Gastroenterology Commons^™

Targeting Transcription Factor Tcf4 By Γ-Mangostin, A Natural Xanthone., Balaji Krishnamachary, Dharmalingam Subramaniam, Prasad Dandawate, Sivapriya Ponnurangam, Pugazhendhi Srinivasan, Prabhu Ramamoorthy, Shahid Umar, Sufi Mary Thomas, Animesh Dhar, Seth Septer, Scott J. Weir, Thomas M. Attard, Shrikant Anant

Manuscripts, Articles, Book Chapters and Other Papers

Given that colon cancer is the third most common cancer in incidence and cause of death in the United States, and current treatment modalities are insufficient, there is a need to develop novel agents. Towards this, here we focus on γ-Mangostin, a bioactive compound present in the Mangosteen (Garcinia mangostana) fruit. γ-Mangostin suppressed proliferation and colony formation, and induced cell cycle arrest and apoptosis of colon cancer cell lines. Further, γ-Mangostin inhibited colonosphere formation. Molecular docking and CETSA (Cellular thermal shift assay) binding assays demonstrated that γ-Mangostin interacts with transcription factor TCF4 (T-Cell Factor 4) at the β-catenin …

Excision Repair Cross-Complementing Group-1 (Ercc1) Induction Kinetics And Polymorphism Are Markers Of Inferior Outcome In Patients With Colorectal Cancer Treated With Oxaliplatin., Devika Rao, Atrayee Basu Mallick, Titto Augustine, Cecilia Daroqui, Jeeshan Jiffry, Amartej Merla, Imran Chaudhary, Raviraja Seetharam, Arjun Sood, Srikanth Gajavelli, Santiago Aparo, Lakshmi Rajdev, Andreas Kaubisch, Jennifer Chuy, Abdissa Negassa, John M. Mariadason, Radhashree Maitra, Sanjay Goel

Department of Medical Oncology Faculty Papers

Background: ERCC1, a component of nucleotide excision repair pathway, is known to repair DNA breaks induced by platinum drugs. We sought to ascertain if ERCC1 expression dynamics and a single nucleotide polymorphism (SNP) rs11615 are biomarkers of sensitivity to oxaliplatin therapy in patients with colorectal cancer (CRC).

Methods: Western blot and qPCR for ERCC1 expression was performed from PBMCs isolated from patients receiving oxaliplatin-based therapy at specified timepoints. DNA was also isolated from 59 biorepository specimens for SNP analysis. Clinical benefit was determined using progression free survival (PFS) for metastatic CRC.

Results: ERCC1 was induced in PBMC in response to …

Using Shared Decision Making And Team-Based Care To Overcome Socioeconomic And Cultural Barriers To Colorectal Cancer Screenings, Amanda Powell, Debra L. Pyle, Kristin Rowse, Misty Weeman, Rachel Kidder, Ruth Hanselman, Suneela Nayak, Stephen Tyzik, Amy Sparks

Operations Transformation

Colorectal cancer is the third leading cause of cancer death in the United States. It disproportionally affects minorities and those in lower socioeconomic groups. The use of fecal immunochemical testing (FIT) is a low barrier, low cost and low risk screening tool as compared to the traditional colonoscopy exam. The use of FIT offers the opportunity to overcome barriers such as cultural, economic and low health literacy.

As part of a large health care system, an internal medicine clinic wanted to increase the use and return of FIT in their clinic patients. A team developed a plan for implementing improvement …

Hot Snare Vs. Cold Snare Polypectomy For Endoscopic Removal Of 4-10mm Colorectal Polyps During Colonoscopy: A Systematic Review And Meta-Analysis Of Randomized Controlled Studies, Mahendran Jayaraj

School of Medicine Faculty Research

Introduction In recent years, cold snare polypectomy (CSP) has increasingly been used over hot snare polypectomy (HSP) for the removal of colorectal polyps (4 – 10 mm in size). However, the optimal technique (CSP vs. HSP), in terms of complete polyp resection and complications, is uncertain. Our aim was to compare incomplete resection rate (IRR) of polyps and complications using CSP vs. HSP. Methods Randomized controlled studies (RCTs) comparing CSP and HSP for removal of 4 – 10 mm colorectal polyps were considered. Studies were included in the analysis if they obtained biopsy specimens from the resection margin to confirm …

The Role Of Activin A Signaling In Gastric Reflux-Related Diseases And The Progression To Esophageal Adenocarcinoma, Cedric J. Roudebush

Honors Undergraduate Theses

Gastroesophageal reflux disease (GERD), or acid reflux, affects 6-9 million people in the United States. It is characterized by a reflux of gastric acid and bile salts from the stomach into the esophagus, causing injuries to the esophagus known as Barrett's esophagus (BE). BE is the main risk factor for the development of esophageal adenocarcinoma (EAC), a devastating cancer in the esophagus whose molecular roots remain poorly understood. In recent years, evidence points to the esophageal epithelium itself as responsible for causing and promoting inflammation upon injury by gastric reflux, namely via an increase in inflammatory cytokine secretion. This project …

Blockade Of Fibroblast Activation Protein In Combination With Radiation Treatment In Murine Models Of Pancreatic Adenocarcinoma., Andrew J Gunderson, Tomoko Yamazaki, Kayla Mccarty, Michaela Phillips, Alejandro F Alice, Shelly Bambina, Lauren Zebertavage, David Friedman, Benjamin Cottam, Pippa Newell, Michael J. Gough, Marka R Crittenden, Pieter Van Der Veken, Kristina H Young

Articles, Abstracts, and Reports

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic stroma with a poor lymphocyte infiltrate, in part driven by cancer-associated fibroblasts (CAFs). CAFs, which express fibroblast activation protein (FAP), contribute to immune escape via exclusion of anti-tumor CD8+ T cells from cancer cells, upregulation of immune checkpoint ligand expression, immunosuppressive cytokine production, and polarization of tumor infiltrating inflammatory cells. FAP is a post-proline peptidase selectively expressed during tissue remodeling and repair, such as with wound healing, and in the tumor microenvironment by cancer-associated fibroblasts. We targeted FAP function using a novel small molecule inhibitor, UAMC-1110, and mice with germline knockout …

Genetic Evolution And Prognostic Determinants Of Pancreatic Cancer On Longitudinal Liquid Biopsies, Vincent Bernard

Dissertations and Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates amongst solid tumors. As early detection of PDAC is unusual and typically incidental, most patients present with locally advanced and metastatic disease where effective therapeutic strategies remain a significant unmet need. Specifically, surrogate biomarkers for tumor monitoring of PDAC may lead to improved elucidation of clinical actionability and prognostic potential. On the other hand, tumor tissue is rarely sampled in patients presenting with de novo or recurrent metastatic PDAC, apart from a fine needle aspiration or a core needle biopsy performed for diagnosis. This precludes the opportunity for …

Intestinal Barrier Tightening By A Cell-Penetrating Antibody To Bin1, A Candidate Target For Immunotherapy Of Ulcerative Colitis., Sunil Thomas, Kevther Hoxha, Walker Alexander, John Gilligan, Rima Dilbarova, Kelly Whittaker, Andrew Kossenkov, George C. Prendergast, James M. Mullin

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Patients afflicted with ulcerative colitis (UC) are at increased risk of colorectal cancer. While its causes are not fully understood, UC is associated with defects in colonic epithelial barriers that sustain inflammation of the colon mucosa caused by recruitment of lymphocytes and neutrophils into the lamina propria. Based on genetic evidence that attenuation of the bridging integrator 1 (Bin1) gene can limit UC pathogenicity in animals, we have explored Bin1 targeting as a therapeutic option. Early feasibility studies in the dextran sodium sulfate mouse model of experimental colitis showed that administration of a cell-penetrating Bin1 monoclonal antibody (Bin1 mAb 99D) …

Prothrombin Complex Concentrates Or Recombinant Factor Viia Are More Effective Than Fresh-Frozen Plasma At Lowering Inr In Patients With Liver Disease, Abel J. Ignatius

Clinical Research in Practice: The Journal of Team Hippocrates

A critical appraisal and clinical application of Kwon JO, MacLaren R. Comparison of fresh-frozen plasma, four-factor prothrombin complex concentrates, and recombinant factor VIIa to facilitate procedures in critically ill patients with coagulopathy from liver disease: a retrospective cohort study. Pharmacotherapy. 2016;36(10):1047-1054. doi: 10.1002/phar.1827

Evaluation Of The Sharkcore, Benjamin L. Witt, Rachel E. Factor, Barbara E. Chadwick, Justin Caron, Ali A. Siddiqui, Douglas G. Adler

Division of Gastroenterology and Hepatology Faculty Papers

Background and Objectives:

EUS guided core biopsy was once rarely performed but is now entering mainstream practice. Neuroendocrine tumors often warrant core biopsy as sufficient tissue must be obtained to allow for special staining to ensure a correct diagnosis. Traditionally these lesions were sampled with FNA needles. We performed a retrospective pilot study to evaluate the clinical value and efficacy of the a new EUS core needle biopsy needle as compared to a standard EUS FNA needle in the evaluation of patients with known or suspected neuroendocrine tumors.

Methods:

A retrospective analysis of the first 10 patients (between January 2015 …

Exploring The Excluded Stomach: A Case Series Of Novel Endoscopic Techniques To Diagnose Gastric Cancer In The Excluded Stomach After Roux-En-Y Gastric Bypass Surgery, Saeed Ali, Abdelkader Chaar, Wesam Frandah, Rola Altoos, Zeeshan Sattar, Muhammad Hasan

Internal Medicine

Gastric cancer is the fifth most common malignancy worldwide and the fourth leading cause of cancer-related deaths. The diagnosis is usually made by direct visualization with supporting histopathology. However, patients with gastric bypass surgery pose a challenge in diagnosis due to the difficulty in the evaluation of the excluded stomach. We present two cases of gastric cancer in the excluded stomach after Roux-en-Y gastric bypass (RYGB) surgery was diagnosed using two different endoscopic approaches.

Capecitabine And Temozolomide In Neuroendocrine Tumor Of Unknown Primary, Aman Chauhan, Zainab Farooqui, Leaundra Murray, Heidi L. Weiss, Zin W. Myint, Arun Kumar A. Raajasekar, B. Mark Evers, Susanne M. Arnold, Lowell B. Anthony

Internal Medicine Faculty Publications

Incidence of low grade well-differentiated neuroendocrine tumors (NET) is on the rise. The North American Neuroendocrine Tumor Society estimates that the United States has more than 150,000 gastroenteropancreatic NET patients. About 10% of metastatic NETs can be unknown primary, and due to their rarity, dedicated treatment algorithms and regimens are not defined. Combination of capecitabine and temozolomide (CAPTEM) is one of the systemic treatments used in gastroenteropancreatic NETs. We explored clinical activity of CAPTEM in NET of unknown primary. Methods. Retrospective review of NET of unknown primary managed at the University of Kentucky over the past five years (2012–2016). …

Plasma Inflammatory Cytokines And Survival Of Pancreatic Cancer Patients., A. Babic, N. Schnure, N. P. Neupane, M. M. Zaman, N. Rifai, M. W. Welch, L. K. Brais, D. A. Rubinson, V. Morales-Oyarvide, C. Yuan, S. Zhang, E. M. Poole, B. M. Wolpin, M. H. Kulke, D. A. Barbie, K. Wong, C. S. Fuchs, K. Ng

Department of Medical Oncology Faculty Papers

OBJECTIVES: Inflammation and inflammatory conditions have been associated with pancreatic cancer risk and progression in a number of clinical, epidemiological, and animal model studies. The goal of the present study is to identify plasma markers of inflammation associated with survival of pancreatic cancer patients, and assess their joint contribution to patient outcome.

METHODS: We measured circulating levels of four established markers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), soluble tumor necrosis factor receptor type II (sTNF-RII), and macrophage inhibitory cytokine-1 (MIC-1)) in 446 patients enrolled in an ongoing prospective clinic-based study. Hazard ratios (HRs) and 95% confidence intervals (CI) for …

Mandatory Multidisciplinary Approach For The Evaluation Of The Lymph Node Status In Rectal Cancer, Marian Diaconescu, Cosmin V. Obleaga, Cecil S. Mirea, Mihai C. Ciorbagiu, Emil Moraru, Ionica D. Vilcea

Journal of Mind and Medical Sciences

Colorectal cancer is the third most frequently reported malignancy and also the third leading cancer-related cause of death worldwide. Lymph node evaluation, both preoperatively and postoperatively, represents an important aspect of the diagnosis and therapeutic strategy in colorectal cancer, such that an accurate preoperative staging is required for a correct therapeutic strategy. Treatment of rectal cancer with positive lymph nodes, a very important predictive prognostic parameter, is currently based on neoadjuvant chemoradiotherapy followed by total/ surgical mesorectal excision and adjuvant regimen.

Preoperative evaluation of the lymph node status in rectal cancer is based on endoscopic ultrasound and magnetic resonance imaging, …

14th Annual Parkview Research Symposium, Michael J. Mirro, Neil Sharma, Tammy Toscos, Roy Robertson Md, Micah Smith Md, Jason Voorhies Md

Presentations and Events

14th Annual Parkview Research Symposium: Innovative Interventions in Healthcare

Objectives

* Discuss latest innovative interventions in informatics, oncology, cardiology, orthopedids and neurosurgery.

* Develop a strategy for efficient diagnosis and treatment planning using the latest innovative techniques and research findings in informatics, oncology, cardiology, orthopedics and neurosurgery.

Beta-Catenin Cleavage Enhances Transcriptional Activation, Tatiana Goretsky, Emily M. Bradford, Qing Ye, Olivia F. Lamping, Tomas Vanagunas, Mary Pat Moyer, Patrick C. Keller, Preetika Sinh, Josep M. Llovet, Tianyan Gao, Qing-Bai She, Linheng Li, Terrence A. Barrett

Internal Medicine Faculty Publications

Nuclear activation of Wnt/β-catenin signaling is required for cell proliferation in inflammation and cancer. Studies from our group indicate that β-catenin activation in colitis and colorectal cancer (CRC) correlates with increased nuclear levels of β-catenin phosphorylated at serine 552 (pβ-Cat⁵⁵²). Biochemical analysis of nuclear extracts from cancer biopsies revealed the existence of low molecular weight (LMW) pβ-Cat⁵⁵², increased to the exclusion of full size (FS) forms of β-catenin. LMW β-catenin lacks both termini, leaving residues in the armadillo repeat intact. Further experiments showed that TCF4 predominantly binds LMW pβ-Cat⁵⁵² in the nucleus of inflamed and …

Site-Specific Selection Reveals Selective Constraints And Functionality Of Tumor Somatic Mtdna Mutations., Deyang Li, Xiaohong Du, Xu Guo, Lei Zhan, Xin Li, Chun Yin, Cheng Chen, Mingkun Li, Bingshan Li, Hushan Yang, Jinliang Xing

Department of Medical Oncology Faculty Papers

BACKGROUND: Previous studies have indicated that tumor mitochondrial DNA (mtDNA) mutations are primarily shaped by relaxed negative selection, which is contradictory to the critical roles of mtDNA mutations in tumorigenesis. Therefore, we hypothesized that site-specific selection may influence tumor mtDNA mutations.

METHODS: To test our hypothesis, we developed the largest collection of tumor mtDNA mutations to date and evaluated how natural selection shaped mtDNA mutation patterns.

RESULTS: Our data demonstrated that both positive and negative selections acted on specific positions or functional units of tumor mtDNAs, although the landscape of these mutations was consistent with the relaxation of negative selection. …

Conference Proceedings: Aurora Scientific Day 2017

Journal of Patient-Centered Research and Reviews

This supplement includes select abstracts presented at the 43rd Annual Aurora Scientific Day research symposium on May 24, 2017. Aurora Scientific Day hosts a forum for original research conducted by faculty, fellows, residents, and other allied health professionals affiliated with Aurora Health Care, an integrated health system headquartered in Milwaukee, Wisconsin.

Gastrointestinal Stromal Tumor Induced Hypercalcemia, Aram Barbaryan, Stefania Bailuc, Padma Poddutoori, Aida Richardson, Aibek E. Mirrakhimov

Internal Medicine Faculty Publications

Hypercalcemia in patients with cancer is a common laboratory finding affecting up to 44% of that patient population. 1,25-Dihydroxyvitamin D₃ mediated hypercalcemia is one of the rare mechanisms of this endocrine emergency in cancer patients. It is even rarer for solid organ neoplasms to present with hypercalcemia mediated through the production of 1,25-dihydroxyvitamin D₃. We report a case of a 77-year-old female who presented to the hospital with hypercalcemia and later was found to have metastatic gastrointestinal stromal tumor. There have been only 5 cases of gastrointestinal stromal tumor described in literature resulting in hypercalcemia. In our …

Intrahepatic Cholangiocarcinoma Presenting As Li-Rads 5 "Hcc", Raja K. Dhanekula, Md, Donald Mitchell, Md, John Farber, Md, Ashwin R. Sama, Md, Jesse M. Civan, Md

Division of Gastroenterology and Hepatology Posters

Background

• Hepatocellular Carcinoma (HCC), if within Milan Criteria, is an indication for liver transplantation.

• In contrast, intrahepatic cholangiocarcinoma (IHCC) is a contra-indication to liver transplantation due to high rates of recurrence.

• LI-RADS 5 classification (synonymous with OPTN-5) carries a near 100% positive predictive value for HCC, allowing prioritization of patients for liver transplantation without histological confirmation.

• The “LI-RADS M” classification indicates the presence of malignancy not meeting diagnostic criteria for HCC. In theory, IHCC lesions should be identified as LI-RADS M and not LI-RADS 5.

Cleveland Clinic Summer Scholars Program, Monica Singh

Trick to the Treat of Internships and Research

No abstract provided.

The Substrate Of The Biopsychosocial Influences In The Carcinogenesis Of The Digestive Tract, Georgică C. Târtea, Cristina Florescu, Daniel Pirici, Daniel Caragea, Elena A. Târtea, Cristin C. Vere

Journal of Mind and Medical Sciences

Digestive cancer represents a severe public health problem, being one of the main causes of death. It is considered a multifactorial disease, with hereditary predisposition, environmental factors, and other factors involved in carcinogenesis. Both the evolution and the pathogenesis of digestive neoplasms remain incompletely elucidated. As a multifactorial disease, it can be approached by taking into account the biopsychosocial influences via enteric nervous system. Many peptides and non-peptides having a neurotransmitter role can be found in the enteric nervous system, which can influence the neoplastic process directly or indirectly by affecting some angiogenic, growth, and metastasis factors. However, neurotransmitters can …

Colorectal Cancer Prevention: Perspectives Of Key Players From Social Networks In A Low-Income Rural Us Region, Nancy E. Schoenberg, Kathryn Eddens, Adam Jonas, Claire Snell-Rood, Christina R. Studts, Benjamin Broder-Oldach, Mira L. Katz

Behavioral Science Faculty Publications

Social networks influence health behavior and health status. Within social networks, “key players” often influence those around them, particularly in traditionally underserved areas like the Appalachian region in the USA. From a total sample of 787 Appalachian residents, we identified and interviewed 10 key players in complex networks, asking them what comprises a key player, their role in their network and community, and ideas to overcome and increase colorectal cancer (CRC) screening. Key players emphasized their communication skills, resourcefulness, and special occupational and educational status in the community. Barriers to CRC screening included negative perceptions of the colonoscopy screening procedure, …

Differences And Similarities In The Clinicopathological Features Of Pancreatic Neuroendocrine Tumors In China And The United States: A Multicenter Study, Li-Ming Zhu, Laura Tang, Xin-Wei Qiao, Edward M. Wolin, Nicholas N. Nissen, Deepti Dhall, Jie Chen, Lin Shen, Yihebali Chi, Yao-Zong Yuan, Qi-Wen Ben, Bin Lv, Ya-Ru Zhou, Chun-Mei Bai, Jie Chen, Yu-Li Song, Tian-Tian Song, Chong-Mei Lu, Run Yu, Yuan-Jia Chen

Markey Cancer Center Faculty Publications

The presentation, pathology, and prognosis of pancreatic neuroendocrine tumors (PNETs) in Asian patients have not been studied in large cohorts. We hypothesized that the clinicopathological features of PNETs of Chinese patients might be different from those of US patients. The objectives of this study were to address whether PNETs in Chinese patients exhibit unique clinicopathological features and natural history, and can be graded and staged using the WHO/ENETS criteria.

This is a retrospective review of medical records of patients with PNETs in multiple academic medical centers in China (7) and the United States (2). Tumor grading and staging were based …

Screening Of Exosomal Micrornas From Colorectal Cancer Cells, Cillian Clancy, Sonja Khan, Claire L. Glynn, Emma Holian, Peter Dockery, Pierce Lalor, James A.L. Brown, Myles Joyce, Michael J. Kerin, Roisin M. Dwyer

Forensic Science Publications

BACKGROUND: Cells release extracellular membrane vesicles including microvesicles known as exosomes. Exosomes contain microRNAs (miRNAs) however the full range within colorectal cancer cell secreted exosomes is unknown. OBJECTIVE: To identify the full range of exosome encapsulated miRNAs secreted from 2 colorectal cancer cell lines and to investigate engineering of exosomes over-expressing miRNAs. METHODS: Exosomes were isolated from HCT-116 and HT-29 cell lines. RNA was extracted from exosomes and microRNA array performed. Cells were engineered to express miR-379 (HCT-116-379) or a non-targeting control (HCT-116-NTC) and functional effects were determined. Exosomes secreted by engineered cells were transferred to recipient cells and the …

Ten-Sational!, Children's Mercy Hospital

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Undifferentiated Carcinoma With Osteoclast-Like Giant Cells Of The Pancreatic Tail, Patrick Hickey Do, Ranjit R. Nair Md, Victoria A. Loven Md, Jeffrey Brodsky Md, Hiral N. Shah Md

Department of Medicine

No abstract provided.

Promoting Colorectal Cancer Screening Among Haitian Americans, Steven S. Coughlin, Erica I. Lubetkin, Jennifer L. Hay, Renald Raphael, Selina A. Smith

Publications and Research

Background

Few studies have examined colorectal cancer screening among Haitian Americans, although striking disparities in colorectal cancer screening and mortality are well-documented among U.S. Blacks. Race, socioeconomic status, and place of birth are factors associated with colorectal cancer incidence and mortality patterns.

Methods

In this article, we summarize published studies on colorectal cancer screening among Haitian Americans, identified through bibliographic searches in PubMed and CINAHL through August 2015, and offer recommendations for further research.

Results

Only one qualitative study and three quantitative surveys have examined colorectal cancer screening among Haitian Americans. A qualitative study found important differences in perceptions of …

Analysis Of The Role Of Astrocyte Elevated Gene-1 In Normal Liver Physiology And In The Onset And Progression Of Hepatocellular Carcinoma, Chadia L. Robertson

Theses and Dissertations

First identified over a decade ago, Astrocyte Elevated Gene-1 (AEG-1) has been studied extensively due to early reports of its overexpression in various cancer cell lines. Research groups all over the globe including our own have since identified AEG-1 overexpression in cancers of diverse lineages including cancers of the liver, colon, skin, prostate, breast, lung, esophagus, neurons and neuronal glia as compared to matched normal tissue. A comprehensive and convincing body of data currently points to AEG-1 as an essential component, critical to the progression and perhaps onset of cancer. AEG-1 is a potent activator of multiple pro-tumorigenic signal transduction …

Mismatch Repair Deficient Tumors Lacking Known Sporadic Causes: Are They All Due To Lynch Syndrome?, Katherine M. Dempsey

Dissertations and Theses (Open Access)

BACKGROUND: Mismatch repair deficient (MMRD) colorectal (CRC) or endometrial (EC) cancers in the absence of MLH1 promoter hypermethylation and BRAF mutations are suggestive of Lynch syndrome (LS). Positive germline genetic test results confirm LS. It is unclear if individuals with MMRD tumors but no identified germline mutation or sporadic cause (MMRD+/germline-) have LS.

HYPOTHESIS: Since LS is hereditary, individuals with LS should have a stronger family history of LS-related cancers than individuals with sporadic tumors. We hypothesized that MMRD+/germline- CRC and/or EC patients would have less suggestive family histories than LS CRC and/or EC patients.

METHODS: 253 individuals with an …