Medical Genetics Commons^™

Cansar 2024-An Update To The Public Drug Discovery Knowledgebase, Phillip W Gingrich, Rezvan Chitsazi, Ansuman Biswas, Chunjie Jiang, Li Zhao, Kevin M Brammer, Zhigang Shu, David S Maxwell, Jeffrey A Tacy, Ioan L Mica, Michael Darkoh, Patrizio Di Micco, Kaitlyn P Russell, Paul Workman, Bissan Al-Lazikani

Faculty, Staff and Student Publications

canSAR (https://cansar.ai) continues to serve as the largest publicly available platform for cancer-focused drug discovery and translational research. It integrates multidisciplinary data from disparate and otherwise siloed public data sources as well as data curated uniquely for canSAR. In addition, canSAR deploys a suite of curation and standardization tools together with AI algorithms to generate new knowledge from these integrated data to inform hypothesis generation. Here we report the latest updates to canSAR. As well as increasing available data, we provide enhancements to our algorithms to improve the offering to the user. Notably, our enhancements include a revised ligandability classifier …

Intrinsic Adaptive Plasticity In Mouse And Human Sensory Neurons, Lisa A Mcilvried, John Smith Del Rosario, Melanie Y Pullen, Andi Wangzhou, Tayler D Sheahan, Richard A Slivicki, Theodore J Price, Bryan A Copits, Robert W Gereau

Faculty, Staff and Student Publications

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory …

Couple-Based Lifestyle Intervention For Minority Prostate Cancer Survivors: A Randomized Feasibility Trial, Dalnim Cho, Yisheng Li, Karen Basen-Engquist, Chiara Acquati, Nga T T Nguyen, Curtis A Pettaway

Faculty, Staff and Student Publications

Background: Black and Hispanic prostate cancer (PCa) survivors, who face a high burden of comorbid conditions and often engage in low levels of physical activity and healthy eating, remain significantly underrepresented in lifestyle intervention studies.

Purpose: Given the significance of spousal influence, we developed a culturally tailored lifestyle intervention for these survivors and their spouses and assessed its feasibility, acceptability, and impact on behavioral change.

Methods: Survivor-spouse couples were randomly assigned to an intervention group (n = 22), which received 12 health-coaching calls over 6 months, or a usual-care control group (n = 9). Assessments were conducted at baseline (T1), …

Cyclin E1/Cdk2 Activation Defines A Key Vulnerability To Wee1 Kinase Inhibition In Gynecological Cancers, Daehwan Kim, Heekyung Chung, Wen Liu, Kangjin Jeong, Tugba Y Ozmen, Matthew J Rames, Xiao Guo, Nathan Jameson, Petrus R De Jong, Steven Yea, Laurie Harford, Jiali Li, Cara A Mathews, Deborah B Doroshow, Vincent J Charles, Doris Kim, Kimberlee Fischer, Ahmed A Samatar, Adrian Jubb, Kevin D Bunker, Kimberly Blackwell, Fiona Simpkins, Funda Meric-Bernstam, Gordon B Mills, Olivier Harismendy, Jianhui Ma, Mark R Lackner

Faculty, Staff and Student Publications

Upregulation of Cyclin E1 and subsequent activation of CDK2 accelerates cell cycle progression from G1 to S phase and is a common oncogenic driver in gynecological malignancies. WEE1 kinase counteracts the effects of Cyclin E1/CDK2 activation by regulating multiple cell cycle checkpoints. Here we characterized the relationship between Cyclin E1/CDK2 activation and sensitivity to the selective WEE1 inhibitor azenosertib. We found that ovarian cancer cell lines with high levels of endogenous Cyclin E1 expression or forced overexpression were exquisitely sensitive to azenosertib and these results extended to in vivo models of ovarian and uterine serous carcinoma. Models with high Cyclin …

Early Treatment Discontinuation In Patients With Deficient Mismatch Repair Or Microsatellite Instability High Metastatic Colorectal Cancer Receiving Immune Checkpoint Inhibitors, Julien Taieb, Margherita Ambrosini, Emily Alouani, Sara Lonardi, Frank A Sinicrope, Alice Boileve, Thibault Mazard, Simon Pernot, Pauline Parent, Javier Ros, Michael J Overman, Priya Jayachandran, Vincenzo Nasca, Lisa Salvatore, Rosine Guimbaud, Chiara Cremolini, David Tougeron, Filippo Pietrantonio

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD).

Methods: To assess whether ETD is associated with similar outcomes compared …

Comprehensive Characterization Of The Transcriptional Landscape In Alzheimer’S Disease (Ad) Brains, Chengxuan Chen, Zhao Zhang, Yuan Liu, Wei Hong, Hande Karahan, Wenbo Li, Meichen Yu, Andrew J Saykin, Kwangsik Nho, Jungsu Kim, Leng Han

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the leading dementia among the elderly with complex origins. Despite extensive investigation into the AD-associated protein-coding genes, the involvement of noncoding RNAs (ncRNAs) and posttranscriptional modification (PTM) in AD pathogenesis remains unclear. Here, we comprehensively characterized the landscape of ncRNAs and PTM events in 1460 samples across six brain regions sourced from the Mount Sinai/JJ Peters VA Medical Center Brain Bank Study and Mayo cohorts, encompassing 33,321 long ncRNAs, 92,897 enhancer RNAs, 53,763 alternative polyadenylation events, and 900,221 A-to-I RNA editing events. We additionally identified 25,351 aberrantly expressed ncRNAs and altered PTM events associated with AD …

Enhanced Motivated Behavior Mediated By Pharmacological Targeting Of The Fgf14/Nav16 Complex In Nucleus Accumbens Neurons, Nolan M Dvorak, Paul A Wadsworth, Guillermo Aquino-Miranda, Pingyuan Wang, Douglas S Engelke, Jingheng Zhou, Nghi Nguyen, Aditya K Singh, Giuseppe Aceto, Zahra Haghighijoo, Isabella I Smith, Nana Goode, Mingxiang Zhou, Yosef Avchalumov, Evan P Troendle, Cynthia M Tapia, Haiying Chen, Reid T Powell, Timothy J Baumgartner, Jully Singh, Leandra Koff, Jessica Di Re, Ann E Wadsworth, Mate Marosi, Marc R Azar, Kristina Elias, Paul Lehmann, Yorkiris M Mármol Contreras, Poonam Shah, Hector Gutierrez, Thomas A Green, Martin B Ulmschneider, Marcello D'Ascenzo, Clifford Stephan, Guohong Cui, Fabricio H Do Monte, Jia Zhou, Fernanda Laezza

Faculty, Staff and Student Publications

Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14R117, a critical residue located within a druggable pocket at the FGF14/Nav1.6 PPI interface. We found that 1028 modulates FGF14/Nav1.6 complex assembly and depolarizes the voltage-dependence of Nav1.6 channel inactivation with …

The Role Of Iowa Gambling Task Performance In Response To Citalopram Treatment For Cocaine Use Disorder, Constanza De Dios, Robert Suchting, Charles E Green, Heather E Webber, F Gerard Moeller, Joy Schmitz

Faculty, Staff and Student Publications

Background:

Cocaine use disorder (CUD) is associated with executive functioning impairments linked to serotonergic function. Previous studies reported efficacy with the selective serotonin reuptake inhibitor citalopram in reducing cocaine use.

Objectives:

The current study explored moderation and mediation of citalopram effects on cocaine use by performance across executive function domains.

Methods:

We conducted a secondary analysis of a double-blind, placebo-controlled, randomized Bayesian adaptive trial investigating citalopram efficacy in CUD treatment-seeking adults. At baseline and mid-treatment, participants completed assessments of decision-making (Iowa Gambling Task; IGT), attention, response inhibition, and cognitive flexibility. Outcomes were longest duration of abstinence (LDA; count of consecutive …

Cardiovascular Disease And Breast Cancer Stage At Diagnosi\S, Ivan Angelov, Allen M Haas, Elizabeth Brock, Lingfeng Luo, Jing Zhao, Sharon H Giordano, Kevin T Nead

Faculty, Staff and Student Publications

Importance: Cardiovascular disease (CVD) and cancer are the leading causes of mortality in the US. Large-scale population-based and mechanistic studies support a direct effect of CVD on accelerated tumor growth and spread, specifically in breast cancer.

Objective: To assess whether individuals presenting with advanced breast cancers are more likely to have prevalent CVD compared with those with early-stage breast cancers at the time of diagnosis.

Design, setting, and participants: This population-based case-control study used data from the Surveillance, Epidemiology, and End Results-Medicare linked databases from 2009 to 2020. The analysis was completed from May 2023 to August 2024. Participants were …

Dexamethasone Dose Intensity Does Not Impact Outcomes In Newly Diagnosed Multiple Myeloma: A Secondary Swog Analysis, Rahul Banerjee, Rachael Sexton, Andrew J Cowan, Aaron S Rosenberg, Sikander Ailawadhi, Shaji Kumar, Sagar Lonial, Brian G M Durie, Paul G Richardson, Saad Z Usmani, Antje Hoering, Robert Z Orlowski

Faculty, Staff and Student Publications

Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM), despite common toxicities, including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 mg once weekly was associated with lower mortality than higher doses. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM has not been fully characterized. We conducted a secondary pooled analysis of the SWOG 0777 and SWOG 1211 studies of NDMM, which used lenalidomide and dexamethasone (Rd) alone, with or without bortezomib, and with or without elotuzumab. The planned …

Nucleus-Translocated Gclm Promotes Chemoresistance In Colorectal Cancer Through A Moonlighting Function, Jin-Fei Lin, Ze-Xian Liu, Dong-Liang Chen, Ren-Ze Huang, Fen Cao, Ting Li, Hui Sheng, Zhi-Bing Liang, Kun Liao, Yi Han, Shan-Shan Li, Zhao-Lei Zeng, Song Gao, Huai-Qiang Ju, Rui-Hua Xu

Faculty, Staff and Student Publications

Metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. Here, utilizing a metabolic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout library screen, we observe that the loss of glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably increases the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy. Mechanistically, we unveil a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B (NF-κB)-repressing factor (NKRF), to promote NF-κB activity and facilitate chemoresistance. In response to platinum drug treatment, GCLM is phosphorylated by P38 …

In Vivo Evaluation Of Novel Nanoparticles And Repurposed Pharmaceuticals To Combat Antimicrobial Resistance, Sarah E. Evans

Theses, Dissertations and Capstones

In a 2019 report by the Centers for Disease Control and Prevention (CDC), infections resistant to antibiotic treatment amount to about three million infections and 48,000 deaths. Antimicrobial resistance is an escalating global threat as existing antibiotics lose efficacy over time. The project described is focused on partnering with pharmaceutical researchers and producers to test new nanoparticle-based or repurposed compounds. The central hypothesis of this thesis is that pharmaceutical formulations such as nanoparticles may provide a cost-effective means of combating the emerging antimicrobial resistance. The nanoparticle compounds allowed for a wide range of customization for the pharmaceutical design, since the …

Covariate Selection For Rna-Seq Differential Expression Analysis With Hidden Factor Adjustment, Farzana Noorzahan, Hyeongseon Jeon, Yet Nguyen

Mathematics & Statistics Faculty Publications

In RNA-seq data analysis, a primary objective is the identification of differentially expressed genes, which are genes that exhibit varying expression levels across different conditions of interest. It is widely known that hidden factors, such as batch effects, can substantially influence the differential expression analysis. Furthermore, apart from the primary factor of interest and unforeseen artifacts, an RNA-seq experiment typically contains multiple measured covariates, some of which may significantly affect gene expression levels, while others may not. Existing methods either address the covariate selection or the unknown artifacts separately. In this study, we investigate two integrated strategies, FSR_sva and SVAall_FSR, …

Characterizing A Rad23 Dependent Ultraviolet Radiation Resistance In Tetrahymena Thermophila, Emma June Liimatta

Graduate Theses/Dissertations

In 2020, 10 million deaths were attributed to cancer, with multidrug resistance being responsible for over 90% of deaths in cancer patients receiving treatment. This study utilized the model organism Tetrahymena thermophila to study how cells become resistant to Ultraviolet Radiation (UV) radiation, a process similar to multidrug resistance, specifically focusing on the nucleotide excision repair and ubiquitin shuttle protein Rad23. The National Cancer Institute documented 30-60% of cancers tested had a mutation in RAD23. Knockdown of RAD23 in Tetrahymena thermophila demonstrated a UV resistance phenotype with decreased nucleotide excision repair and differential expression of proteins active within caspase-independent …

Glutamatergic Lateral Habenula Neurons Modulate Consolidation Of Associative Memories, Snigdha Srivastava, I-Ching Wang, Mikhail Y Kochukov, Jessica L Swanson, Mauro Costa-Mattioli, Benjamin R Arenkiel

Duncan NRI Faculty and Staff Publications

INTRODUCTION: Despite the rise in psychiatric disorders worldwide, the underlying brain circuits responsible for these devastating conditions remain elusive. The lateral habenula (LHb) has emerged as a key brain structure in depression studies due to its hyperactive state in both patients and animal models. While this aligns with known roles in driving aversive states and regulating serotonin release, it is still unclear how acute and transient activity changes in the LHb can influence higher order cognitive processes such as learning, memory, and behavioral adaptation. Given the importance of these processes to psychiatric conditions, understanding how LHb activity impacts cognitive function …

To Discard Or Not To Discard 1pns? A Systematic Review And Meta-Analysis On 291,474 Embryos, T. Lee, F. Qi, K. Peirce, J. Natalwala, V. Chapple, P. J. Mark, K. Sanders, Y. Liu

Research outputs 2022 to 2026

Unlike embryos that display two pronuclei (2PN), monopronucleated (1PN) embryos are assumed to be haploid and can be routinely discarded. Although there are reports of live births after 1PN embryo transfer, the developmental and clinical prognosis of 1PN embryos has not been systematically evaluated. The aim of this review was to elucidate the developmental, clinical and neonatal outcomes of 1PN embryos compared with 2PN embryos. Twenty-four studies met the inclusion criteria. The blastulation rate was lower in 1PN embryos compared with 2PN embryos [risk ratio (RR) 0.50, 95% CI 0.48–0.51]. The live birth rate was lower in 1PN blastocysts when …

Establishment Of Reference Intervals For Serum Immunoglobulin G N-Glycosylation Features In Healthy Chinese Adults: A Nationwide Survey In The Framework Of Predictive, Preventive, And Personalized Medicine, Changyu Liu, Yinghao Wang, Xingang Li, Xiaojia Xu, Ruirui Xu, Cuihong Tian, Zhixian Chen, Xinxia Lu, Yuejin Li, Meng Wang, Zhaoyang Tang, Xueyu Chen, Guoyong Ding, Xuerui Tan, Dong Li, Haifeng Hou, Wei Wang

Research outputs 2022 to 2026

Background: Immunoglobulin G (IgG) N-glycosylation plays a vital role in the pathogenesis of autoimmune disorders, inflammatory diseases, and viral infections. While various models of serum IgG N-glycosylation have been developed to identify individuals at high risk for relevant diseases, reference intervals (RIs) for the levels of IgG N-glycans have not been established yet. Identifying RIs for serum IgG N-glycans closely associated with biological aging and disease risk contributes to predictive, preventive, and personalized medicine (PPPM/3PM), which results in improvement of patients’ outcomes, enhancement of healthcare efficiency, and in reducing burden of chronic diseases. This study is aimed at defining the …

Ancestry-Dependent Immunologic And Prognostic Effects Characterize The Prostate Cancer Urinary Proteome, Annie Ha, Jaron Arbet, Zhuyu Qiu, Amanda Khoo, Brian P. Main, Meinusha Govindarajan, Matthew Waas, Stanley K. Liu, O. John Semmes, Julius O. Nyalwidhe, Paul C. Boutros, Thomas Kislinger

Leroy T. Canoles Jr. Cancer Research Center Faculty Publications

Urine is an attractive biomarker analyte for non-invasive longitudinal monitoring of health and disease, particularly for diseases of the genitourinary tract, like prostate and bladder cancer. The composition of an individual's urine reflects both genetic and lifestyle characteristics that differ across geographies and populations, like diet, hydration and other socio-economic factors. While men of African ancestry have elevated prostate cancer risk, it is unclear to what extent this influences urinary biomarkers. We therefore quantified the urinary proteomes of 329 localized prostate cancer patients: 135 self-identifying as White and 194 self-identifying as Black. We identified 110 proteins that significantly differed between …

A Non-Toxic Analgesic Elicits Cell-Specific Genomic And Epigenomic Modulation By Targeting The Pag Brain Region, Hernan A. Bazan, Brian L. Giles, Surjyadipta Bhattacharjee, Scott Edwards, Nicolas G. Bazan

School of Medicine Faculty Publications

Acetaminophen (ApAP) is widely used for pain management, but overuse or overdose leads to hepatotoxicity, making it the leading cause of acute liver failure globally. There is an urgent need for safer pain medications, as other non-opioid analgesics like non-steroidal anti-inflammatory drugs (NSAIDs) are nephrotoxic. We have identified SRP-001 as a safer, non-hepatotoxic, novel analgesic that overcomes ApAP's limitations by avoiding NAPQI formation and preserving hepatic tight junctions. Using coupled RNA and ATAC sequencing, from the periaqueductal gray (PAG) midbrain region, we compared the genetic and epigenetic signatures of SRP-001 and ApAP treatments following complete Freund's adjuvant (CFA)-induced inflammatory pain …

Impact Of Personalized Risk Scores On Shared Decision Making In Left Ventricular Assist Device Implantation: Findings From A Qualitative Study, Holland Kaplan, Kristin Kostick-Quenet, Benjamin Lang, Robert J Volk, Jennifer Blumenthal-Barby

Center for Medical Ethics and Health Policy Staff Publications

Objective: To assess stakeholders' perspectives on integrating personalized risk scores (PRS) into left ventricular assist device (LVAD) implantation decisions and how these perspectives might impact shared decision making (SDM).

Methods: We conducted 40 in-depth interviews with physicians, nurse coordinators, patients, and caregivers about integrating PRS into LVAD implantation decisions. A codebook was developed to identify thematic patterns, and quotations were consolidated for analysis. We used Thematic Content Analysis in MAXQDA software to identify themes by abstracting relevant quotes.

Results: Clinicians had varying preferences regarding PRS integration into LVAD decision making, while patients and caregivers preferred real-time discussions about PRS with …