Medical Specialties Commons^™

Protein Sumoylation Promotes Camp-Independent Epac1 Activation, Wenli Yang, Fang C Mei, Wei Lin, Mark A White, Li Li, Yue Li, Sheng Pan, Xiaodong Cheng

Faculty, Staff and Student Publications

Protein SUMOylation is a prevalent stress-response posttranslational modification crucial for maintaining cellular homeostasis. Herein, we report that protein SUMOylation modulates cellular signaling mediated by cAMP, an ancient and universal stress-response second messenger. We identify K561 as a primary SUMOylation site in exchange protein directly activated by cAMP (EPAC1) via site-specific mapping of SUMOylation using mass spectrometry. Sequence and site-directed mutagenesis analyses reveal that a functional SUMO-interacting motif in EPAC1 is required for the binding of SUMO-conjugating enzyme UBC9, formation of EPAC1 nuclear condensate, and EPAC1 cellular SUMOylation. Heat shock-induced SUMO modification of EPAC1 promotes Rap1/2 activation in a cAMP-independent manner. …

Impact Of Isotype On The Mechanism Of Action Of Agonist Anti-Ox40 Antibodies In Cancer: Implications For Therapeutic Combinations, Jane E Willoughby, Lang Dou, Sabyasachi Bhattacharya, Heather Jackson, Laura Seestaller-Wehr, David Kilian, Laura Bover, Kui S Voo, Kerry L Cox, Tom Murray, Mel John, Hong Shi, Paul Bojczuk, Junping Jing, Heather Niederer, Andrew J Shepherd, Laura Hook, Stephanie Hopley, Tatyana Inzhelevskaya, Chris A Penfold, C Ian Mockridge, Vikki English, Sara J Brett, Roopa Srinivasan, Christopher Hopson, James Smothers, Axel Hoos, Elaine Paul, Stephen L Martin, Peter J Morley, Niranjan Yanamandra, Mark S Cragg

Faculty, Staff and Student Publications

BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.

METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in …

Hur Controls Glutaminase Rna Metabolism, Douglas Adamoski, Larissa M Dos Reis, Ana Carolina Paschoalini Mafra, Felipe Corrêa-Da-Silva, Pedro Manoel Mendes De Moraes-Vieira, Ioana Berindan-Neagoe, George A Calin, Sandra Martha Gomes Dias

Faculty, Staff and Student Publications

Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and …

Author Correction: Distinct Molecular And Immune Hallmarks Of Inflammatory Arthritis Induced By Immune Checkpoint Inhibitors For Cancer Therapy, Sang T Kim, Yanshuo Chu, Mercy Misoi, Maria E Suarez-Almazor, Jean H Tayar, Huifang Lu, Maryam Buni, Jordan Kramer, Emma Rodriguez, Zulekha Hussain, Sattva S Neelapu, Jennifer Wang, Amishi Y Shah, Nizar M Tannir, Matthew T Campbell, Don L Gibbons, Tina Cascone, Charles Lu, George R Blumenschein, Mehmet Altan, Bora Lim, Vincente Valero, Monica E Loghin, Janet Tu, Shannon N Westin, Aung Naing, Guillermo Garcia-Manero, Noha Abdel-Wahab, Hussein A Tawbi, Patrick Hwu, Isabella C Glitza Oliva, Michael A Davies, Sapna P Patel, Jun Zou, Andrew Futreal, Adi Diab, Linghua Wang, Roza Nurieva

Faculty, Staff and Student Publications

No abstract provided.

Baseline Data Collections Of Lipopolysaccharide Content In 414 Herbal Extracts And Its Role In Innate Immune Activation, Vindy Tjendana Tjhin, Masataka Oda, Masashi Yamashita, Tomoko Iwaki, Yasuko Fujita, Koji Wakame, Hiroyuki Inagawa, Gen-Ichiro Soma

Faculty, Staff and Student Publications

Some herbal extracts contain relatively high amounts of lipopolysaccharide (LPS). Because orally administered LPS activates innate immunity without inducing inflammation, it plays a role as an active ingredient in herbal extracts. However, the LPS content in herbal extracts remains extensively unevaluated. This study aimed to create a database of LPS content in herbal extracts; therefore, the LPS content of 414 herbal extracts was measured and the macrophage activation potential was evaluated. The LPS content of these hot water extracts was determined using the kinetic-turbidimetric method. The LPS concentration ranged from a few ng/g to hundreds of μg/g (Standard Escherichia coli …

Antitumor Effects Of Resveratrol Opposing Mechanisms Of Helicobacter Pylori In Gastric Cancer, Daniela Trautmann, Francesca Suazo, Keila Torres, Layla Simón

Faculty, Staff and Student Publications

Gastric cancer is an aggressive and multifactorial disease. Helicobacter pylori (H. pylori) is identified as a significant etiological factor in gastric cancer. Although only a fraction of patients infected with H. pylori progresses to gastric cancer, bacterial infection is critical in the pathology and development of this malignancy. The pathogenic mechanisms of this bacterium involve the disruption of the gastric epithelial barrier and the induction of chronic inflammation, oxidative stress, angiogenesis and metastasis. Adherence molecules, virulence (CagA and VacA) and colonization (urease) factors are important in its pathogenicity. On the other hand, resveratrol is a natural polyphenol with …

Genetically Engineering Glycolysis In T Cells Increases Their Antitumor Function, Raphaëlle Toledano Zur, Orna Atar, Tilda Barliya, Shiran Hoogi, Ifat Abramovich, Eyal Gottlieb, Noga Ron-Harel, Cyrille J Cohen

Faculty, Staff and Student Publications

BACKGROUND: T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells.

METHODS: Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction …

Exploring The Functionality Of Technology-Driven Cpr Training Methodologies Among Healthcare Practitioners: A Randomized Control Pilot Study, Nazrin Ahmad, Mazlinda Musa, Fairrul Kadir, Syed Sharizman, Aizuddin Hidrus, Hamidah Hassan, Rohani Mamat, Baidi Baddiri

Journal of the Saudi Heart Association

Introduction: Cardiopulmonary resuscitation training in Malaysia has evolved from traditional to modern approaches, embracing technology for better outcomes. Smartphone-based training apps offer interactive learning with simulations and real-time feedback, improving cardiopulmonary resuscitation skills anytime, anywhere. This study evaluates the effectiveness of the smart-cardiopulmonary resuscitation application for healthcare practitioners. Methods: This randomized controlled pilot study was conducted with 30 healthcare practitioners at the University of Malaysia Sabah. Participants underwent a Cardiopulmonary Resuscitation Practical formal educational training program, and data were collected using a Basic Life Support questionnaire and skills assessment checklist sourced from the American Heart Association (2020). Data analysis was …

Salvage Of A Kidney Transplant With A Mycotic Extrarenal Pseudoaneursym Using Donor Vessels, Audrey Horn, Kelli L. Summers, William Fuell, Adarsh Vijay, Hoonbae Jeon, Melissa Donovan, Kiara Tulla, Anil Paramesh

School of Medicine Faculty Publications

A 63-year-old male developed a mycotic pseudoaneurysm (MPA) two months after a renal transplant at the anastomotic site. He presented with uncontrolled hypertension and elevated creatinine. The pseudoaneurysm occurred at the anastomosis between the two donor renal arteries and the left external iliac artery. We describe a unique surgical reconstruction where the MPA was resected and the vasculature was reconstructed using deceased donor vessels. A deceased donor common iliac artery including superior gluteal and inferior gluteal branches were used as a jump graft from the contralateral common iliac artery to the two transplanted renal arteries. The external iliac artery was …

Serum From Patients With Cirrhosis Undergoing Liver Transplantation Induces Permeability In Human Pulmonary Microvascular Endothelial Cells, Michael Bokoch, Fengyun Xu, Krishna Govindaraju, Elliot Lloyd, Kyle Tsutsui, Rishi Kothari, Dieter Adelmann, Jérémie Joffre, Judith Hellman

Department of Anesthesiology Faculty Papers

INTRODUCTION: Patients with cirrhosis undergoing liver transplantation frequently exhibit systemic inflammation, coagulation derangements, and edema, indicating endothelial dysfunction. This syndrome may worsen after ischemia-reperfusion injury of the liver graft, coincident with organ dysfunction that worsens patient outcomes. Little is known about changes in endothelial permeability during liver transplantation. We hypothesized that sera from these patients would increase permeability in cultured human endothelial cells

METHODS: Adults with cirrhosis presenting for liver transplantation provided consent for blood collection during surgery. Sera were prepared at five time points spanning the entire operation. The barrier function of human pulmonary microvascular endothelial cells in culture …

What’S The N? On Sample Size Vs. Subject Number For Brain-Behavior Neurophysiology And Neuromodulation, Wael F Asaad, Sameer A Sheth

Duncan NRI Faculty and Staff Publications

Neurophysiology and neuromodulation strive to understand the neural basis of behavior through a one-to-one correspondence between a particular brain and its behavioral output. Within this framework, studies with few subjects but sufficient sample sizes can be both rigorous and impactful.

Controlled Delivery Of Rosuvastatin Or Rapamycin Through Electrospun Bismuth Nanoparticle-Infused Perivascular Wraps Promotes Arteriovenous Fistula Maturation, Allan John R Barcena, Joy Vanessa D Perez, Marvin R Bernardino, Erin Marie D San Valentin, Jossana A Damasco, Carleigh Klusman, Benjamin Martin, Karem A Court, Biana Godin, Gino Canlas, Natalie Fowlkes, Richard R Bouchard, Jizhong Cheng, Steven Y Huang, Marites P Melancon

Faculty, Staff and Student Publications

In the context of arteriovenous fistula (AVF) failure, local delivery enables the release of higher concentrations of drugs that can suppress neointimal hyperplasia (NIH) while reducing systemic adverse effects. However, the radiolucency of polymeric delivery systems hinders long-term in vivo surveillance of safety and efficacy. We hypothesize that using a radiopaque perivascular wrap to deliver anti-NIH drugs could enhance AVF maturation. Through electrospinning, we fabricated multifunctional perivascular polycaprolactone (PCL) wraps loaded with bismuth nanoparticles (BiNPs) for enhanced radiologic visibility and drugs that can attenuate NIH—rosuvastatin (Rosu) and rapamycin (Rapa). The following groups were tested onto the AVFs of a total …

Sump Syndrome: The Forgotten Cause Of Painless Jaundice In The Elderly, Mark Ayoub, Amna Anees

Journal of Community Hospital Internal Medicine Perspectives

Painless jaundice is a common presentation of abdominal malignancy seen in elderly patients. While malignancy may be a common cause of obstructive jaundice in that population group, anchor bias should always be avoided. We present a case of an elderly woman who presented with painless jaundice and weight loss. She had a very remote history of cholecystitis. She was found to have Sump syndrome due to a stricture at the Choledochoduodenostomy (CDD) site. She underwent endoscopic retrograde cholangiopancreatography (ERCP) with stent placement which shortly led to resolution of her jaundice. Biopsy from the stricture site came back negative for malignancy.

Calcitriol Unleashed: A Rare Culprit In Hypercalcemia Associated With Rare Primary Pancreatic Lymphoma - A Case Report, Dania Kaur, Abhinav Vyas, Sowmya Sagireddy, Rabia Qazi, Sarah Elsayed, Jyoti Verma, Prutha Pathak, Rachna Valvani

Journal of Community Hospital Internal Medicine Perspectives

Hypercalcemia of Malignancy is a complicated condition often linked to parathyroid hormone, parathyroid hormone-related peptide, or bone metastasis. This report presents a unique case of calcitriol-mediated hypercalcemia in an 89-year-old female with primary pancreatic lymphoma, highlighting the rarity and complexity of this presentation. Initially, the patient's condition was thought to be related to sarcoidosis, but the recurrence of hypercalcemia led to the discovery of pancreatic B-cell lymphoma as the underlying cause. It also emphasizes the need to explore new treatment options. Interestingly, it demonstrates the successful use of cinacalcet in treating calcitriol-induced hypercalcemia in malignancies, which could be a potential …

A Rare Case Of Anca-Negative Rapidly Progressive Glomerulonephritis, Jerry Kenmoe, Elizabeth Mikhail, Fahimeh Talaei, Arvind Kunadi

Journal of Community Hospital Internal Medicine Perspectives

ANCA-negative rapidly progressive glomerulonephritis (RPGN) is a rare condition caused by glomerular injury in the absence of detectable antineutrophil cytoplasmic antibodies (ANCAs). While comprehensive epidemiologic data is limited, ANCAnegative RPGN is known to comprise 5-20% of all glomerulonephritis cases. We report the case of a 43-year-old male who presented to the hospital after a snowmobile accident with symptoms of general malaise along with the emergence of a new-onset rash and tea-colored urine. Further workup with CT-guided kidney biopsy confirmed the diagnosis of RPGN by revealing histopathological findings of crescentic glomerulonephritis and significant glomerular inflammation. Treatment was promptly initiated with prednisone …

Immunotherapy Induced Adrenal Insufficiency: An Underdiagnosed Cause Of Persistent Hypotension In Cancer, Nina H. Cheng, Hannah Lee, Divya Balchander, Remy Mimms, Mahesh Krishnamurthy

Journal of Community Hospital Internal Medicine Perspectives

Endocrinopathies following immunotherapy have infrequently been documented in the literature. Adrenal insufficiency is a rare consequence of pembrolizumab immunotherapy, with incidence reported to be between 0.98 and 1.3%. We present the case of a 34-year-old female with triple negative breast cancer on chemotherapy who presented with generalized weakness with tachycardia, tachypnea and hypotension unresponsive to fluids. Despite initial improvement with intravenous hydrocortisone and midodrine, the patient continued to be symptomatically hypotensive following discharge and required re-admission. AM cortisol level was found to be < 0.5 ug/dl and ACTH was

Ruptured Infectious Pseudoaneurysm Of The Common Carotid Artery In A 14-Year-Old Girl. Management In The Dr Congo, Alphonse Nzomvuama, Jean Jacques Kalongo, Blondel Bayenekene, Stéphane Yanda, M. Jacques Nsuami

School of Medicine Faculty Publications

The infectious pseudoaneurysm of the common carotid artery is a rare observation in children. We present a case of ruptured infectious common carotid aneurysm in a 14-year-old girl managed in the Democratic Republic of Congo. We performed an arterial reconstruction with a saphenous vein patch. Post-operative course was simple. The patient was discharged from the hospital at post-operative day 15. She was doing well and had returned to school. Rupture of an infectious pseudoaneurysm of the common carotid artery constitutes a serious, life-threatening accident. As we have shown in this case report, its management with successful results is indeed possible, …

Home Blood Pressure Telemonitoring And Nurse Case Management In Black And Hispanic Patients With Stroke: A Randomized Clinical Trial, Gbenga Ogedegbe, Jeanne A Teresi, Stephen K Williams, Adebayo Ogunlade, Chigozirim Izeogu, Joseph P Eimicke, Jian Kong, Stephanie A Silver, Olajide Williams, Helen Valsamis, Susan Law, Steven R Levine, Salina P Waddy, Tanya M Spruill

Faculty, Staff and Student Publications

Importance: Black and Hispanic patients have high rates of recurrent stroke and uncontrolled hypertension in the US. The effectiveness of home blood pressure telemonitoring (HBPTM) and telephonic nurse case management (NCM) among low-income Black and Hispanic patients with stroke is unknown.

Objective: To determine whether NCM plus HBPTM results in greater systolic blood pressure (SBP) reduction at 12 months and lower rate of stroke recurrence at 24 months than HBPTM alone among Black and Hispanic stroke survivors with uncontrolled hypertension.

Design, setting, and participants: Practice-based, multicenter, randomized clinical trial in 8 stroke centers and ambulatory practices in New York City. …

Buprenorphine Vs. Morphine: Impact On Neonatal Opioid Withdrawal Syndrome (Nows) Outcomes In A Single Center Retrospective Study, Saminathan Anbalagan, V. Anderson, Michael Favara, D. Stark, David Carola, Kolawole Solarin, Susan Adeniyi-Jones, Walter K. Kraft, Zubair H. Aghai

Jefferson Hospital Staff Papers and Presentations

Objectives: To compare clinical outcomes for infants with neonatal opioid withdrawal syndrome (NOWS) treated with buprenorphine or morphine.

Study design: Retrospective study of infants born ≥35 weeks’ gestation and admitted to the NICU for NOWS treatment between 2011 and 2022. Length of treatment, length of stay in the hospital, and the need for secondary medications were compared between buprenorphine and morphine treated neonates. Multiple regression analysis was performed, adjusting for baseline differences and confounders.

Results: 417 neonates were treated with morphine and 232 with buprenorphine. The buprenorphine group had shorter treatment days [-10.8 days; 95% CI: -8.08 to …

Multidisciplinary Approach To Diagnostic Radiology Education: A Novel Educational Intervention For Turkish Medical Students, Parth Patel, Emre Altınmakas, Görkem Ayas, Rachel Stanietzky, Madeline L. Stewart, Abdelrahman Elshikh, Disha Ram, Hrishika Bhosale, Mohamed Eltaher, Serageldin Kamel, Munevver N. Duran, Umut Yücel, Mohamed Badawy, Scott Rohren, Khaled M. Elsayes

School of Medicine Faculty Publications

Teleconferencing can facilitate a multidisciplinary approach to teaching radiology to medical students. This study aimed to determine whether an online learning approach enables students to appreciate the interrelated roles of radiology and other specialties during the management of different medical cases. Turkish medical students attended five 60-90-minute online lectures delivered by radiologists and other specialists from the United States and Canada through Zoom meetings between November 2020 and January 2021. Student ambassadors from their respective Turkish medical schools recruited their classmates with guidance from the course director. Students took a pretest and posttest to assess the knowledge imparted from each …

Addressing Disparities In Pediatric Congenital Heart Disease: A Call For Equitable Health Care, Devyani Chowdhury, Pietro A Elliott, S Yukiko Asaki, Shahnawaz Amdani, Quang-Tuyen Nguyen, Christina Ronai, Seda Tierney, Victor Y Levy, Kriti Puri, Carolyn A Altman, Jonathan N Johnson, Julie S Glickstein

Faculty, Staff and Students Publications

While significant progress has been made in reducing disparities within the US health care system, notable gaps remain. This article explores existing disparities within pediatric congenital heart disease care. Congenital heart disease, the most common birth defect and a leading cause of infant death, has garnered substantial attention, revealing certain disparities within the US health care system. Factors such as race, ethnicity, insurance coverage, socioeconomic status, and geographic location are all commonalities that significantly affect health disparities in pediatric congenital heart disease. This comprehensive review sheds light on disparities from diverse perspectives in pediatric care, demonstrates the inequities and inequalities …

A Mechanistic Lnk Between Inflammation And Atrial Fibrillation?, Joshua A Keefe, Shuai Zhao, Xander H T Wehrens

Faculty, Staff and Students Publications

No abstract provided.

Individual And Joint Associations Of High-Sensitivity Troponin I And High-Sensitivity Troponin T With Cardiac Phenotypes And Outcomes In The General Population: An Analysis From The Dallas Heart Study, Rebecca Vigen, Colby Ayers, Jarett Berry, Anand Rohatgi, Vijay Nambi, Christie M Ballantyne, Torbjorn Omland, Christopher R De Filippi, James De Lemos

Faculty, Staff and Students Publications

Background: High-sensitivity troponin I (hs-cTnI) and T (hs-cTnT) provide complementary information regarding cardiovascular disease risk. The explanation for their distinct risk profiles is incompletely understood.

Methods and results: hs-cTnI and hs-cTnT were measured in Dallas Heart Study participants. Associations of hs-cTnI and hs-cTnT with demographics and phenotypes were assessed using linear regression. Associations with incident heart failure, atherosclerotic cardiovascular disease, global cardiovascular disease, and cardiovascular and all-cause mortality were assessed using Cox models. Among 3276 participants (56% women, 50% Black persons, median age 43 years), the correlation between hs-cTnI and hs-cTnT was modest (Spearman rho=0.35). Variables associated with hs-cTnI but …

A Pan-Cancer Patient-Derived Xenograft Histology Image Repository With Genomic And Pathologic Annotations Enables Deep Learning Analysis, Brian S White, Xing Yi Woo, Soner Koc, Todd Sheridan, Steven B Neuhauser, Shidan Wang, Yvonne A Evrard, Li Chen, Ali Foroughi Pour, John D Landua, R Jay Mashl, Sherri R Davies, Bingliang Fang, Maria Gabriela Raso, Kurt W Evans, Matthew H Bailey, Yeqing Chen, Min Xiao, Jill C Rubinstein, Brian J Sanderson, Michael W Lloyd, Sergii Domanskyi, Lacey E Dobrolecki, Maihi Fujita, Junya Fujimoto, Guanghua Xiao, Ryan C Fields, Jacqueline L Mudd, Xiaowei Xu, Melinda G Hollingshead, Shahanawaz Jiwani, Saul Acevedo, Pdxnet Consortium, Brandi N Davis-Dusenbery, Peter N Robinson, Jeffrey A Moscow, James H Doroshow, Nicholas Mitsiades, Salma Kaochar, Chong-Xian Pan, Luis G Carvajal-Carmona, Alana L Welm, Bryan E Welm, Ramaswamy Govindan, Shunqiang Li, Michael A Davies, Jack A Roth, Funda Meric-Bernstam, Yang Xie, Meenhard Herlyn, Li Ding, Michael T Lewis, Carol J Bult, Dennis A Dean, Jeffrey H Chuang

Faculty, Staff and Students Publications

Patient-derived xenografts (PDX) model human intra- and intertumoral heterogeneity in the context of the intact tissue of immunocompromised mice. Histologic imaging via hematoxylin and eosin (H&E) staining is routinely performed on PDX samples, which could be harnessed for computational analysis. Prior studies of large clinical H&E image repositories have shown that deep learning analysis can identify intercellular and morphologic signals correlated with disease phenotype and therapeutic response. In this study, we developed an extensive, pan-cancer repository of >1,000 PDX and paired parental tumor H&E images. These images, curated from the PDX Development and Trial Centers Research Network Consortium, had a …

Celecoxib-Tramadol Co-Crystal In Patients With Moderate-To-Severe Pain Following Bunionectomy With Osteotomy: Secondary Analyses By Baseline Pain Intensity And Use Of Rescue Medication Of A Phase 3, Randomized, Double-Blind, Factorial, Active- And Placebo-Controlled Trial, Eugene R. Viscusi, Oscar De Leon-Casasola, Jesús Cebrecos, Adam Jacobs, Adelaida Morte, Esther Ortiz, Mariano Sust, Anna Vaqué, Ira Gottlieb, Stephen Daniels, Derek Muse, Michael E. Kuss, Sebastián Videla, Neus Gascón, Carlos Plata-Salamán

Department of Anesthesiology Faculty Papers

BACKGROUND: In the randomized, phase 3, SUSA-301 trial, celecoxib-tramadol co-crystal (CTC) provided significantly greater analgesia compared with celecoxib, tramadol, or placebo in adults with acute, moderate-to-severe, postoperative pain. This post hoc, secondary analysis further evaluated the use of rescue medication and the incidence of treatment-emergent adverse events (TEAEs).

METHODS: Patients (N = 637) were randomized 2:2:2:1 to receive oral CTC 200 mg twice daily (BID; n = 184), tramadol 50 mg four times daily (QID; n = 183), celecoxib 100 mg BID (n = 181), or placebo QID (n = 89). Post hoc analyses were conducted on the use of …

Improving Laboratory Animal Genetic Reporting: Lag-R Guidelines, Lydia Teboul, James Amos-Landgraf, Fernando J Benavides, Marie-Christine Birling, Steve D M Brown, Elizabeth Bryda, Rosie Bunton-Stasyshyn, Hsian-Jean Chin, Martina Crispo, Fabien Delerue, Michael Dobbie, Craig L Franklin, Ernst-Martin Fuchtbauer, Xiang Gao, Christelle Golzio, Rebecca Haffner, Yann Hérault, Martin Hrabe De Angelis, Kevin C Kent Lloyd, Terry R Magnuson, Lluis Montoliu, Stephen A Murray, Ki-Hoan Nam, Lauryl M J Nutter, Eric Pailhoux, Fernando Pardo Manuel De Villena, Kevin Peterson, Laura Reinholdt, Radislav Sedlacek, Je Kyung Seong, Toshihiko Shiroishi, Cynthia Smith, Toru Takeo, Louise Tinsley, Jean-Luc Vilotte, Søren Warming, Sara Wells, C Bruce Whitelaw, Atsushi Yoshiki, Asian Mouse Mutagenesis Resource Association, Celphedia Infrastructure, Infrafrontier Consortium, International Mammalian Genome Society, International Mouse Phenotyping Consortium, International Society For Transgenic Technologies, Mutant Mouse Resource And Research Centers, Phenomics Australia, Rrrc- Rat Resource And Research Center, Guillaume Pavlovic

Faculty, Staff and Student Publications

The biomedical research community addresses reproducibility challenges in animal studies through standardized nomenclature, improved experimental design, transparent reporting, data sharing, and centralized repositories. The ARRIVE guidelines outline documentation standards for laboratory animals in experiments, but genetic information is often incomplete. To remedy this, we propose the Laboratory Animal Genetic Reporting (LAG-R) framework. LAG-R aims to document animals' genetic makeup in scientific publications, providing essential details for replication and appropriate model use. While verifying complete genetic compositions may be impractical, better reporting and validation efforts enhance reliability of research. LAG-R standardization will bolster reproducibility, peer review, and overall scientific rigor.

Assessment Of Patient-Derived Xenograft Growth And Antitumor Activity: The Nci Pdxnet Consensus Recommendations, Funda Meric-Bernstam, Michael W Lloyd, Soner Koc, Yvonne A Evrard, Lisa M Mcshane, Michael T Lewis, Kurt W Evans, Dali Li, Lawrence Rubinstein, Alana Welm, Dennis A Dean, Anuj Srivastava, Jeffrey W Grover, Min J Ha, Huiqin Chen, Xuelin Huang, Kaushik Varadarajan, Jing Wang, Jack A Roth, Bryan Welm, Ramaswamy Govinden, Li Ding, Salma Kaochar, Nicholas Mitsiades, Luis Carvajal-Carmona, Meenhard Herylyn, Michael A Davies, Geoffrey I Shapiro, Ryan Fields, Jose G Trevino, Joshua C Harrell, Nci Pdxnet Consortium, James H Doroshow, Jeffrey H Chuang, Jeffrey A Moscow

Faculty, Staff and Student Publications

Although patient-derived xenografts (PDX) are commonly used for preclinical modeling in cancer research, a standard approach to in vivo tumor growth analysis and assessment of antitumor activity is lacking, complicating the comparison of different studies and determination of whether a PDX experiment has produced evidence needed to consider a new therapy promising. We present consensus recommendations for assessment of PDX growth and antitumor activity, providing public access to a suite of tools for in vivo growth analyses. We expect that harmonizing PDX study design and analysis and assessing a suite of analytical tools will enhance information exchange and facilitate identification …

Inhibition Of Malt1 And Bcl2 Induces Synergistic Antitumor Activity In Models Of B-Cell Lymphoma, Joshua P Plotnik, Adam E Richardson, Haopeng Yang, Estela Rojas, Velitchka Bontcheva, Colleen Dowell, Sydney Parsons, Ashley Wilson, Vida Ravanmehr, Christine Will, Paul Jung, Haizhong Zhu, Sarathy Karunan Partha, Sanjay C Panchal, Raghuveer Singh Mali, Frederick J Kohlhapp, Ryan A Mcclure, Cyril Y Ramathal, Mariam D George, Manisha Jhala, Nathaniel L Elsen, Wei Qiu, Russell A Judge, Chin Pan, Anthony Mastracchio, Jared Henderson, Jonathan A Meulbroek, Michael R Green, William N Pappano

Faculty, Staff and Student Publications

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 …

Loss Of The Dna Repair Gene Rnase H2 Identifies A Unique Subset Of Ddr-Deficient Leiomyosarcomas, Michael S Nakazawa, Ian M Silverman, Victoria Rimkunas, Artur Veloso, Dominik Glodzik, Adrienne Johnson, Toshiro K Ohsumi, Shreyaskumar R Patel, Anthony P Conley, Christina L Roland, Pamela T Soliman, Hannah C Beird, Chia-Chin Wu, Davis R Ingram, Rossana Lazcano, Dawon Song, Khalida M Wani, Alexander J Lazar, Timothy A Yap, Wei-Lien Wang, J Andrew Livingston

Faculty, Staff and Student Publications

Targeting the DNA damage response (DDR) pathway is an emerging therapeutic approach for leiomyosarcoma (LMS), and loss of RNase H2, a DDR pathway member, is a potentially actionable alteration for DDR-targeted treatments. Therefore, we designed a protein- and genomic-based RNase H2 screening assay to determine its prevalence and prognostic significance. Using a selective RNase H2 antibody on a pan-tumor microarray (TMA), RNase H2 loss was more common in LMS (11.5%, 9/78) than across all tumors (3.8%, 32/843). In a separate LMS cohort, RNase H2 deficiency was confirmed in uterine LMS (U-LMS, 21%, 23/108) and soft-tissue LMS (ST-LMS; 30%, 39/102). In …

Post-Immunotherapy Ctla-4 Ig Treatment Improves Antitumor Efficacy, Stephen Mok, Didem Ağaç Çobanoğlu, Huey Liu, James J Mancuso, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether …