medical Humanities. I am the faculty advisor for the Bioethics Interest Group for medical students here. I teach both medical students and graduate students. I serve on the ethics committees of the Milwaukee County Behavioral Health Division, Froedtert Hospital and Curative Care Network. I am co-director of the Bioethics Pathway for medical students. My ethical interests include informed consent; clinical trials and placebo surgery; do not resuscitate orders; use of scarce resources; errors in medicine; pain management and palliative care; professionalism; and ethical issues in behavioral health care.
â&#x20AC;&#x153;Spirituality at the End of Lifeâ&#x20AC;? Morgenweck CJ. Current Opinion in Anaesthesiology. 2018;31(2):185-189. With the increased emphasis on care of the whole patient, there is an increased need to address the psychosocial and spiritual needs of the patient. Particularly at the end of life, spiritual concerns may come to the fore as patients reflect on their impending death. Physicians may recognize this spiritual distress but may be uncomfortable with providing spiritual support. Some physicians wish to both screen for and support patients in their spiritual quest. Other physicians express concern about causing more distress to patients in a time of significant need. Descriptions of educational tools, as well as the appropriate engagement of chaplains, nurses and palliative care specialists have emerged. Integration of these team members will enhance care of the patient. While not every patient has an interest in spiritual conversation, most do and medical teams need to become more educated about appropriate spiritual engagement. The recent literature has not yet settled on a single all encompassing definition of spirituality; however reading multiple articles creates an understanding of the most common elements across definitions. Given the increasing emphasis on interprofessional relationships to maximize patient health and a majority of patients expressing interest in spirituality, it is reasonable to learn about assessment tools, how to start the engagement and when and to whom to hand off the discussion.
“Deactivation of 12(S)-HETE through (omega-1)-hydroxylation and Betaoxidation in Alternatively Activated Macrophages” Kriska T, Thomas MJ, Falk JR, Campbell WB. Journal of Lipid Research. 2018;59(4):615-624. Polarization of macrophages to pro-inflammatory M1 and to anti-inflammatory alternatively activated M2 states is implicated in experimental hypertension. Also, 12/15Lipoxygenase and its enzymatic products 12(S)- and 15(S)-HETE are essential for the development of hypertension since 12/15-lipoxygenase knockout mice are unsusceptible to hypertension. Our results show that M2, unlike M1, macrophages catabolize 12(S)-HETE into 12,19-dihydroxyeicosatetraenoic acid and 8-hydroxy-6,10-hexadecadienoic acid. This metabolism of 12(S)-HETE involves cytochrome P450s (CYP2E1 and CYP1B1) and peroxisomal β-oxidation enzymes. 12(S)-HETE enhances vasoconstrictions to angiotensin II by 40%; however, its two metabolites were inactive. M2 macrophages may exert a portion of their anti-inflammatory activity by metabolizing the pro-inflammatory 12(S)-HETE.
Tamas Kriska, PhD Research Scientist Department of Pharmacology & Toxicology
Ian Chang, DO Rheumatology Fellow Department of Medicine
“Crystalline Arthropathy and Bone Health” Chang I, Gazeley D. Current Opinion in Rheumatology. 2018;30(2):173-176. The purpose of this review is to provide insight on the proposed association between crystal arthritis and bone health. Crystal arthritis is the most common type of inflammatory arthritis, and fractures contribute to significant morbidity and mortality, therefore, the relationship between the two is of clinical importance. A systematic review and metaanalysis of available data suggest a correlation between increased serum uric acid and lower risk of fracture. Findings support an association between bone health and crystal arthritis which warrants further study and may have implications for how we treat gout.
“The Membrane-distal Regions of Integrin α Cytoplasmic Domains Contribute Differently to Integrin Inside-out Activation” Thinn AMM, Want Z, Zhu J. Scientific Reports. 2018;8(1):5067.
Our paper represents a comprehensive molecular analysis of the role of integrin α cytoplasmic tails in the conformational transition of integrins to the activated states. The systematic construction of integrin α subunit chimeras allowed us to study the activation of almost all α integrins that can pair with integrin β1, β2, or β3 integrin subunits in situ. Briefly, we found that the non-conserved membrane distal regions attributed to the integrin conformational activation strongly by its sequence identity. Overall, our work delivers a useful platform for investigating the molecular mechanisms of integrin α cytoplasmic tails in integrin-mediated cell adhesive functions.
Aye Myat Myat Thinn PhD Student Department of Biochemistry
Muhammad Bilal Abid, MD, MRCP Fellow Physician Department of Medicine Division of Infectious Diseases
“Pegylated Filgrastim Versus Filgrastim for Stem Cell Mobilization in Multiple Myeloma After Novel Agent Induction” Abid MB, De Mel S, Abid MA, et al. Clinical Lymphoma Myeloma Leukemia. 2018;18(3):174179. The current standard of care for transplant-eligible multiple myeloma patients is novel agent-based (NA) induction followed by high-dose chemotherapy and autologous stem cell transplant (ASCT). This study analyzed the efficacy of pegfilgrastim in peripheral blood stem cell (PBSC) mobilization compared to filgrastim, exclusively after NA-based induction in a homogeneous group of myeloma patients. We analyzed 89 patients treated at 2 transplant centers in Singapore who received NA-based induction chemotherapy, PBSC mobilization with vinorelbine/cyclophos-phamide, high-dose melphalan conditioning and ASCT. This study demonstrates that a single dose of pegfilgrastim is comparable to filgrastim in terms of the timing and efficacy of PBSC harvest and could potentially spare the patient of 6 days of filgrastim injections.
“The Influence of Constructed Family Membership on HIV Risk Behaviors among Gay, Bisexual, and Other Men Who Have Sex with Men in New Orleans” Zarwell MC, Robinson WT. Journal of Urban Health. 2018;95(2):179-187. Many gay and bisexual men (GBM) belong to social groups within the LGBT community, including constructed families (CF) in which members refer to their friends as family. During the 2014 National HIV Behavioral Surveillance system in New Orleans, 553 GBM were recruited via venue-based time-space sampling and completed a structured survey. GBM of color were more likely to belong to CF and those with a shared family name were less likely to engage in risky sexual behaviors. GBM who did not belong to any social groups reported higher sexual risk. These findings contribute to understanding variation in risk among GBM.
Meagan Zarwell, PhD Postdoctoral Fellow Center for AIDS Intervention Research
Hans W. Hauschild, MS Senior Research Engineer Department of Neurosurgery
“The Influence of Child Restraint Lower Attachment Method on Protection Offered by Forward Facing Child Restraint Systems in Oblique Loading Conditions” Hauschild WH, Humm JR, Pintar FA, et al. Traffic Injury Prevention. 2018;19(sup1):S139-S145.
This study investigated child restraint system (CRS) lower anchor attachment systems effect on a 3-year-old center seated child during an oblique vehicle crash. Three lower attachment systems were dynamically evaluated, rigid, dual flexible webbing, and single flexible webbing; all systems were evaluated with and without a tether. The tether had greater influence on the test dummy for the flexible webbing systems than the rigid system. Results found the dual webbing and rigid attached CRS performed better than the single webbing, reducing head excursions approximately 23% and 19% respectively, thereby reducing potential head contact injuries; and also reducing neck tension loads approximately 38% and 26% respectively.
“Secretory Carcinoma of the Parotid with Adenoid Cystic Carcinoma Cytological Pattern: A Cytological-pathological Correlation with Literature Review” Kravtsov O, Hunt B, Peterson J, Carrillo L, Bonneau P, Giorgadze T. Annals of Diagnostic Pathology. 2018;33:58-61. Secretory carcinoma (SC) is a rare low-grade malignant tumor, defined by ETV6-NTRK3 fusion. We describe a case in 58-year-old male with slowly growing parotid mass. FNA of the mass showed pleomorphic cells with abundant globular metachromatic material, resembling that of adenoid cystic carcinoma, was noted. FNA diagnosis of SC was made. ETV6 FISH and excised tumor morphology confirmed the diagnosis. Finding the globular metachromatic material in SC, that is generally seen in adenoid cystic carcinoma, broadens a cytological differential diagnosis of both entities. Cytological differential diagnosis, clinical, histological, immunohistochemical, and molecular features of secretory carcinomas are discussed in this study.
Oleksandr Kravtsov, MD Pathology Resident, PGY IV Department of Pathology
Alex Nielsen, BS Medical Student, M4 Department of Surgery
“Perioperative Bleeding and Blood Transfusion are Major Risk Factors for Venous Thromboembolism following Bariatric Surgery” Nielsen AW, Helm MC, Kindel T, et al. Surgical Endoscopy. 2018;32(5):2488-1495. Bariatric surgery patients who receive postoperative blood transfusion are at a significantly increased risk for VTE. The etiology of VTE in those who are transfused is likely multifactorial and possibly related to withholding chemoprophylaxis and the potential of a hypercoagulable state induced by the transfusion. In those who bleed, consideration should be given to reinitiating chemoprophylaxis when safe, extending treatment after discharge, and screening ultrasound.