Medicine and Health Sciences Commons^™

Next-Generation Sequencing-Based Msi Scoring Predicts Benefit In Mismatch Repair-Deficient Tumors Treated With Nivolumab: Follow-Up On Nci-Match Arm Z1d, Jonathan D Schoenfeld, Nilofer S Azad, Jacob Gross, Li Chen, Michael J Overman, Katrina Kao, Latifa Jackson, Donna Brunnquell, Xiangning Bu, Christina Coppola, Ping Guan, Jennifer Lee, David Sims, Rebecca Fuchs, Jason L Weirather, Kathleen L Pfaff, Lauren Gunasti, Srin Ranasinghe, Stanley R Hamilton, Victoria Wang, Peter J O'Dwyer, Catherine J Wu, Scott J Rodig, David R Patton, Lyndsay Harris

Faculty, Staff and Student Publications

Purpose: Mismatch repair-deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment.

Patients and methods: We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-Molecular Analysis for Therapy Choice arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with noncolorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole-exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples.

Results: In this dMMR population, more extensive …

Inadequate Intensification Of Ldl-Cholesterol Lowering Therapy After Coronary Revascularization: Insights From The Gould Registry, Benjamin E Peterson, Deepak L Bhatt, Christie M Ballantyne, James A De Lemos, Robert S Rosenson, Mikhail N Kosiborod, Christopher P Cannon

Faculty, Staff and Students Publications

Background: Patients with a history of coronary revascularization are at a higher risk for subsequent cardiovascular events and all-cause mortality. Lowering LDL-cholesterol (LDL-C) levels post-revascularization significantly reduces these risks.

Methods: This analysis compared LDL-C-lowering therapies at baseline and over time among patients with and without prior coronary revascularization in the GOULD registry (a prospective multicenter cohort study). Baseline- and 24-month follow-up characteristics-including LDL-C levels and strategies for lipid-lowering therapy (LLT)-were evaluated.

Results: Out of 5006 patients, 2195 (43.8%) had prior coronary revascularization. At baseline, these patients had lower LDL-C (99.2 mg/dL vs. 102.5 mg/dL; p < 0.001) and were more likely to be on intensive LLT (52.8% vs. 42.7%; p < 0.001). At 24 months, they had small reductions in LDL-C (-15.6% vs. -13.7%; p = 0.145) and were more likely to be on intensive LLT (61.9% vs. 51.5%; p < 0.001). Similar LDL-C reductions were observed in the PCSK9i group regardless of revascularization status.

Conclusions: Despite slightly better baseline …

Framework, Design, And Baseline Data Of A Collective Impact Initiative To Strengthen The Community Health Worker Workforce Ecosystem In Texas, Shreela V Sharma, Heidi Hagen Mcpherson, Jemima John, Rosalia Guerrero, Sisan B Tennyson, Deborah Banerjee, Nadia Siddiqui, Sheila Savannah, Peter Durand, Amanda Gao, Sean A Haley, Elisa Garcia, Jennifer Cofer, Adrick Harris

Faculty, Staff and Student Publications

BACKGROUND: The Health Equity Collective (HEC), a multi-sector systems-level collective impact coalition in the Greater Houston region, partnered with the City of Houston Health Department (HHD) to launch a 2-year effort to implement a comprehensive approach towards strengthening the regional Community Health Workers (CHW) workforce infrastructure as a pathway to advancing health equity. Our paper presents the logic model, methods, and baseline qualitative and quantitative data from this initiative.

METHODS: In the fall of 2022, the Health Equity Collective brought together a Network of CHW-employing or training organizations in the Greater Houston region. This Network was the working group of …

Reassessing Estrogen Receptor Expression Thresholds For Breast Cancer Prognosis In Her2-Negative Patients Using Shape Restricted Modeling, Wenli Dong, Takeo Fujii, Jing Ning, Toshiaki Iwase, Jing Qin, Naoto T Ueno, Yu Shen

Faculty, Staff and Student Publications

We used a novel shape-restricted Cox model to determine the desirable ER expression cutoff to predict breast cancer prognoses. Our model treats ER as a continuous variable using a flexible monotone-shaped Cox regression to assess its association with survival outcomes holistically. The study included 3055 patients with stage II/III HER2-negative breast cancer. The primary outcomes were time to recurrence or death (TTR) and overall survival (OS). The shape-restricted Cox model identified 10% ER as the preferred cutoff to predict TTR. The finding was confirmed by the log-rank test and standard Cox model that patients with ER ≥ 10% had TTR …

Outcomes Of Arteriovenous Malformation Patients With Multiple Versus Single Feeders: A Multicenter Retrospective Study With Propensity-Score Matching, Basel Musmar, Nimer Adeeb, Hammam Abdalrazeq, Joanna M Roy, Stavropoula I Tjoumakaris, Hamza Adel Salim, Douglas Kondziolka, Jason Sheehan, Christopher S Ogilvy, Howard Riina, Sandeep Kandregula, Adam A Dmytriw, Kareem El Naamani, Ahmed Abdelsalam, Natasha Ironside, Deepak Kumbhare, Cagdas Ataoglu, Muhammed Amir Essibayi, Abdullah Keles, Sandeep Muram, Daniel Sconzo, Arwin Rezai, Omar Alwakaa, Salem M Tos, Ufuk Erginoglu, Johannes Pöppe, Rajeev D Sen, Christoph J Griessenauer, Jan-Karl Burkhardt, Robert M Starke, Mustafa K Baskaya, Laligam N Sekhar, Michael R Levitt, David J Altschul, Malia Mcavoy, Assala Aslan, Abdallah Abushehab, Christian Swaid, Adib A Abla, Saman Sizdahkhani, Sravanthi Koduri, Elias Atallah, Spyridon Karadimas, M Reid Gooch, Robert H Rosenwasser, Christopher Stapleton, Matthew Koch, Visish M Srinivasan, Peng R Chen, Spiros Blackburn, Joseph Cochran, Omar Choudhri, Bryan Pukenas, Darren Orbach, Edward Smith, Pascal J Mosimann, Ali Alaraj, Mohammad A Aziz-Sultan, Aman B Patel, Hugo H Cuellar, Michael Lawton, Bharat Guthikonda, Jacques Morcos, Pascal Jabbour

Faculty, Staff and Student Publications

Introduction: The impact of multiple feeding arteries on clinical outcomes of cerebral arteriovenous malformations (AVMs) is not well understood. This study aims to compare outcomes between AVMs with multiple versus single feeding arteries.

Patients and methods: Data from the Multicenter International Study for Treatment of Brain AVMs (MISTA) consortium were analyzed. Propensity score matching (PSM) was used to balance cohorts. Subgroup analysis was conducted for ruptured and unruptured AVMs and different treatment options, and multivariable logistic regression was applied to assess the impact of feeding artery origin.

Results: Among 953 patients, 661(69.4%) had multiple feeding arteries, and 292 (30.6%) had …

Single-Cell Rna Sequencing Identifies Molecular Biomarkers Predicting Late Progression To Cdk4/6 Inhibition In Patients With Hr+/Her2- Metastatic Breast Cancer, Linjie Luo, Peng Yang, Sofia Mastoraki, Xiayu Rao, Yan Wang, Nicole M Kettner, Akshara Singareeka Raghavendra, Debasish Tripathy, Senthil Damodaran, Kelly K Hunt, Jing Wang, Ziyi Li, Khandan Keyomarsi

Faculty, Staff and Student Publications

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with endocrine therapy are the standard treatment for patients with hormone receptor-positive, HER2-negative metastatic breast cancer (mBC). Despite the efficacy of CDK4/6is, intrinsic resistance occurs in approximately one-third of patients, highlighting the need for reliable predictive biomarkers.

Methods: Single-cell RNA sequencing analyzed metastatic tumors from HR+/HER2- mBC patients pre-CDK4/6i treatment at baseline (BL) and/or at disease progression. BL samples were from CDK4/6i responders (median progression-free survival [mPFS] = 25.5 months), while progressors were categorized as early-progressors (EP, mPFS = 3 months) and late-progressors (LP, mPFS = 11 months). Metastatic sites included liver, …

Genetic And Environmental Contribution To Phenotypic Resemblance Between Iranian Couples: Tehran Cardiometabolic And Genetic Study (Tcgs), Parisa Riahi, Amir Hossein Saeidian, Albert Tenesa, Carolyn T Hogan, Michael March, Kamran Guity, Mahmoud Amiri Roudbar, Asieh Zahedi, Maryam Zarkesh, Farideh Neshati, Mehdi Hedayati, Fereidoun Azizi, Hakon Hakonarson, Maryam S Daneshpour, Mahdi Akbarzadeh

Faculty, Staff and Students Publications

Objective: To provide an applied framework for assessing the genetic contribution to assortative mating (AM) using height as a model trait and disclose the trace of certain pieces of evidence of AM in the form of the shared environmental effects from long-term cohabitation on spouses' anthropometric traits and lipid serum levels.

Methods: 2315 genotyped couples were extracted from the Tehran Cardiometabolic Genetic Study (TCGS). Pearson correlation analysis was used to assess the relationship between spouses' height. The GCTA-GREML was used to assess the SNP-based heritability of individual and spousal heights with AM adjustments. We used a recent GWAS meta-analysis of …

High-Output Cardiac Failure Caused By Large Coronary Artery Fistulas Treated With Coil Embolization, Nawal Mustafa, Blain Tafaesse, Hajra Nadeem, Muhammad Mustafa

The VAD Journal

There are many causes of high-output cardiac failure. We present a unique case of high-output cardiac failure caused by multiple coronary-to-pulmonary artery (PA) fistulas, which, to our knowledge, is a rare finding that has not been previously researched. The purpose of our case report is to highlight the importance of considering coronary-to-PA fistulas in the differential diagnosis of patients presenting with high-output cardiac failure. Our patient presented to the emergency department with shortness of breath and underwent nuclear stress testing, which, through cardiac catheterization, revealed coronary-to-PA fistulas as the cause of the high-output cardiac failure. These fistulas were successfully treated …

Proxy Panels Enable Privacy-Aware Outsourcing Of Genotype Imputation, Degui Zhi, Xiaoqian Jiang, Arif Harmanci

Faculty, Staff and Student Publications

One of the major challenges in genomic data sharing is protecting participants' privacy in collaborative studies and in cases when genomic data are outsourced to perform analysis tasks, for example, genotype imputation services and federated collaborations genomic analysis. Although numerous cryptographic methods have been developed, these methods may not yet be practical for population-scale tasks in terms of computational requirements, rely on high-level expertise in security, and require each algorithm to be implemented from scratch. In this study, we focus on outsourcing of genotype imputation, a fundamental task that utilizes population-level reference panels, and develop protocols that rely on using …

Single-Cell Analysis Identifies Ifi27l2a As A Gene Regulator Of Microglial Inflammation In The Context Of Aging And Stroke In Mice, Gab Seok Kim, Elisabeth Harmon, Manuel C Gutierrez, Sodam Kim, Lauren Vance, Haven Burrous, Jessica M Stephenson, Anjali Chauhan, Anik Banerjee, Zachary Wise, Andrea Doan, John Ahn, Ting Wu, Jesus Bautista-Garrido, Juneyoung Lee, Chunfeng Tan, Joo Eun Jung, Louise D Mccullough, Joshua D Wythe, Sean P Marrelli

Faculty, Staff and Student Publications

Inflammation is a significant driver of ischemic stroke pathology in the brain. To identify potential regulators of inflammation, we performed single-cell RNA sequencing (scRNA-seq) of young and aged mouse brains following stroke and found that interferon alpha-inducible protein 27 like 2 A (Ifi27l2a) was significantly up-regulated, particularly in microglia of aged brain. Ifi27l2a is induced by interferons for viral host defense and has been linked with pro-inflammatory cellular mechanisms. However, its potential role in neurodegeneration is unknown. Using a combination of cell culture, experimental stroke models in mice, and human autopsy brain samples, we demonstrated that induction of Ifi27l2a occurs …

Mage-A4 Induces Non-Small Cell Lung Cancer And Tumor-Promoting Plasma Cell Accumulation, Dominique Armstrong, Cheng-Yen Chang, Monica J Hong, Linda Green, Yichao Shen, William Hudson, Kelsey E Mauk, Li-Zhen Song, Sheetal Jammi, Benjamin Casal, Brianna Burns, Chad J Creighton, Alexandre Carisey, Xiang H-F Zhang, Neil J Mckenna, Sung Wook Kang, Hyun-Sung Lee, William Decker, David B Corry, Farrah Kheradmand

Faculty, Staff and Students Publications

Adaptive immunity is critical in eliminating tumors, but cancer-intrinsic factors can subvert this function. Melanoma antigen-A4 (MAGE-A4), a cancer-testis antigen, is expressed in solid tumors and correlates with poor survival, but its role in tumorigenesis and antitumor immunity remains unclear. We found that expression of MAGE-A4 was highly associated with the loss of PTEN, a tumor suppressor, in human non–small cell lung cancers (NSCLC). Here, we show that constitutive expression of human MAGE-A4 with Pten loss in mouse airway epithelia results in metastatic adenocarcinoma. Tumors showed distinct enrichment in IgA+ CD138+ CXCR4+ plasma cells (PCs) and increased expression of …

Divergence In Cellular Markers Observed In Single-Cell Transcriptomics Datasets Between Cultured Primary Trabecular Meshwork Cells And Tissues, Alice Tian, Sangbae Kim, Hasna Baidouri, Jin Li, Xuesen Cheng, Janice Vranka, Yumei Li, Rui Chen, Vijaykrishna Raghunathan

Faculty, Staff and Students Publications

The trabecular meshwork within the outflow apparatus is critical in maintaining intraocular pressure homeostasis. In vitro studies employing primary cell cultures of the human trabecular meshwork (hTM) have conventionally served as surrogates for investigating the pathobiology of TM dysfunction. Despite its abundant use, translation of outcomes from in vitro studies to ex vivo and/or in vivo studies remains a challenge. Given the cell heterogeneity, performing single-cell RNA sequencing comparing primary hTM cell cultures to hTM tissue may provide important insights on cellular identity and translatability, as such an approach has not been reported before. In this study, we assembled a …

Multimodal Objective Assessment Of Impulsivity In Healthy And Mood Disorder Participants, Bishal Lamichhane, Nidal Moukaddam, Ramiro Salas, Wayne Goodman, Ashutosh Sabharwal

Faculty, Staff and Students Publications

Impulsivity represents an individual's tendency to act on urges without sufficient forethought. Heightened impulsivity is a hallmark of many mental health disorders. Objective impulsivity assessments could improve risk evaluation, diagnosis, and behavioral outcome monitoring in impulsivity-related health disorders. Towards objective impulsivity assessment, in this work, we identify impulsivity correlates in objective measurements, investigate their complementarity, and contrast impulsivity mechanisms across health conditions. We analyzed behavioral tests, heart rate variability (HRV), and fMRI-based brain connectivity in 227 healthy participants and 34 participants with mood disorders. Impulsivity dimensions had complementary correlates in objective measurements, with fMRI providing the strongest correlates. Multimodal assessment …

Identification Of Distinct Stool Metabolites In Women With Endometriosis For Non-Invasive Diagnosis And Potential For Microbiota-Based Therapies, Chandni Talwar, Goutham Venkata Naga Davuluri, Abu Hena Mostafa Kamal, Cristian Coarfa, Sang Jun Han, Surabi Veeraragavan, Krishna Parsawar, Nagireddy Putluri, Kristi Hoffman, Patricia Jimenez, Scott Biest, Ramakrishna Kommagani

Faculty, Staff and Students Publications

Background: Endometriosis, a poorly studied gynecological condition, is characterized by the presence of ectopic endometrial lesions resulting in pelvic pain, inflammation, and infertility. These associated symptoms contribute to a significant burden, often exacerbated by delayed diagnosis. Current diagnostic methods involve invasive procedures, and existing treatments provide no cure.

Methods: Microbiome-metabolome signatures in stool samples from individuals with and without endometriosis were determined using unbiased metabolomics and 16S bacteria sequencing. Functional studies for selected microbiota-derived metabolites were conducted in vitro using patient-derived cells and in vivo by employing murine and human xenograft pre-clinical disease models.

Findings: We discovered a unique bacteria-derived …

Plasma Micrornas To Select Optimal Patients For Antibody Production From Anti-Addiction Vaccines, Thomas R Kosten, Amrit Koirala, David A Nielsen, Coreen B Domingo, Ynhi T Thomas, Preethi H Gunaratne, Cristian Coarfa

Faculty, Staff and Students Publications

Background: Cocaine and illicit amphetamines (disguised as “Adderall”) are being laced with fentanyl and producing accidental and intentional fatal overdoses. Vaccines can prevent these overdoses, but 33% of humans generate insufficient anti-drug antibody (AB) levels. Plasma microRNAs (miRs) can be used to predict non-responders. We have plasma stored from 152 cocaine vaccine trial participants following three vaccinations over 9 weeks and examined miRs as potential response biomarkers. Methods: We compared 2517 miRs before anti-cocaine vaccination in participants with the highest (n = 25) to the lowest (n = 23) antibody levels. False Discovery Rates (FDRs) were applied to identify differentially …

Successful Posthospitalisation Oncology Workflow Implementing Lace+ Score To Stratify And Reduce Readmissions Within A Safety-Net Hospital, Cindy M Pabon, Janine Wong, Marcela Perez, Jessica Jimenez-Abarca, Lianchun Xiao, Lymesia Jackson, Anne Park, Anjali Lankford, Vinita Akula, Saumil Datar, Taylor Hopper, Yaser Alkhatib, Terri Earles, Tejal Patel

Faculty, Staff and Student Publications

Background: Patients with advanced cancers visit the emergency room and get hospitalised frequently, with potentially half of these visits being avoidable. Our institution provides comprehensive, low-cost cancer treatment to a safety-net population in Texas. We performed a retrospective review of hospital readmission patterns amongst our oncology patients and developed a posthospitalisation workflow to reduce readmissions.

Method: Following discharge, oncology patients were risk stratified based on their Length of stay, Acuity of admission, Charlson comorbidity index score and Emergency department visits+index in the past 6 months. The higher the score, the quicker the outpatient oncology follow-up. In addition to addressing acute …

Structure-Activity Relationship Studies Of Dna Methyltransferase 1 Monovalent Degraders, Chao Qian, Youngeun Lee, Yulin Han, Yue Zhong, Jujun Zhou, Joel Hrit, Ling Xie, Qin Chen, H Ümit Kaniskan, Xian Chen, Scott Rothbart, Xiaodong Cheng, Yan Xiong, Jian Jin

Faculty, Staff and Student Publications

DNA methyltransferase 1 (DNMT1), which catalyzes maintenance methylation of hemimethylated DNA during DNA replication, is overexpressed in cancer. Recently, the first-in-class DNMT1-selective noncovalent small-molecule inhibitors, GSK3484862 and GSK3685032, were discovered. These inhibitors were also reported to degrade DNMT1. However, structure–activity relationship (SAR) studies of these monovalent DNMT1 degraders are lacking. Here, we report our SAR studies of this scaffold on degrading DNMT1, which led to the discovery of multiple lead degraders, including compound 4 (MS9024). Compound 4 potently and selectively degraded DNMT1 in multiple cancer cell lines in a concentration-, time-, and proteasome-dependent manner without altering DNMT1 transcription. Further mechanism-of-action …

Inhibition Of Histone Methyltransferase Ezh2 For Immune Interception Of Colorectal Cancer In Lynch Syndrome, Charles M Bowen, Fahriye Duzagac, Abel Martel-Martel, Laura Reyes-Uribe, Mahira Zaheer, Jacklyn Thompson, Nan Deng, Ria Sinha, Soham Mazumdar, Melissa W Taggart, Abhinav K Jain, Elena Tosti, Winfried Edelmann, Krishna M Sinha, Eduardo Vilar

Faculty, Staff and Student Publications

Colorectal precancers in Lynch syndrome (LS) exhibit a distinct immune profile, presenting unique opportunities for developing immune-interception strategies to prevent carcinogenesis. Epigenetic modulation by EZH2 of immune-related genes is implicated in the carcinogenesis of different cancer types, including colorectal cancer. This study utilizes a mouse model of LS and ex vivo colonic organoids to assess the effects of the EZH2 inhibitor GSK503 on immune regulatory pathways, tumorigenesis, and epigenetic reprogramming. Our findings revealed that GSK503 significantly increased CD4+ and CD8+ T cells in both splenocytes and colonic mucosa of treated mice compared with controls. Additionally, a preventive dose of GSK503 …

Navigating Epstein-Barr Virus (Ebv) And Post-Transplant Lymphoproliferative Disorder (Ptld) In Pediatric Liver Transplantation: Current Knowledge And Strategies For Treatment And Surveillance, Erin Y Chen, Natasha Dilwali, Krupa R Mysore, Sara Hassan, Sara Kathryn Smith, Wikrom Karnsakul

Faculty, Staff and Students Publications

Epstein-Barr virus (EBV) is strongly associated with the development of post-transplant lymphoproliferative disorder (PTLD) in pediatric liver transplant recipients. PTLD is one of the most common malignancies following liver transplantation and is associated with significant morbidity and mortality. Factors such as EBV-serostatus mismatch and prolonged or high levels of immunosuppression impact a patient's risk of developing PTLD. While pre-transplant EBV serological screening and post-transplant monitoring of EBV-DNA levels are strongly recommended, universal guidelines for its prevention and management are lacking. Due to a lack of robust prospective studies, current clinical practices vary widely. The treatment of PTLD typically involves reducing …

Prediction Of Cognitive Conversion Within The Alzheimer’S Disease Continuum Using Deep Learning, Siyu Yang, Xintong Zhang, Xinyu Du, Peng Yan, Jing Zhang, Wei Wang, Jing Wang, Lei Zhang, Huaiqing Sun, Yin Liu, Xinran Xu, Yaxuan Di, Jin Zhong, Caiyun Wu, Jan D Reinhardt, Yu Zheng, Ting Wu

Faculty, Staff and Students Publications

Background: Early diagnosis and accurate prognosis of cognitive decline in Alzheimer's disease (AD) is important to timely assignment to optimal treatment modes. We aimed to develop a deep learning model to predict cognitive conversion to guide re-assignment decisions to more intensive therapies where needed.

Methods: Longitudinal data including five variable sets, i.e. demographics, medical history, neuropsychological outcomes, laboratory and neuroimaging results, from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort were analyzed. We first developed a deep learning model to predicted cognitive conversion using all five variable sets. We then gradually removed variable sets to obtained parsimonious models for four different …

Contribution Of Rare Chromosome 22q112 Copy Number Variants To Non-Syndromic Bicuspid Aortic Valve, Helene Digregorio, Sara Mansoorshahi, Steven G Carlisle, Catherina Tovar Pensa, Abi Watts, Courtney Mcneely, Anna Sabate-Rotes, Anji Yetman, Hector I Michelena, Julie F A De Backer, Laura Muiño Mosquera, Malenka M Bissell, Maria Grazia Andreassi, Ilenia Foffa, Dawn S Hui, Anthony Caffarelli, Yuli Y Kim, Rodolfo Citro, Margot De Marco, Justin T Tretter, Kim L Mcbride, Simon C Body, Dianna M Milewicz, Siddharth K Prakash, Ebav Investigators

Faculty, Staff and Student Publications

Background: Bicuspid aortic valve (BAV) is the most common congenital heart defect in adults, often leading to complications such as thoracic aortic aneurysms and aortic stenosis. While BAV is frequently associated with 22q11.2 deletion syndrome (22q11.2DS), the contribution of rare copy number variants (CNVs) in this region to non-syndromic BAV is less clear. This study is aimed to assess the role of rare 22q11.2 CNVs in patients with early-onset BAV (EBAV) and to determine whether these variants are linked to an increased risk of complications.

Methods: Whole genome microarray genotyping was conducted on 272 patients with BAV with early onset …

Efficacy And Safety Of Nivolumab Plus Ipilimumab In Patients With Metastatic Variant Histology (Non-Clear Cell) Renal Cell Carcinoma, Mohammad Jad Moussa, Jaanki Khandelwal, Nathaniel R Wilson, Kiran L Malikayil, Devaki Shilpa Surasi, Tharakeswara K Bathala, Yiyun Lin, Priya Rao, Pheroze Tamboli, Kanishka Sircar, Helen Ajufo, Khaled M Elsayes, Amishi Shah, Andrew C Johns, Sangeeta Goswami, Elshad Hasanov, Eric Jonasch, Pavlos Msaouel, Matthew T Campbell, Omar Alhalabi, Nizar M Tannir

Faculty, Staff and Student Publications

Background: Nivolumab plus ipilimumab (nivo/ipi) is a standard of care first-line (1 L) therapy for patients with metastatic clear-cell renal cell carcinoma (ccRCC), but its role in patients with metastatic, non-ccRCC has not been fully defined. We report a single-institution experience with nivo/ipi in non-ccRCC.

Methods: Between November 2017 and February 2024, 55 patients with metastatic non-ccRCC received nivo/ipi at MD Anderson Cancer Center. The tumor response was assessed by blinded radiologists using RECIST v1.1. The overall response rate (ORR), progression-free survival (PFS), PFS milestone, duration of response (DoR), and overall survival (OS) were determined. Next-generation sequencing (NGS) was performed …

The Mir-290 And Mir-302 Clusters Are Essential For Reprogramming Of Fibroblasts To Induced Pluripotent Stem Cells, Julia Ye, Ryan M Boileau, Ronald J Parchem, Robert L Judson-Torres, Robert Blelloch

Faculty, Staff and Students Publications

The miR-290 and miR-302 clusters of microRNAs are highly expressed in naïve and primed pluripotent stem cells, respectively. Ectopic expression of the embryonic stem cell (ESC)-specific cell cycle regulating family of microRNAs arising from these two clusters dramatically enhances the reprogramming of both mouse and human somatic cells to induced pluripotency. Here, we used genetic knockouts to dissect the requirement for the miR-290 and miR-302 clusters during the reprogramming of mouse fibroblasts into induced pluripotent stem cells (iPSCs) with retrovirally introduced Oct4, Sox2, and Klf4. Knockout of either cluster alone did not negatively impact the efficiency of reprogramming. Resulting cells …

Designing Patient-Centered Interventions For Emergency Care: Participatory Design Study, Woosuk Seo, Shruti Jain, Vivian Le, Jiaqi Li, Zhan Zhang, Hardeep Singh, Kalyan Pasupathy, Prashant Mahajan, Sun Young Park

Faculty, Staff and Students Publications

Background: Emergency departments (EDs) are high-pressure environments where clinicians diagnose patients under significant constraints, including limited medical histories, severe time pressures, and frequent interruptions. Current ED care practices often inadequately support meaningful patient participation. Most interventions prioritize clinical workflow and health care provider communication, inadvertently overlooking patients' needs. Additionally, patient-facing technologies in EDs are typically developed without meaningful patient input, leading to solutions that may not effectively address patients' specific challenges. To enhance both patient-centered care practices and the diagnosis process in EDs, patient involvement in technology design is essential to ensure their needs during emergency care are understood and …

Intensive Lifestyle Intervention, Cardiac Biomarkers, And Cardiovascular Outcomes In Diabetes: Look Ahead Cardiac Biomarker Ancillary Study, Kershaw V Patel, Zainali Chunawala, Subodh Verma, Matthew W Segar, Katelyn R Garcia, Chiadi E Ndumele, Thomas J Wang, James L Januzzi, Antoni Bayes-Genis, Javed Butler, Carolyn S P Lam, Christie M Ballantyne, James A De Lemos, Alain G Bertoni, Mark Espeland, Ambarish Pandey

Faculty, Staff and Students Publications

Background: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) are associated with cardiovascular outcomes and are recommended for measurement in type 2 diabetes (T2D). However, the effects of an intensive lifestyle intervention (ILI) targeting weight loss on cardiac biomarkers and the prognostic association of changes in these biomarkers with risk of adverse cardiovascular outcomes in T2D are not well-established.

Objectives: This study sought to evaluate the effects of an ILI on cardiac biomarkers and the association of changes in cardiac biomarkers with risk of cardiovascular outcomes in T2D.

Methods: Participants of the Look AHEAD (Action for Health …

Increasing Covid-19 Testing And Vaccination Uptake In The Take Care Texas Community-Based Randomized Trial: Adaptive Geospatial Analysis, Kehe Zhang, Jocelyn V Hunyadi, Marcia C De Oliveira Otto, Miryoung Lee, Zitong Zhang, Ryan Ramphul, Jose-Miguel Yamal, Ashraf Yaseen, Alanna C Morrison, Shreela Sharma, Mohammad Hossein Rahbar, Xu Zhang, Stephen Linder, Dritana Marko, Rachel White Roy, Deborah Banerjee, Esmeralda Guajardo, Michelle Crum, Belinda Reininger, Maria E Fernandez, Cici Bauer

Faculty, Staff and Student Publications

BACKGROUND: Geospatial data science can be a powerful tool to aid the design, reach, efficiency, and impact of community-based intervention trials. The project titled Take Care Texas aims to develop and test an adaptive, multilevel, community-based intervention to increase COVID-19 testing and vaccination uptake among vulnerable populations in 3 Texas regions: Harris County, Cameron County, and Northeast Texas.

OBJECTIVE: We aimed to develop a novel procedure for adaptive selections of census block groups (CBGs) to include in the community-based randomized trial for the Take Care Texas project.

METHODS: CBG selection was conducted across 3 Texas regions over a 17-month period …

Repeat Expansion In A Fragile X Model Is Independent Of Double Strand Break Repair Mediated By Pol Θ, Rad52, Rad54 Or Rad54b, Bruce E Hayward, Geum-Yi Kim, Carson J Miller, Cai Mccann, Megan G Lowery, Richard D Wood, Karen Usdin

Faculty, Staff and Student Publications

Microsatellite instability is responsible for the human repeat expansion diseases (REDs). The mutagenic process differs from classical cancer-associated microsatellite instability (MSI) in that it requires the mismatch repair proteins that normally protect against MSI. LIG4, an enzyme essential for non-homologous end-joining (NHEJ), the major pathway for double-strand break repair (DSBR) in mammalian cells, protects against expansion in mouse models. Thus, NHEJ may compete with the expansion pathway for access to a common intermediate. This raises the possibility that expansion involves an NHEJ-independent form of DSBR. Pol θ, a polymerase involved in the theta-mediated end joining (TMEJ) DSBR pathway, has been …

Comparative Transcriptomics Reveals A Mixed Basal, Club, And Hillock Epithelial Cell Identity In Castration-Resistant Prostate Cancer, Samuel P Pitzen, Amber N Rudenick, Yinjie Qiu, Weijie Zhang, Sarah A Munro, Braedan M Mccluskey, Colleen Forster, Hannah E Bergom, Atef Ali, Ella Boytim, John T Lafin, Simon Linder, Mazlina Ismail, Wout Devlies, Conner J Sessions, Frank Claessens, Steven Joniau, Gerhardt Attard, Wilbert Zwart, Peter S Nelson, Eva Corey, Yuzhuo Wang, Joshua M Lang, Himisha Beltran, Douglas Strand, Emmanuel S Antonarakis, Justin Hwang, Paari Murugan, R Stephanie Huang, Scott M Dehm

Faculty, Staff and Student Publications

Inhibiting the androgen receptor (AR) is effective for treatment of advanced prostate cancers because of their AR-dependent luminal epithelial cell identity. Tumors progress during therapy to castration-resistant prostate cancer (CRPC) by restoring AR signaling and maintaining luminal identity or by converting through lineage plasticity to a neuroendocrine (NE) identity or double-negative CRPC (DNPC) lacking luminal or NE identities. Here, we show that DNPC cells express genes defining basal, club, and hillock epithelial cells from benign prostate. We identified KLF5 as a regulator of genes defining this mixed basal, club, and hillock cell identity in DNPC models. KLF5-mediated upregulation of

Regression Modeling Of Cumulative Incidence Function For Left-Truncated Right-Censored Competing Risks Data: A Modified Pseudo-Observation Approach, Rong Rong, Jing Ning, Hong Zhu

Faculty, Staff and Student Publications

Statistical methods have been developed for regression modeling of the cumulative incidence function (CIF) given left-truncated right-censored competing risks data. Nevertheless, existing methods typically involve complicated weighted estimating equations or nonparametric conditional likelihood function and often require a restrictive assumption that censoring and/or truncation times are independent of failure time. The pseudo-observation (PO) approach has been used in regression modeling of CIF for right-censored competing risks data under covariate-independent censoring or covariate-dependent censoring. We extend this approach to left-truncated right-censored competing risks data and propose to directly model the CIF based on POs, under general truncation and censoring mechanisms. We …

Nprl2 Gene Therapy Induces Effective Antitumor Immunity In Kras/Stk11 Mutant Anti-Pd1 Resistant Metastatic Non-Small Cell Lung Cancer (Nsclc) In A Humanized Mouse Model, Ismail M Meraz, Mourad Majidi, Renduo Song, Feng Meng, Lihui Gao, Qi Wang, Jing Wang, Elizabeth J Shpall, Jack A Roth

Faculty, Staff and Student Publications

Expression of NPRL2/TUSC4, a tumor-suppressor gene, is reduced in many cancers including NSCLC. Restoration of NPRL2 induces DNA damage, apoptosis, and cell-cycle arrest. We investigated NPRL2 antitumor immune responses in aPD1R/KRAS/STK11^mt NSCLC in humanized-mice. Humanized-mice were generated by transplanting fresh human cord blood-derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung-metastases were developed from KRAS/STK11^mt/aPD1R A549 cells and treated with NPRL2 w/wo pembrolizumab. NPRL2-treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. Antitumor effect was greater in humanized than non-humanized-mice. NPRL2 + pembrolizumab was not synergistic in KRAS/STK11^mt/aPD1R tumors but was …