Medicine and Health Sciences Commons^™

Cyclic Amp-Dependent Regulation Of Ryanodine Receptors In Healthy And Diseased Hearts, Mohit M Hulsurkar, Isabelle Ong, Joshua A Keefe, Issam H Abu-Taha, Dobromir Dobrev, Xander H T Wehrens

Faculty, Staff and Students Publications

Cyclic adenosine monophosphate (cAMP) is a critical second messenger in cardiomyocytes, regulating essential cellular functions. Upon G-protein-coupled receptor stimulation, adenylyl cyclase (AC) synthesizes cAMP, which phosphodiesterase (PDE) enzymes subsequently degrade. Recent studies challenge the traditional view of uniform cAMP signaling, revealing nanodomain-specific regulation within cardiomyocytes. This localized cAMP signaling modulates key Ca2+-handling proteins, including ryanodine receptor type-2 (RyR2), through channel-bound protein kinases and PDEs. Additionally, nucleoside-diphosphate kinases (NDPKs), particularly NDPK-C, contribute to cAMP synthesis and RyR2 regulation. Elevated NDPK-C levels in failing hearts correlate with increased cAMP levels, enhanced sarcoplasmic reticulum Ca2+ release, and cardiac arrhythmias. Furthermore, cAMP influences the …

Differential Longitudinal Effects Of Glucose-Lowering Medications On Glucagon And C-Peptide Responses In The Glycemia Reduction Approaches In Diabetes: A Comparative Effectiveness Study (Grade), Steven E Kahn, Mark Tripputi, John M Lachin, Ashok Balasubramanyam, Mary Ann Banerji, Joshua Barzilay, Robert M Cohen, W Timothy Garvey, Michaela R Gramzinski, Neda Rasouli, Mary Rhee, Jesse C Seegmiller, Vatsala Singh, William I Sivitz, Michael W Steffes, Kristina Utzschneider, Ralph A Defronzo

Faculty, Staff and Students Publications

Objective: To determine the longitudinal effects on α-cell function of four classes of glucose-lowering agents added to metformin in adults with type 2 diabetes.

Research design and methods: In a multicenter, randomized study, 5,047 participants ≥30 years of age with type 2 diabetes taking 1,000-2,000 mg metformin daily, HbA1c 6.8%-8.5%, were randomized to receive insulin glargine U100, glimepiride, liraglutide, or sitagliptin. In a subset of 724 participants, baseline and longitudinal measures of α-cell function were assessed as the fasting glucagon concentration and change in glucagon from fasting to 30 min following oral glucose (glucagon index [GGI]). Whether these measures and …

Factors Associated With Rare Pediatric Cancer Trial Enrollment: A Report From The Children's Oncology Group Rare Tumors Committee, Brian R Englum, Jin Piao, Lindsay Younis, Reto M Baertschiger, Kenneth S Chen, Emily Christison-Lagay, Hetal Dholaria, Robyn Gartrell, M John Hicks, Junne Kamihara, Sarah G Mitchell, Manuela Orjuela-Grimm, Farzana Pashankar, Samara L Potter, Jennifer H Aldrink, Jeremy Rosenblum, Michael R Sargen, Kris Ann P Schultz, Brittani K N Seynnaeve, Mary Wedekind, Theodore W Laetsch

Faculty, Staff and Students Publications

Background: Over 90% of US children with cancer are treated at Children's Oncology Group (COG) centers, which seek to maximize enrollment in therapeutic and biobanking studies. Rare cancers have demonstrated lower than expected COG enrollment. We evaluated trends in COG rare cancer enrollment compared to US incidence from Surveillance, Epidemiology, and End Results (SEER) registries, examining the impact of COG therapeutic trials and Project:EveryChild, a cancer biobank/registry.

Procedure: COG and SEER data from 2002 to 2020 were queried for US patients younger than 18 years old with adrenocortical carcinoma (ACC), nasopharyngeal carcinoma (NPC), retinoblastoma (RB), thyroid carcinoma, and melanoma. We …

Utility And Utilization Of Transabdominal Ultrasound In Pediatric Patients With Acute Recurrent Or Chronic Pancreatitis, Nicholas Norris, David Troendle, Michael Wilschanski, Fuchenchu Wang, Gretchen A Cress, Maisam A Abu-El-Haija, Ankur Chugh, Reuven Zev Cohen, Elissa M Downs, Douglas S Fishman, Cheryl E Gariepy, Matthew J Giefer, Tanja Y Gonska, Amit S Grover, Sohail Z Husain, Douglas Lindblad, Quin Y Liu, Asim Maqbool, Jacob A Mark, Brian A Mcferron, Megha S Mehta, Veronique D Morinville, Kenneth Ng, Robert A Noel, Chee Y Ooi, Emily R Perito, Zachary M Sellers, Andrew T Trout, Yuhua Zheng, Ying Yuan, Mark E Lowe, Aliye Uc, Consortium For The Study Of Chronic Pancreatitis, Diabetes And Pancreatic Cancer

Faculty, Staff and Students Publications

Objectives: Transabdominal ultrasound (TAUS) is frequently utilized in pediatric acute pancreatitis, but less is known about its use in acute recurrent (ARP) or chronic pancreatitis (CP). Our aim was to describe TAUS utilization and findings from the largest multicenter cohort of pediatric ARP and CP, the International Study Group of Pediatric Pancreatitis: In Search for a CuRE-2 (INSPPIRE-2).

Methods: Demographic and imaging data from physician questionnaires were obtained for patients with available TAUS data. Utilization and findings were compared between ARP and CP groups. Kappa statistics were used to compare agreement of TAUS to computed tomography (CT), magnetic resonance imaging/cholangiopancreatography …

Bet Inhibitor-Based Combinations Targeting Novel Dependencies In Mecom-Rearranged (R) Aml, Christine E Birdwell, Warren Fiskus, Christopher P Mill, Tapan M Kadia, Naval Daver, Courtney D Dinardo, Koji Sasaki, John A Davis, Kaberi Das, Hanxi Hou, Antrix Jain, Anna Malovannaya, Lauren B Flores, Rasoul Pourebrahim, Selina Yuan, Xiaoping Su, Michele Ceribelli, Kapil N Bhalla

Faculty, Staff and Student Publications

MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry …

Life-Extending Interventions Do Not Necessarily Result In Compression Of Morbidity: A Case Example Offering A Robust Statistical Approach, Deependra K Thapa, Wasiuddin Najam, Erik S Parker, Xi Rita Wang, Daniel L Smith, Ufuk Beyaztas, James F Nelson, Steven N Austad, Gary A Churchill, David B Allison

Children’s Nutrition Research Center Staff Publications

Despite extensive research on life-extending interventions, rigorous statistical techniques to determine their impact on compression of morbidity (CoM) are rarely used. We present a case example of an analytical method for examining the effect of life-extending dietary interventions on CoM by comparing the rates of decline in vitality and survival toward the end of life. Using data from previous experimental studies in mice, we calculated the average rate of vitality decline by fitting exponential decay models to individual vitality trajectories and compared this rate with the rate of survival decline estimated from Cox proportional hazards model. The results showed that, …

Seeg-Guided Responsive Neurostimulation To Treat Neocortical Epilepsy: A Multicenter Retrospective Study Of The Efficacy And Safety Of Depth Electrode-Mediated Neuromodulation, Sina Sadeghzadeh, Jon T Willie, Et Al.

2020-Current year OA Pubs

OBJECTIVES: Pivotal trials have established the effectiveness of the Responsive Neurostimulation System (RNS® System) in treating focal epilepsy. In clinical trials, depth leads were primarily used to treat mesial temporal seizure onsets while cortical strip leads were used to treat neocortical seizure onsets. Here, we systematically analyze the safety and efficacy of stereoelectroencephalography (sEEG)-guided depth leads to provide responsive stimulation to neocortical gray matter.

METHODS: Patients were stratified as strong responders (>median cohort seizure reduction %), weak responders (>0% and ≤median cohort seizure reduction %), and anti-responders (≤0%) based on percent seizure reduction at 1 year post-implant (1-Y). …

Patient-Reported Outcomes In The Serena-6 Trial Of Camizestrant Plus Cdk4/6 Inhibitor In Patients With Advanced Breast Cancer And Emergent Esr1 Mutations During First-Line Endocrine-Based Therapy, E L Mayer, C Ma, Et Al.

2020-Current year OA Pubs

BACKGROUND: In SERENA-6, switching from aromatase inhibitor (AI) to camizestrant with continuation of CDK4/6 inhibitor (CDK4/6i) guided by emergence of ESR1 mutations (ESR1-mut) during first-line AI-CDK4/6i in patients with hormone receptor (HR)-positive advanced breast cancer (ABC) resulted in statistically significant and clinically meaningful improvement in progression-free survival compared with AI-CDK4/6i and reduction in the risk of deterioration in global health status (GHS)/quality of life (QoL) (hazard ratio 0.54). Here we report additional data from patient-reported outcomes (PROs).

PATIENTS AND METHODS: Patients completed PRO questionnaires at pre-specified timepoints, including the European Organisation for Research and Treatment of Cancer (EORTC) oncology-specific EORTC …

Intersecting Challenges: Substance Use And Mental Health Disparities Across Self-Reported Disability Status, Jessica Williams, Xiao Li, Hannah S Szlyk, Erin Kasson, Nathaniel A Dell, Alex Ramsey, Patricia A Cavazos-Rehg

2020-Current year OA Pubs

PURPOSE: Substance use and substance use disorders (SUD) disproportionately affect people with disabilities (PWD), yet PWD remain under-represented in addiction treatment literature. While recent work has begun to address SUD prevalence and recovery service gaps, little is known about how disability status shapes substance use outcomes. The present study is the first to our knowledge to investigate how recovery, mental health comorbidities, and barriers to care differ across disability status using structured survey data from people who use substances.

METHODS: 333 participants who use substances and provided information about their disability status in the baseline survey for a digital intervention …

Ultrasound Applications In The Treatment Of Major Depressive Disorder: A Systematic Review Of Techniques And Therapeutic Potentials In Clinical Trials And Animal Model Studies, Gansheng Tan, Hong Chen, Eric C Leuthardt

2020-Current year OA Pubs

OBJECTIVE: Major depressive disorder (MDD) is a debilitating condition that inflicts significant personal and economic burdens and affects approximately 8% of the US population. Approximately 30% of patients with MDD do not respond to conventional antidepressant and psychotherapeutic treatments. Current treatment options for refractory MDD include transcranial magnetic stimulation (TMS) and invasive surgical procedures such as surgical ablation, vagus nerve stimulation, and deep brain stimulation. In this context, therapeutic ultrasound emerges as a promising alternative for treating refractory MDD, which has the unique advantage of combining noninvasiveness with selective targeting. Over the past ten years, there has been growth in …

Accelerated Diffusion Basis Spectrum Imaging With Tensor Computations, Kainen L Utt, Jacob S Blum, Donsub Rim, Sheng-Kwei Song

2020-Current year OA Pubs

This paper introduces an advanced framework for accelerated processing of diffusion-weighted imaging (DWI) data that utilizes an entire-image modeling approach to optimize the estimation of diffusion parameters from DWIs by mapping input diffusion data to predicted signals and estimating parameter values via a stochastic gradient descent optimizer (Adam). To validate this approach, we applied this framework to diffusion basis spectrum imaging (DBSI) and analyzed in vivo human brain and ex vivo mouse brain DWIs. Results demonstrate significant improvements to computational speed and signal-to-noise ratio (SNR) in estimated parameter maps compared to standard DBSI. Our approach is applicable to any diffusion …

Technical Considerations And Contemporary Literature Review Of The Gore Thoracic Branch Endoprosthesis®, Bruno P Schmid, Lucas R Kanamori, Hannah V Oden-Brunson, Dora Babocs, Ying Huang, Jorge Miranda, Steven Maximus, Gustavo S Oderich

Faculty, Staff and Students Publications

Thoracic endovascular aortic repair (TEVAR) has become the preferred treatment for various thoracic aortic pathologies, including blunt thoracic aortic injury, aneurysms, and dissections. Involvement of Ishimaru Zone 2 occurs in up to 60% of TEVAR cases requiring extension across the distal aortic arch and left subclavian artery (LSA). Coverage of the LSA without revascularization increases the risk of complications such as upper extremity ischemia, stroke, and spinal cord injury. Therefore, the preservation of LSA perfusion during TEVAR is essential. Cervical debranching remains an effective alternative to preserve flow to the LSA, but it poses risks of bleeding, infection, and nerve …

Evaluation Of Large Language Models As Decision Support Tools For Head And Neck Cancer Management: A Blinded Multidisciplinary Simulation Study, Sholem Hack, Ron J. Karni, Antonino Maniaci, Christopher E. Fundakowski, Luca Castellani, Fabiola Incandela, Remo Accorona, Miguel Mayo-Yanez, Martina Violati, Lorenzo Giannini, Niccolo' Mevio, Alberto Maria Saibene

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

BACKGROUND: The management of head and neck cancer relies on multidisciplinary expertise; however, access to tumor boards remains variable. Large language models (LLMs) may support guideline-based decision-making, although performance in complex oncologic scenarios is not well defined.

METHODS: Fourteen synthetic cases based on real tumor board encounters were evaluated. Five blinded comparator arms produced recommendations: a human expert, Non-RAG-GPT-4, Non-RAG-GPT-5, RAG-GPT-4, and RAG-GPT-5. Eight head and neck oncologic surgeons scored each recommendation for appropriateness, clarity, specificity, and feasibility using 5-point Likert scales. Paired permutation testing and inter-rater reliability were assessed.

RESULTS: LLM outputs showed close alignment with expert recommendations. RAG-based …

Leveraging The Pedsnet Clinical Research Network And Electronic Health Record Data To Enhance Efficiency Of Trial Enrollment For A Rare Pediatric Rheumatic Disease, Pamela F Weiss, Levon Utidjian, Mitchell Maltenfort, Hanieh Razzaghi, Timothy G Brandon, Cassandra Muir, Cora Sears, Edward J Oberle, Jennifer Cooper, Kevin Baszis, Mary B Toth, Esi M Morgan, Christopher B Forrest

2020-Current year OA Pubs

BACKGROUND: We evaluated the PEDSnet clinical research network for study enrollment of juvenile spondyloarthritis, a rare rheumatic disease that includes enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA). METHODS: An electronic health record (EHR)-based typology was developed by an interdisciplinary team to query EHR data for a spectrum of pediatric rheumatic diseases (2009–2023) from 8 PEDSnet centers. The prevalence, characteristics and drug exposures for juvenile spondyloarthritis was explored to gauge feasibility of leveraging the network for study enrollment. Next, the typology was adapted to identify subjects for a clinical trial; the efficiency of EHR typology query was compared to standard screening …

Human Chorionic Gonadotropin Decreases Cerebral Cystic Encephalomalacia And Parvalbumin Interneuron Degeneration In A Pro-Inflammatory Model Of Mouse Neonatal Hypoxia-Ischemia, Benjamin Miller, Alexander Crider, Bhooma Aravamuthan, Rafael Galindo

2020-Current year OA Pubs

Human chorionic gonadotropin (hCG) is an immunoregulatory and neurotrophic glycoprotein of potential clinical utility in the neonate at risk for cerebral injury. However, hCG has not been demonstrated to affect the pro-degenerative actions of inflammation in neonatal brain injury. Here we utilize a neonatal mouse model of mild hypoxia-ischemia (HI) combined with intraperitoneal administration of lipopolysaccharide (LPS) to evaluate the neuroprotective actions of hCG in the setting of systemic inflammation. Intraperitoneal treatment with hCG significantly decreased tissue loss and cystic degeneration in the hippocampus and cerebral cortex of term-equivalent neonatal mice exposed to LPS and HI. Noting that parvalbumin immunoreactive …

Sequential Platinum And Parp Inhibition Enhances Pd1 Immunotherapy Efficacy In Murine Brca2 Mutated Pancreatic Cancer, John C Mcvey, Max M Wattenberg, Heather Coho, Kayjana Infante, Kelly Markowitz, Devora Delman, Cynthia Clendenin, Emma E Furth, Rashmi Tondon, Ben Z Stanger, Robert H Vonderheide, Kim A Reiss, Gregory L Beatty

2020-Current year OA Pubs

Pancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy to treat, but emerging evidence suggests that specific subtypes may respond more favorably to certain therapies. BRCA-mutated PDAC represents a distinct subtype that is particularly sensitive to DNA-damaging therapies. The current standard of care for advanced BRCA-mutated PDAC involves induction platinum-based chemotherapy followed by maintenance therapy with a poly (ADP-ribose) polymerase inhibitor (PARPi). However, the randomized phase III POLO trial, upon which this standard is based, did not demonstrate an improved overall survival in patients who received olaparib compared to those who received placebo, highlighting the need for new therapeutic approaches. Additionally, …

Novel R Shiny Tool For Survival Analysis With Time-Varying Covariate In Oncology Studies: Overcoming Biases And Enhancing Collaboration, Yimei Li, Yang Qiao, Fei Gao, Jordan Gauthier, Qiang Ed Zhang, Jenna Voutsinas, Wendy Leisenring, Ted Gooley, Corinne Summers, Alexandre Hirayama, Cameron Turtle, Rebecca Gardner, Jarcy Zee, Qian Vicky Wu

Wills Eye Hospital Papers

PURPOSE: Our study is motivated by evaluating the role of hematopoietic cell transplantation (HCT) after chimeric antigen receptor T-cell (CAR-T) therapy for ALL, a debated topic. Because patients may receive HCT at different times after CAR-T infusion or never, HCT post-CAR-T should be considered as a time-varying covariate (TVC).

METHODS: Standard Cox models and Kaplan-Meier (KM) curves (naïve method) assume that TVC status is known and fixed at baseline, which can yield biased estimates. Landmark analysis is a popular alternative but depends on a chosen landmark time. Time-dependent (TD) Cox model is better suited for TVC although visualizing survival curves …

Supercharging-Enhanced Ndia-Ms Enables Global Profiling Of Drug-Induced Proteome Solubility Shifts, Yun Xiong, Huimin Zhang, Lin Tan, Bo Wei, John N Weinstein, Philip L Lorenzi

Faculty, Staff and Student Publications

Mass spectrometry (MS) is indispensable for high-throughput quantitation of protein expression. But protein function is regulated by factors beyond abundance alone. Here, we evaluate two supercharging reagents, dimethyl sulfoxide (DMSO) and m-nitrobenzyl alcohol (mNBA), in narrow-window data-independent acquisition (nDIA)-MS. DMSO markedly enhances MS signal and protein identification, whereas mNBA primarily increases peptide identifications. Optimizating nDIA-MS with 3% DMSO boosts signal intensity by up to 56%, enabling identification of ~9,600 proteins from 1 µg HeLa digest in 15 min. Using this methodology, we quantify solubility and abundance changes in 8,694 proteins across three cell lines following short-term treatment with the proteasome …

Beyond Bile Acids Synthesis: Metabolomics Profiling Highlights Extensive Metabolic Dysregulation And Treatment Response In Ctx, Monte A Del Monte, Jennifer Hanson, Penelope E Bonnen

Faculty, Staff and Students Publications

Background: Cerebrotendinous xanthomatosis (CTX) is an inherited metabolic disorder caused by variants in CYP27A1 leading to loss of sterol-27-hydroxylase activity. Sterol-27-hydroxylase generates two classes of bioactive signaling molecules: bile acids and oxysterols. The broader metabolic consequences resulting from perturbations in bile acid and oxysterol signaling and their reversibility with FDA-approved treatment chenodeoxycholic acid (CDCA), are not fully described.

Methods: To establish a comprehensive map of metabolic consequences of CTX, we performed large-scale, untargeted plasma metabolomics in a single subject with CTX, both before and after 6 months of CDCA therapy, and compared results with a reference cohort of over 1100 …

Partial Versus Full Revision In Cementless Single-Stage Exchange For Hip Periprosthetic Joint Infection: A Multicenter Comparative Study With 10-Year Survivorship Analysis, Wenbo Mu, Atthakorn Jarusriwanna, Boyong Xu, Scot A. Brown, Xiaogang Zhang, Alexander Dawes, Javad Parvizi Md, Li Cao

Rothman Institute Papers

BACKGROUND: Periprosthetic joint infection (PJI) is one of the most challenging complications following total hip arthroplasty (THA). Traditional management typically involves full revision to ensure comprehensive infection eradication. However, for patients with well-fixed implants, partial revision in a single-stage cementless approach may provide a viable alternative, potentially preserving bone stock and reducing operative time. The relative efficacy of this approach compared with full revision remains to be fully explored. This multicenter study aims to determine whether partial revision in cementless single-stage exchange surgery offers comparable infection control outcomes to full revision for select patients with well-fixed implants.

METHODS: We conducted …

Downregulation Of Slc40a1 Leads To Iron Accumulation In Fibrotic Lung Fibroblasts, Quanjin Dang, Chaoqun Huang, Yurong Liang, Akshaya Surendran, Dharanya Muthiah, Kishore Vaddadi, Sankha Hewawasam, Tingting W Mills, Lin Liu

Faculty, Staff and Student Publications

Iron is an essential nutrient for almost all organisms. However, excess iron generates reactive oxygen species and causes tissue injuries. Iron is implicated in idiopathic pulmonary fibrosis (IPF). In this study, we examined iron accumulation in fibrotic lung fibroblasts and the underlying mechanisms. We hypothesize that the downregulation of Solute Carrier Family 40 Member 1 (SLC40A1) results in iron accumulation in lung fibroblasts of IPF patients. Using a Prussian Blue iron staining, we found that iron accumulated in the fibrotic region of the lungs from IPF patients and bleomycin- and asbestos-induced lung fibrosis mice. Iron was partially co-localized with the …

The Origin Of Hepatocellular Carcinoma Depends On Metabolic Zonation, Jason Guo, Roger Liang, Andrew Chung, Zhijie Li, Boyuan Li, Eric Chen, Lin Li, Jingjing Wang, Meng-Hsiung Hsieh, Ivy Xiangyi Fang, Benjamin Kroger, Yunguan Wang, Min Zhu, Xiongzhao Ren, Greg Mannino, Yuemeng Jia, Yonglong Wei, Stephen Moore, Daniel J Siegwart, Stephen S Chung, Zixi Wang, Tripti Sharma, Suman Komjeti, Yi Han, Purva Gopal, Guanghua Xiao, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. Although the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown whether cancers arise from some zones but not others and whether there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 (catenin beta 1) and Arid2 (AT-rich interaction domain 2) mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), in mouse models showed that position and metabolic context determine clone fates. Ctnnb1/Arid2-driven cancers were much more likely to arise in zone 3. The …

Establishing T1 And Ecv Mapping Based Nomogram Differentiate Acute Ischemic And Nonischemic Myocardial Injury: A Proof-Of-Concept Study, Yanping Su, Kan Liu, Et Al.

2020-Current year OA Pubs

OBJECTIVES: To develop and validate a nomogram based on T1 and extracellular volume fraction (ECV) mapping derived from cardiovascular magnetic resonance (CMR) for differentiating ischemic from nonischemic cardiomyopathies during the acute phase.

METHODS: This retrospective study included patients who underwent CMR at the Fifth Affiliated Hospital of Wenzhou Medical University (internal dataset) and the Fifth Affiliated Hospital of Sun Yat-sen University (external dataset). Patients were assigned to a training set (n = 73), a test set (n = 30), an internal validation set (n = 28), and an external validation set (n = 16). Six multivariable logistic regression models were …

Olutasidenib In Recurrent/Relapsed Locally Advanced Or Metastatic Idh1-Mutated Chondrosarcoma: Phase 1b/2 Trial, Robin L Jones, Roman Groisberg, Jean-Yves Blay, Howard Colman, Macarena De La Fuente, Patricia Roxburgh, Mwe Mwe Chao, Hua Tian, Florence Duffaud, Rastislav Bahleda, Brian A Van Tine

2020-Current year OA Pubs

Chondrosarcomas are rare cartilaginous neoplasms with limited treatment options. Isocitrate dehydrogenase 1/2 (mIDH1/2) mutations occur in 65% of chondrosarcomas. Here we report safety and efficacy of olutasidenib, an mIDH1 inhibitor, evaluated in patients with locally advanced or metastatic mIDH1 chondrosarcoma (Clinicaltrials.gov identifier: NCT03684811). The primary endpoint was objective response rate by tumor evaluation; secondary endpoints included adverse events, progression-free and overall survival. Patients received olutasidenib 150 mg twice daily. Twenty-three patients were enrolled; 16 were diagnosed with conventional chondrosarcoma (cCS). Median age was 57 (range, 30-71) years. In 21 response-evaluable patients, 11 (52%) had stable disease, 8 (38%) had progressive …

Designing Inclusive Newborn Sequencing Research: Insights From Parents In Underrepresented Communities, Maya C Del Rosario, Sheyenne A Walmsley, Barbara W Harrison, Crystal T Stephens, Bethany Zettler, Greysha Rivera-Cruz, Priyal Agrawal, Amy Brower, Stephanie Chigbu, Kurt D Christensen, Casie A Genetti, Richetta Givens, Nina B Gold, Inez V Reeves, Isabella Schichter, Habib Shariat, Sandra Simon, Hadley Stevens Smith, Melissa Uveges, Robert C Green, Ingrid A Holm, Stacey Pereira

Center for Medical Ethics and Health Policy Staff Publications

Background: It is essential that studies of genomic sequencing (GS) in newborns and children include individuals from under-represented racial and ethnic groups (URG) to ensure future applications are equitably implemented. We conducted interviews with parents from URG to better understand their perspectives on GS research, develop strategies to reduce barriers to enrollment, and facilitate research participation.

Methods: Semi-structured interviews with 50 parents from URG.

Results: Nearly all parents said they would be interested in participating in an infant GS study. Parents were interested in participating in GS research for reasons including clinical utility, personal utility, and/or family health benefits. Deterrents …

Kdm4a Promotes Nepc Progression Through Regulation Of Myc Expression, Celia Sze Ling Mak, Ming Zhu, Jie Fu, Xin Liang, Xiaoxuan Wang, Fei Yuan, Feng Wang, Anh G Hoang, Xingzhi Song, Peter Shepherd, Derek Liang, Jessica Suh, Jordan Contreras, Thisawin Dang, Cindy Yan, Brandon Figueroa, Mathias Mazzocco, Athena Luo, Bijeta Pradhan, Jiwon Park, Mirrah Bashir, Miao Zhang, Eric Metzger, Roland Schüle, Abhinav K Jain, Ellen Karasik, Daniel Frigo, Barbara A Foster, Min Gyu Lee, Paul Corn, Christopher J Logothetis, Ana Aparicio, Nora Navone, Patricia Troncoso, Zhi Tan, Jianhua Zhang, Sue-Hwa Lin, Guocan Wang

Faculty, Staff and Students Publications

Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal subtype of prostate cancer (PCa) that often emerges in response to androgen receptor pathway inhibitors (ARPIs), which are widely used in treating metastatic castration-resistant and hormone-sensitive prostate cancer. The incidence of NEPC is increasing, yet effective therapeutic strategies remain limited due to an incomplete understanding of its molecular drivers. Through transcriptomic analyses of human prostate tumor samples, we identified the histone lysine demethylase KDM4A as uniquely overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Functional validation demonstrated that KDM4A is a key regulator of NEPC progression and a …

Defining The Heterogeneous Molecular Landscape Of Lung Cancer Cell Responses To Epigenetic Inhibition, Chuwei Lin, Catherine M Sniezek, Christopher D Mcgann, Rashmi Karki, Ross M Giglio, Benjamin A Garcia, José L Mcfaline-Figueroa, Devin K Schweppe

2020-Current year OA Pubs

Epigenetic inhibitors exhibit powerful antiproliferative and anticancer activities. However, cellular responses to small-molecule epigenetic inhibition are heterogeneous and dependent on factors such as the genetic background and metabolic state of cells, as well as on-/off-target engagement of individual small-molecule compounds. The molecular study of the extent of this heterogeneity often measures changes in a single cell line. To more comprehensively profile the effects of small-molecule perturbations and their influence on heterogeneous cellular responses, we present a molecular resource based on the quantification of chromatin, proteome, and transcriptome remodeling due to histone deacetylase inhibitors (HDACi) in non-isogenic cell lines. Through quantitative …

Mast Cells Promote Pathology And Susceptibility In Tuberculosis, Ananya Gupta, Vibha Taneja, Javier Rangel-Moreno, Nilofer Naqvi, Abhimanyu, Yun Tao, Mushtaq Ahmed, Kuldeep Singh Chauhan, Daniela Trejo-Ponce De Leon, Gustavo Ramírez-Martínez, Luis Jiménez-Alvarez, Cesar Luna-Rivero, Joaquin Zuniga, Deepak Kaushal, Shabaana A Khader

2020-Current year OA Pubs

Tuberculosis (TB), caused by the bacterium

Cabozantinib And Thromboembolism In Patients With Cancer: A Systematic Review, Meta-Analysis, And Retrospective Study, Harish Eswaran, Rohan R Kasthuri, Pavan K Bendapudi, Alok A Khorana, Raj S Kasthuri, Nick Van Es, Steven P Grover

Faculty, Staff and Student Publications

Antiangiogenic agents, including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), represent an important class of treatments for a range of solid tumors. However, concerns have arisen over potential associations between antiangiogenic agents and thromboembolic events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) that compared a frequently used VEGFR TKI, cabozantinib, with placebo or usual care. The primary outcome was the risk of any thromboembolism. Secondary outcomes included the risk of venous thromboembolism (VTE), risk of arterial thromboembolism (ATE) and progression-free survival. 14 RCTs were included with a combined total of 4204 patients, …

Structures Of Invertebrate Pezo-1 Isoforms With A Compact Architecture And A Dispensable Pore-Distal N-Terminal Blade, Briar Bell, Angela M Jaramillo-Granada, Daniel J Orlin, Wei-Hsiang Weng, Haosheng Wen, Marcos Sotomayor, Alexander T Chesler, Matthew L Baker, Julio F Cordero-Morales, Valeria Vásquez

Faculty, Staff and Student Publications

PIEZO channels are mechanosensitive ion channels conserved from plants to humans, yet structures exist for only a few mammalian orthologs. We define the structural and functional diversity of Caenorhabditis elegans PEZO-1, a single gene with extensive alternative splicing, by determining cryo-electron microscopy structures of three representative isoforms: G (full length), K (lacking the pore-distal N-terminal blade), and L (missing most of the blade). PEZO-1G displays mechanically evoked currents yet adopts a compact, semi-flattened conformation that significantly differs from the mammalian domes. The blades exhibit a three-step slope architecture stabilized by inter-blade latching among transmembrane helical units, yielding a circular, steering-wheel-like …