Medicine and Health Sciences Commons^™

Altered Thermal Preference By Preoptic Estrogen Receptor Alpha Neurons In Postpartum Females, Nan Zhang, Meng Yu, Qianru Zhao, Bing Feng, Yue Deng, Jonathan C Bean, Qingzhuo Liu, Benjamin P Eappen, Yang He, Kristine M Conde, Hailan Liu, Yongjie Yang, Longlong Tu, Mengjie Wang, Yongxiang Li, Na Yin, Hesong Liu, Junying Han, Darah Ave Threat, Nathan Xu, Taylor Smiley, Pingwen Xu, Lulu Chen, Tianshu Zeng, Yanlin He, Chunmei Wang

Faculty, Staff and Students Publications

OBJECTIVE: This study aims to investigate how reproductive experience (RE) alters thermal preference and thermoregulation in female mice, with a focus on estrogen receptor alpha (ERα)-expressing neurons in the preoptic area (POA).

METHODS: Thermal preference and body temperature were measured in female mice with and without RE, and virgin female mice with selective deletion of ERα from the POA (ERα

RESULTS: We showed that female mice prefer a cooler environment starting from late pregnancy and persisting long term postpartum. Female mice with RE (>4 weeks post-weaning) displayed lower body temperature and a lower thermal preferred temperature, and lost preference …

Anesthetic Management For Proximal Aortic Repair, Thomas R Powell, Emily B Shah, Ali Khalifa, Vicente Orozco-Sevilla, Daniel A Tolpin

Faculty, Staff and Students Publications

Surgical repair of the proximal aorta is a complex endeavor, requiring cardiopulmonary bypass (CPB) and often the use of hypothermic circulatory arrest (HCA). In addition to the normal considerations for patients undergoing cardiopulmonary bypass, additional challenges include cerebral and end-organ protection during periods of circulatory arrest. This review aims to provide an up-to-date, evidence-based review on anesthetic management for proximal aortic repair.

Anesthetic Considerations For Repair Of Thoracoabdominal Aortic Aneurysms, David A Lyubashevsky, Thomas Powell, Ali Khalifa, Vicente Orozco-Sevilla, Daniel A Tolpin

Faculty, Staff and Students Publications

Anesthetic management of open thoracoabdominal aneurysm (TAAA) repair poses a number of challenges for even the most experienced of cardiovascular anesthesiologists. This procedure encompasses a large number of unique anesthetic techniques, including one-lung ventilation, invasive hemodynamic monitoring, left-heart bypass, massive transfusion, selective renal and visceral perfusion, and central nervous system monitoring with CSF drainage. In this article, we aim to describe the anesthetic management for thoracoabdominal aortic aneurysm repair, including preoperative workup, intraoperative management, as well as postoperative concerns in the intensive care unit.

Anesthetic Considerations For Endovascular Repair Of The Thoracic Aorta, Olivia M Valencia, Thomas Powell, Ali Khalifa, Vicente Orozco-Sevilla, Daniel A Tolpin

Faculty, Staff and Students Publications

Thoracic aorta pathologies, especially those of the ascending aorta and aortic arch, were traditionally approached via open surgical repair. This carries risk of ischemic end-organ damage and other complications. Endovascular repair of ascending aorta and aortic arch pathologies is becoming more successful and widespread, thereby posing numerous challenges to the anesthesiologist. This article reviews the anesthesia-pertinent pathophysiology, repair techniques, preoperative evaluation, intraoperative management, and postoperative care of patients presenting for endovascular repair of thoracic aorta pathologies.

A Multicenter Training And Interrater Reliability Study Of The Based Score For Infantile Epileptic Spasms Syndrome, John R Mytinger, Dara V F Albert, Shawn C Aylward, Christopher W Beatty, Sonam Bhalla, Sonal Bhatia, Guy N Brock, Micheal A Ciliberto, Purva R Choudhari, Daniel J Clark, Jennifer Madan Cohen, Theresa M Czech, Megan M Fredwall, Ernesto Gonzalez-Giraldo, Chellamani Harini, Senyene E Hunter, Amanda G Sandoval Karamian, Akshat Katyayan, Isaac Kistler, Neil Kulkarni, Virginia B Liu, Corinne Mccabe, Thomas Murray, Kerri Neville, Shital H Patel, Spriha Pavuluri, Donald J Phillips, Debopam Samanta, Deepa Sirsi, Emily M Spelbrink, Carl E Stafstrom, Maija Steenari, Danielle S Takacs, Tyler Terrill, Linh Tran, Jorge Vidaurre, Daniel W Shrey

Faculty, Staff and Students Publications

PURPOSE: The best possible outcomes in infantile epileptic spasms syndrome require electroclinical remission; however, determining electrographic remission is not straightforward. Although the determination of hypsarrhythmia has inadequate interrater reliability (IRR), the Burden of AmplitudeS and Epileptiform Discharges (BASED) score has shown promise for the reliable interictal assessment of infantile epileptic spasms syndrome. Our aim was to develop a BASED training program and assess the IRR among learners. We hypothesized moderate or better IRR for the final BASED score and the presence or absence of epileptic encephalopathy (+/-EE).

METHODS: Using a web-based application, 31 learners assessed 12 unmarked EEGs (length 1-6 …

Thalamic Deep Brain Stimulation Improves Movement In A Cerebellar Model Of Lesion-Based Status Dystonicus, Megan X Nguyen, Amanda M Brown, Tao Lin, Roy V Sillitoe, Jason S Gill

Faculty, Staff and Students Publications

Dystonia is the third most common movement disorder and an incapacitating co-morbidity in a variety of neurologic conditions. Dystonia can be caused by genetic, degenerative, idiopathic, and acquired etiologies, which are hypothesized to converge on a "dystonia network" consisting of the basal ganglia, thalamus, cerebellum, and cerebral cortex. In acquired dystonia, focal lesions to subcortical network regions lead to dystonia that can be difficult to manage with canonical treatments, including deep brain stimulation (DBS). While studies in animal models have begun to parse the contribution of individual nodes in the dystonia network, how acquired injury to the cerebellar outflow tracts …

Histology-Grounded Automated Plaque Subtype Segmentation In Intravascular Optical Coherence Tomography, Paul Young, Drew Nolen, Thomas E Milner, Alexandra Gruslova, Deborah Vela, Louis Maximilian Buja, Luis A Diaz Sanmartin, Paul Rad, Marc D Feldman

Faculty, Staff and Student Publications

Background: Intravascular optical coherence tomography (IVOCT) adoption has been limited by the complexity of image interpretation. The interpretation of histologic subtypes beyond lipid, calcium, and fibrous is challenging to human readers. To assist and standardize IVOCT image analysis, we demonstrate an artificial intelligence algorithm based on a histology data set that identifies lipid pools, fibrofatty, calcified lipid, and calcified fibrous in human coronary arteries for the first time.

Methods: Sixty-seven human coronary arteries were imaged with IVOCT within 24 hours after death and then underwent histologic examination. IVOCT images were coregistered and segmented into histologic subtypes: lipid pools, fibrofatty tissue, …

Author Correction: Ctla4 Blockade Abrogates Keap1/Stk11-Related Resistance To Pd-(L)1 Inhibitors, Ferdinandos Skoulidis, Haniel A Araujo, Minh Truong Do, Yu Qian, Xin Sun, Ana Galan Cobo, John T Le, Meagan Montesion, Rachael Palmer, Nadine Jahchan, Joseph M Juan, Chengyin Min, Yi Yu, Xuewen Pan, Kathryn C Arbour, Natalie Vokes, Stephanie T Schmidt, David Molkentine, Dwight H Owen, Regan Memmott, Pradnya D Patil, Melina E Marmarelis, Mark M Awad, Joseph C Murray, Jessica A Hellyer, Justin F Gainor, Anastasios Dimou, Christine M Bestvina, Catherine A Shu, Jonathan W Riess, Collin M Blakely, Chad V Pecot, Laura Mezquita, Fabrizio Tabbó, Matthias Scheffler, Subba Digumarthy, Meghan J Mooradian, Adrian G Sacher, Sally C M Lau, Andreas N Saltos, Julia Rotow, Rocio Perez Johnson, Corinne Liu, Tyler Stewart, Sarah B Goldberg, Jonathan Killam, Zenta Walther, Kurt Schalper, Kurtis D Davies, Mark G Woodcock, Valsamo Anagnostou, Kristen A Marrone, Patrick M Forde, Biagio Ricciuti, Deepti Venkatraman, Eliezer M Van Allen, Amy L Cummings, Jonathan W Goldman, Hiram Shaish, Melanie Kier, Sharyn Katz, Charu Aggarwal, Ying Ni, Joseph T Azok, Jeremy Segal, Lauren Ritterhouse, Joel W Neal, Ludovic Lacroix, Yasir Y Elamin, Marcelo V Negrao, Xiuning Le, Vincent K Lam, Whitney E Lewis, Haley N Kemp, Brett Carter, Jack A Roth, Stephen Swisher, Richard Lee, Teng Zhou, Alissa Poteete, Yifan Kong, Tomohiro Takehara, Alvaro Guimaraes Paula, Edwin R Parra Cuentas, Carmen Behrens, Ignacio I Wistuba, Jianjun Zhang, George R Blumenschein, Carl Gay, Lauren A Byers, Don L Gibbons, Anne Tsao, J Jack Lee, Trever G Bivona, D Ross Camidge, Jhannelle E Gray, Natasha B Leighl, Benjamin Levy, Julie R Brahmer, Marina C Garassino, David R Gandara, Edward B Garon, Naiyer A Rizvi, Giorgio Vittorio Scagliotti, Jürgen Wolf, David Planchard, Benjamin Besse, Roy S Herbst, Heather A Wakelee, Nathan A Pennell, Alice T Shaw, Pasi A Jänne, David P Carbone, Matthew D Hellmann, Charles M Rudin, Lee Albacker, Helen Mann, Zhou Zhu, Zhongwu Lai, Ross Stewart, Solange Peters, Melissa L Johnson, Kwok K Wong, Alan Huang, Monte M Winslow, Michael J Rosen, Ian P Winters, Vassiliki A Papadimitrakopoulou, Tina Cascone, Philip Jewsbury, John V Heymach

Faculty, Staff and Student Publications

No abstract provided.

Monte Carlo Modeling Of An Experimental Benchtop L-Shell X-Ray Fluorescence Imaging/Ct System Adopting Two Silicone Drift Detectors, Neerajan Nepal, Amrit Kaphle, Sandun Jayarathna, Sang Hyun Cho

Faculty, Staff and Student Publications

L-shell x-ray fluorescence (XRF) photons induced from gold nanoparticles (GNPs) after being irradiated by an x-ray beam allow for highly sensitive XRF imaging/computed tomography (XFCT) of biological samples containing GNPs at low concentrations on the order of parts-per-million (ppm). The primary goal of this Monte Carlo (MC) study was to investigate the feasibility of upgrading an existing experimental benchtop XRF/XFCT imaging setup adopting a single silicon drift detector (SDD), developed based on the aforementioned concept (often known as L-shell XFCT), by deploying another SDD within the same setup. Specifically, an MC model of the original single SDD L-shell XFCT setup, …

Proceedings Of The National Cancer Institute Workshop On Combining Immunotherapy With Radiotherapy: Challenges And Opportunities For Clinical Translation, Zachary S Morris, Sandra Demaria, Arta M Monjazeb, Silvia C Formenti, Ralph R Weichselbaum, James Welsh, Heiko Enderling, Jonathan D Schoenfeld, Joshua D Brody, Heather M Mcgee, Michele Mondini, Michael S Kent, Kristina H Young, Lorenzo Galluzzi, Sana D Karam, Willemijn S M E Theelen, Joe Y Chang, Mai Anh Huynh, Adi Daib, Sean Pitroda, Caroline Chung, Raphael Serre, Clemens Grassberger, Jie Deng, Quaovi H Sodji, Anthony T Nguyen, Ravi B Patel, Simone Krebs, Anusha Kalbasi, Caroline Kerr, Claire Vanpouille-Box, Logan Vick, Todd A Aguilera, Irene M Ong, Fernanda Herrera, Hari Menon, Deedee Smart, Jalal Ahmed, Robyn D Gartrell, Christina L Roland, Fatemeh Fekrmandi, Binita Chakraborty, Eric H Bent, Tracy J Berg, Alan Hutson, Samir Khleif, Andrew G Sikora, Lawrence Fong

Faculty, Staff and Student Publications

Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear. The National Cancer Institute-Immuno-Oncology Translational Network-Society for Immunotherapy of Cancer-American Association of Immunology Workshop on Combining Immunotherapy with Radiotherapy was convened to identify and prioritise opportunities and challenges for radiotherapy and immunotherapy combinations. Sessions examined the immune effects of radiation, barriers to anti-tumour immune response, previous clinical trial data, immunological and …

Development And Characterization Of Orthotopic Patient-Derived Xenograft Models Of Peritoneal Metastatic Mucinous Appendiceal Adenocarcinoma, Ichiaki Ito, Vinay K Pattalachinti, Abdelrahman Mg Yousef, Saikat Chowdhury, Mohammad M Fanaeian, Emaan Haque, Betul Beyza Gunes, Mahmoud Yousef, Emma R Salle, Mohammad A Zeineddine, Shuangxi Ji, Ruonan Li, Wenyi Wang, Beth A Helmink, Melissa W Taggart, Michael G White, Keith F Fournier, Natalie W Fowlkes, John Paul Shen

Faculty, Staff and Student Publications

Background: Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous group of tumors for which few preclinical models exist. The lack of preclinical models of AA has hindered drug development and is a major factor in why AA remains without a single FDA-approved systemic treatment.

Materials and methods: Tumors from 16 patients with appendiceal neoplasms (15 AA and one HAMN) were implanted into flank and peritoneal cavity of immunodeficient mice leading to the successful establishment of 3 AAPDX models. Histological, immunohistochemical, genetic, and transcriptomic comparison of patient and PDX tumors were performed.

Results: Higher tumor grade, peritoneal implantation, and RAS/RAF mutation …

Impact Of Postprogression Therapies On Overall Survival: Recommendations From The 2023 Kidney Cancer Association Think Tank Meeting, Stephanie A Berg, Salvatore La Rosa, Tian Zhang, Phillip M Pierorazio, Laurence Albiges, Kathryn E Beckermann, Matthew T Campbell, Maria I Carlo, Katie Coleman, Daniel J George, Daniel M Geynisman, Ritchie Johnson, Eric Jonasch, Jodi K Maranchie, Bradley A Mcgregor, Daniel D Shapiro, Eric A Singer, Brian M Shuch, Walter M Stadler, Nizar M Tannir, Yousef Zakharia, Ulka N Vaishampayan, Peter F Thall, Pavlos Msaouel

Faculty, Staff and Student Publications

Modern advances in systemic and localized therapies for patients with renal cell carcinoma (RCC) have significantly improved patients' outcomes. If disease progression occurs after initial treatment, clinicians often have multiple options for a first salvage therapy. Because salvage and initial treatments both may affect overall survival time, and they may interact in unanticipated ways, there is a growing need to determine sequences of initial therapy and first salvage therapy that maximize overall survival while maintaining quality of life. The complexity of this problem grows if a second salvage therapy must be chosen for patients with treatment-resistant disease or a second …

American Association Of Physicists In Medicine (Aapm) Chapter Climate Check: Mixed Methods Analysis Of Survey Responses, Ashley J Cetnar, Ghada Aldosary, Meghan C Koo, Holly Lincoln, Angélica Pérez-Andújar, Surendra Prajapati, Samantha J Simiele, Kristi R G Hendrickson

Faculty, Staff and Student Publications

Introduction: The American Association of Physicists in Medicine (AAPM) recently shared results and recommendations from its first Equity, Diversity, and Inclusion (EDI) Climate Survey, which was designed to assess the climate at the workplace, the AAPM organization, and the AAPM regional chapter level. This work further explores the status of EDI at the regional chapter level.

Methods: AAPM's EDI Survey was distributed to 5500 members and had a response rate of 25%. In the survey, three open-ended comment boxes were provided for feedback, including one for regional AAPM members. Sixty-four percent of respondents indicated they were part of a regional …

Psychometric Evaluation Of The Scleroderma Skin Questionnaire: A Novel Patient-Reported Outcome For Skin Disease In Patients With Systemic Sclerosis, Jeong Min Yu, John M Vanburen, Angela Child, Jessica S Alvey, Lisa A Mandl, Laura C Pinheiro, Shervin Assassi, Elana J Bernstein, Flavia V Castelino, Lorinda Chung, Luke Evnin, Tracy M Frech, Faye N Hant, Laura K Hummers, Dinesh Khanna, Kimberly S Lakin, Dorota Lebiedz-Odrobina, Yiming Luo, Ashima Makol, Jerry A Molitor, Duncan F Moore, Carrie Richardson, Nora Sandorfi, Ami A Shah, Ankoor Shah, Victoria K Shanmugam, Brian Skaug, Virginia D Steen, Elizabeth R Volkmann, Jessica K Gordon

Faculty, Staff and Student Publications

Objective: We aimed to evaluate the psychometric properties of the Scleroderma Skin Questionnaire (SSQ), a novel patient-reported outcome (PRO) to assess systemic sclerosis (SSc)-related skin symptoms.

Methods: Participants were recruited from the SSc Collaborative National Quality and Efficacy Registry (CONQUER). Internal consistency was determined using Cronbach α and McDonald ω total (ωt). The correlation of the SSQ was assessed with the modified Rodnan skin score (mRSS), physician global assessment (PGA), Scleroderma Health Assessment Questionnaire, 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29), and patient global assessment to assess criterion, convergent, and divergent validity. Correlations were also assessed between patients' self-reported recall …

Resolving Tissue Complexity By Multimodal Spatial Omics Modeling With Miso, Kyle Coleman, Amelia Schroeder, Melanie Loth, Daiwei Zhang, Jeong Hwan Park, Ji-Youn Sung, Niklas Blank, Alexis J Cowan, Xuyu Qian, Jianfeng Chen, Jiahui Jiang, Hanying Yan, Laith Z Samarah, Jean R Clemenceau, Inyeop Jang, Minji Kim, Isabel Barnfather, Joshua D Rabinowitz, Yanxiang Deng, Edward B Lee, Alexander Lazar, Jianjun Gao, Emma E Furth, Tae Hyun Hwang, Linghua Wang, Christoph A Thaiss, Jian Hu, Mingyao Li

Faculty, Staff and Student Publications

Spatial molecular profiling has provided biomedical researchers valuable opportunities to better understand the relationship between cellular localization and tissue function. Effectively modeling multi-modal spatial omics data is crucial for understanding tissue complexity and underlying biology. Furthermore, improvements in spatial resolution have led to the advent of technologies that can generate spatial molecular data with sub-cellular resolution, requiring the development of computationally efficient methods that can handle the resulting large-scale datasets. MISO (MultI-modal Spatial Omics) is a versatile algorithm for feature extraction and clustering, capable of integrating multiple modalities from diverse spatial omics experiments with high spatial resolution. Its effectiveness is …

An Inducible Foxl2-Dependent Mouse Model Of Ovarian Adult Type Granulosa Cell Tumor, Jian Li, Thomas Welte, Katherine Calzoncinth, Veena K Vuttaradhi, Allison L Brodsky, Kwong-Kwok Wong, Manu M Sebastian, Barrett Lawson, Charles V Kingsley, R Tyler Hillman

Faculty, Staff and Student Publications

Background: Adult-type granulosa cell tumors (AGCTs) are rare ovarian sex cord/stromal tumors with near-universal hotspot mutations in FOXL2 (c.C402G; p.Cys134Trp). Progress in the treatment of relapsed AGCT has been hindered by the lack of high-fidelity FOXL2-based mouse models. To address this critical unmet need, we created and validated a genetically engineered inducible mouse model of the human FOXL2 mutation that recapitulates the key features of the human disease.

Methods: Gene targeting in embryonic stem cells was used to introduce a Cre-inducible Foxl2C130W allele (mouse equivalent of the human oncogenic mutation) into the endogenous mouse Foxl2 locus. Animals with the Foxl2C130W-FLEx …

Loncastuximab In High-Risk And Heavily Pretreated Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Realworld Analysis From 21 Us Centers, Viktoriya Zelikson, Ashwath Gurumurthi, Yazeed Sawalha, Kaitlin Annunzio, Aditi Saha, Ning Dong, David Qualls, Behzad Amoozgar, Brad Kahl, John Baird, Pavan Challa, Scott F Huntington, Jennifer Santos, Steven Bair, Mayur Narkhede, Shuning Li, Zachary Frosch, Carrie Ho, Stephen D Smith, Allison Winter, Daniel Landsburg, Fateeha Furqan, Mehdi Hamadani, Katelin Baird, Jason Romancik, Hanan Alharthy, Jennie Law, Leyla Bojanini, Ranjana Advani, Boyu Hu, Patrick Connor Johnson, Natalie S Grover, Mwanasha Merril, Jennifer L Crombie, Nazila Shafagati, Cole Sterling, Loretta J Nastoupil, Narendranath Epperla, Emily C Ayers

Faculty, Staff and Student Publications

Outcomes in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor. Loncastuximab- teserine (Lonca) is an antibody-drug conjugate which was approved by the Food and Drug Administration for the treatment of patients with R/R DLBCL who have received at least two prior lines of therapy, based on the results of the LOTIS-2 trial. However, there are limited data regarding its efficacy in the real-world setting. This retrospective study included 21 US centers and evaluated outcomes of patients with R/R DLBCL treated with Lonca. Our analysis comprises 187 patients with notably higher-risk baseline features compared to those of the …

Molecular Testing For The World Health Organization Classification Of Central Nervous System Tumors: A Review, Craig Horbinski, David A Solomon, Rimas V Lukas, Roger J Packer, Priscilla Brastianos, Patrick Y Wen, Matija Snuderl, Mitchel S Berger, Susan Chang, Maryam Fouladi, Joanna J Phillips, Burt Nabors, Daniel J Brat, Jason T Huse, Kenneth Aldape, Jann N Sarkaria, Matthias Holdhoff, Terry C Burns, Katherine B Peters, Ingo K Mellinghoff, David Arons, Evanthia Galanis

Faculty, Staff and Student Publications

Importance: Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions and hospital systems. This is in large part because there is a persistent reluctance among third-party payers to cover molecular testing. The objective of this Review is to describe why comprehensive molecular biomarker testing is now required for the accurate diagnosis and grading and prognostication of CNS tumors and, in so doing, to justify …

Encorafenib, Cetuximab And Chemotherapy In Braf-Mutant Colorectal Cancer: A Randomized Phase 3 Trial, Scott Kopetz, Takayuki Yoshino, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S Maughan, Elena Beyzarov, Xiaoxi Zhang, Graham Ferrier, Xiaosong Zhang, Josep Tabernero

Faculty, Staff and Student Publications

Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, …

High-Dose Methotrexate Usage Without Drug-Level Monitoring In Advanced Pediatric Mature B-Cell Non-Hodgkin Lymphoma In A Resource-Limited Setting In Malawi, Rizine R Mzikamanda, Loviisa Mulanje, Casey L Mcatee, Apatsa Matatiyo, Zoe Mwale, Grace Chirwa, Watipaso Wanda, Atupele Miranda Mpasa, Stella Wachepa, Minke H W Huibers, Steve Martin, Tamiwe Tomoka, Maurice Mulenga, Yuri Fedoriw, Gugulethu Mapurisa, Julie M Gastier Foster, Nader El-Mallawany, Katherine D Westmoreland, Peter Wasswa, Carl E Allen, Nmazuo Ozuah

Faculty, Staff and Students Publications

Purpose: Excellent survival for advanced (stages II with high lactate dehydrogenase, III, and IV) pediatric mature B-cell non-Hodgkin lymphoma (MB-NHL) has been achieved with intensive regimens, but adoption in sub-Saharan Africa is limited by inadequate supportive care. We provide real-world data on treating advanced MB-NHL with high-dose methotrexate (HD-MTX; ≥1,000 mg/m2/cycle) where real-time serum MTX monitoring is unavailable.

Methods: We identified two cohorts-a retrospective (January 2017-December 2020) cohort treated with 1,000 or 3,000 mg/m2/cycle of HD-MTX and a prospective (July 2022-July 2023) cohort-with a modified LMB96 protocol containing 3,000 mg/m2/cycle of HD-MTX. All doses of HD-MTX were given over 3 …

Cardiomyopathies And A Brief Insight Into Dox-Induced Cardiomyopathy, Sampat Singh Tanwar, Sumeet Dwivedi, Sheema Khan, Seema Sharma

School of Medicine Publications

Background: Cardiomyopathy is a heterogeneous group of myocardial disorders characterized by structural and functional abnormalities of the heart muscle. It is classified into primary (genetic, mixed, or acquired) and secondary categories, resulting in various phenotypes including dilated, hypertrophic, and restrictive patterns. Hypertrophic cardiomyopathy, the most common primary form, can cause exertional dyspnea, presyncope, and sudden cardiac death. Dilated cardiomyopathy typically presents with heart failure symptoms, while restrictive cardiomyopathy is rarer and often associated with systemic diseases. Diagnosis involves a comprehensive evaluation including history, physical examination, electrocardiography, and echocardiography. Treatment options range from pharmacotherapy and lifestyle modifications to implantable cardioverter-defibrillators and …

Convergence On Camk4: A Key Modulator Of Autism-Associated Signaling Pathways In Neurons, Jacqueline Kaiser, Alana Risteska, Abbey G Muller, Haoxiong Sun, Bethany Lei, Kevin Nay, Anthony R Means, Margot A Cousin, David H Drewry, Jonathan S Oakhill, Bruce E Kemp, Anthony J Hannan, Michael Berk, Mark A Febbraio, Andrew L Gundlach, Elisa L Hill-Yardin, John W Scott

Faculty, Staff and Students Publications

Although the precise underlying cause(s) of autism spectrum disorder remain unclear, more than 1000 rare genetic variations are associated with the condition. For many people living with profound autism, this genetic heterogeneity has impeded the identification of common biological targets for therapy development for core and comorbid traits that include significant impairments in social communication and repetitive and restricted behaviors. A substantial number of genes associated with autism encode proteins involved in signal transduction and synaptic transmission that are critical for brain development and function. CAMK4 is an emerging risk gene for autism spectrum disorder that encodes the CaMK4 (calcium/calmodulin-dependent …

Long Covid Illness: Disparities In Understanding And Receipt Of Care In Emergency Department Populations, Robert M Rodriguez, Karen Reyes, Vijaya Arun Kumar, Brian Chinnock, Stephanie A Eucker, Kristin L Rising, Zubaid Rafique, Michael Gottlieb, Graham Nichol, Dana Morse, Melanie Molina, Mireya I Arreguin, Lindsey Shughart, Christopher Conn, Svea Eckstrand, Heba Mesbah, Lauren Chakraborty, Robert D Welch

Faculty, Staff and Students Publications

Study objective: Most long coronavirus disease (long COVID) studies rely on traditional surveillance methods that miss underserved populations who use emergency departments (EDs) as their primary health care source. In medically underserved ED populations, we sought to determine (1) whether there are gaps in awareness and self-declared understanding about long COVID illness, and (2) the prevalence, impact on school/work attendance, and receipt of care for long COVID symptoms.

Methods: This study was a cross-sectional, convenience sample survey study of adult patients at 11 geographically representative US EDs from December 2022 to October 2023. Awareness and self-declared understanding about long COVID …

A Sample Size Analysis Of A Mathematical Model Of Longitudinal Tumor Volume And Progression-Free Survival For Bayesian Individual Dynamic Predictions In Recurrent High-Grade Glioma, Daniel J Glazar, Solmaz Sahebjam, Hsiang-Husan M Yu, Dung-Tsa Chen, Menal Bhandari, Heiko Enderling

Faculty, Staff and Student Publications

Patients with recurrent high-grade glioma (rHGG) have a poor prognosis with median progression-free survival (PFS) ofheterogenous, suggesting a clinical need for prognostic models. Bayesian data analysis can exploit individual patient follow-up imaging studies to adaptively predict the risk of progression. We propose a novel sample size analysis for Bayesian individual dynamic predictions and demonstrate proof of principle. We coupled a nonlinear mixed effects tumor growth inhibition model with a survival model. Longitudinal tumor volumes and time-to-progression were simulated for 2000 in silico rHGG patients. Bayesian individual dynamic predictions of PFS curves were evaluated using area under the receiver operating characteristic …

A Phase 1 Study Of Durvalumab As Monotherapy Or Combined With Tremelimumab With Or Without Azacitidine In Patients With Myelodysplastic Syndrome, Guillermo Garcia-Manero, Manila Gaddh, Uwe Platzbecker, R Coleman Lindsley, Sarah M Larson, Timothy Chevassut, Pierre Fenaux, Rami Komrokji, Roger Lyons, Aref Al-Kali, Yu Jiang, John Bothos, Danielle M Townsley, Amer M Zeidan

Faculty, Staff and Student Publications

Upregulation of programmed death ligand-1 (PD-L1) has been observed in patients with MDS, and its expression on myeloblasts is associated with progression to AML. This open-label, phase 1 study evaluated the safety and tolerability of the PD-L1 antibody durvalumab as monotherapy (part 1) and in combination with tremelimumab, with or without azacitidine (part 2), in patients with MDS who progressed following hypomethylating agent treatment. Sixty-seven adults with MDS were enrolled (part 1, 40 with low/intermediate-1 or intermediate-2/high IPSS risk status; part 2, 27 with intermediate-2/high IPSS risk status). Primary safety endpoints included dose-limiting toxicities (DLTs) and treatment-emergent adverse events (TEAEs). …

Cd147 Mediates The Metabolic Reprogramming Of Cancer Associated Fibroblasts Induced By Evs Released By Differentiating Cancer Stem Cells, Filomena Colella, Federica Calapà, Giulia Artemi, Erica Pazzaglia, Rita Colonna, Sara Vitale, Giacomo Lazzarino, Federica Vincenzoni, Micol Eleonora Fiori, Ruggero De Maria, Sara Lucchisani, Giannicola Genovese, Luigi Perelli, Barbara Tavazzi, Alessandro Sgambato, Donatella Lucchetti

Faculty, Staff and Student Publications

Several reports have demonstrated that CD147, an N-glycosylated protein that is exchanged by cells in soluble form or through small extracellular vesicles (sEVs), can promote cancer progression. However, its activity related to EVs in colorectal cancer (CRC) is still not fully understood. Previously, we showed that sEV secretion during CRC stem cell (CR-CSCs) differentiation is partially controlled by CD147, and that CD147-expressing sEVs (sEVs-CD147) activate a signalling cascade in recipient cells, inducing molecular invasive features in CR-CSCs. In the present study, we demonstrated that sEVs-CD147 increase the expression of myofibroblast and activation markers in cancer-associated fibroblasts (CAF). In sEVs-CD147-activated CAF, …

Systems Neuroimmunology: Current Bottlenecks, Research Priorities And Future Directions, Harini Iyer, Christophe Benoist, Staci D Bilbo, Lisa M Boulanger, Michael D Burton, Brian P Daniels, Aleksandra Deczkowska, Martin F Flajnik, Mélanie G Gareau, Peter M Grace, Javier E Irazoqui, Susanna Rosi, Irene Salinas, Anne Schaefer, Caroline L Sokol, Dionna W Williams, Robyn S Klein

Faculty, Staff and Student Publications

Strategies to advance the field of neuroimmunology by embracing its complexity via inclusion of its multidisciplinary properties were discussed at a meeting in Cold Spring Harbor. Attendees proposed fostering of open communications and funding of collaborations across disciplines, and the recognition that our understanding of the neuroimmune system requires interdisciplinary science.

Reducing Igg Accumulation Via Neonatal Fc Receptor (Fcrn) Blockade Relieves Neuropathic Pain, Nathan T Fiore, Kendal F Willcox, Dorsa Dayani, Younus A Zuberi, Cobi J Heijnen, Peter M Grace

Faculty, Staff and Student Publications

Preclinical and clinical studies have established that autoreactive immunoglobulin G (IgG) can drive neuropathic pain. We recently demonstrated that sciatic nerve chronic constriction injury (CCI) in male and female mice results in the production of pronociceptive IgG, which accumulates around the lumbar region, including within the dorsal root ganglia (DRG) and spinal cord, facilitating the development of neuropathic pain. These data raise the intriguing possibility that neuropathic pain may be alleviated by reducing the accumulation of IgG. To this end, we tested whether biologic inhibition or genetic deletion of the neonatal Fc receptor (FcRn) would attenuate mechanical hypersensitivity (allodynia) and …

Exome Sequencing Identifies Helb As A Novel Susceptibility Gene For Non-Mucinous, Non-High-Grade-Serous Epithelial Ovarian Cancer, Ed M Dicks, Jonthan P Tyrer, Suzana Ezquina, Michelle Jones, John Baierl, Pei-Chen Peng, Michael Diaz, Ellen Goode, Stacey J Winham, Thilo Dörk, Toon Van Gorp, Anna De Fazio, David D L Bowtell, Dale W Garsed, Kunle Odunsi, Kirsten Moysich, Marina Pavanello, Florentia Fostira, Penelope M Webb, Jana Soukupová, Paul A Cohen, Weiva Sieh, Renée Turzanski Fortner, Charite Ricker, Beth Karlan, Ian Campbell, James D Brenton, Susan J Ramus, Simon A Gayther, Paul D P Pharoah

Faculty, Staff and Student Publications

Rare, germline loss-of-function variants in a handful of DNA repair genes are associated with epithelial ovarian cancer. The aim of this study was to evaluate the role of rare, coding, loss-of-function variants across the genome in epithelial ovarian cancer. We carried out a gene-by-gene burden test with various histotypes using data from 2573 non-mucinous cases and 13,923 controls. Twelve genes were associated at a False Discovery Rate of less than 0.1 of which seven were the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2. The other five genes were OR2T35, HELB, MYO1A and GABRP which …

A Predictive Chromatin Architecture Nexus Regulates Transcription And Dna Damage Repair, Audesh Bhat, Sonali Bhan, Aindrila Kabiraj, Raj K Pandita, Keneth S Ramos, Sandhik Nandi, Shreya Sopori, Parthas S Sarkar, Arti Dhar, Shruti Pandita, Rakesh Kumar, Chandrima Das, John A Tainer, Tej K Pandita

Faculty, Staff and Student Publications

Genomes are blueprints of life essential for an organism's survival, propagation, and evolutionary adaptation. Eukaryotic genomes comprise of DNA, core histones, and several other nonhistone proteins, packaged into chromatin in the tiny confines of nucleus. Chromatin structural organization restricts transcription factors to access DNA, permitting binding only after specific chromatin remodeling events. The fundamental processes in living cells, including transcription, replication, repair, and recombination, are thus regulated by chromatin structure through ATP-dependent remodeling, histone variant incorporation, and various covalent histone modifications including phosphorylation, acetylation, and ubiquitination. These modifications, particularly involving histone variant H2AX, furthermore play crucial roles in DNA damage …