Medical Genetics Commons^™

Association Between The 2022 Aha/Acc/Hfsa Heart Failure Staging And Cardiovascular And Kidney Outcomes In Patients With Diabetes And Kidney Disease: A Post Hoc Analysis Of The Scored Randomized Controlled Trial, Ayodele Odutayo, Deepak L Bhatt, Vikas S Sridhar, Michael Szarek, Christopher P Cannon, Lawrence A Leiter, Darren K Mcguire, Julia B Lewis, Renato D Lopes, Benjamin M Scirica, Kausik K Ray, Michael J Davies, Phillip Banks, Manon Girard, Subodh Verma, Jacob A Udell, Bertram Pitt, Ph Gabriel Steg, David Z I Cherney

Faculty, Staff and Student Publications

Background: The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America heart failure (HF) classification incorporates cardiac biomarkers to identify early risk of HF. The HF stages may also guide the prognosis and management of cardiovascular and kidney-related events.

Methods: SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) was a randomized trial in diabetes with kidney disease comparing sotagliflozin versus placebo on cardiovascular death, HF hospitalizations, and urgent HF visits. SCORED participants were grouped by HF stage post hoc. Stage A: no …

Disease-Specific And Overall Survival For Patients With Lacrimal Gland Adenoid Cystic Carcinoma In Recent Decades, Bita Esmaeli, Zhouxuan Li, Tracy J Lu, Hila Goldberg, Jing Ning, James Matthew Debnam, Steven Jay Frank, Renata Ferrarotto

Faculty, Staff and Student Publications

Purpose: To evaluate the presenting symptoms, and the overall survival (OS) and disease-specific survival (DSS) in patients with lacrimal gland adenoid cystic carcinoma (LGACC).

Methods: This retrospective single-centre cohort study included all consecutive patients with LGACC treated by the primary author from November 1998 through August 2024. Demographic data, presenting symptoms, the histological subtype of LGACC, type of surgical treatment, adjuvant radiotherapy or chemotherapy, T category at presentation and survival data were reviewed. Correlations between histological subtypes, T-category, type of surgery (eye sparing vs orbital exenteration), and DSS and OS were analysed.

Results: 52 patients had a median age of …

Single-Photon Emission Computed Tomography Functional Liver Imaging To Facilitate Reirradiation For Liver Malignancies: A Phase I Trial, Enoch Chang, Emma B Holliday, Janio Szklaruk, William D Erwin, Ethan B Ludmir, Sonal S Noticewala, Prajnan Das, Albert C Koong, Bruce D Minsky, Grace L Smith, Gabriel O Sawakuchi, Rachael M Martin-Paulpeter, Joshua S Niedzielski, Luis A Perles, Sam Beddar, Veronica S Valino, Joshua L Nguyen, Kanwal P S Raghav, Milind Javle, Ahmed O Kaseb, Arvind N Dasari, Michael J Overman, Christine M Parseghian, Bruno C Odisio, Armeen Mahvash, Joshua D Kuban, Shu-En Shen, Xin S Wang, Aashish C Gupta, Mais M Al Taie, Kristy K Brock, Ching-Wei D Tzeng, Jean-Nicolas Vauthey, Franklin C L Wong, Eugene J Koay

Faculty, Staff and Student Publications

Background & aims: This phase I trial evaluated the safety of hypofractionated liver reirradiation (reRT) with preferential sparing of functional liver identified by technetium-99m sulfur colloid single-photon emission computed tomography (Tc-99m SC SPECT; hereafter SPECT) for patients previously treated with external beam radiotherapy or transarterial radioembolization.

Methods: A 3+3 design evaluated the safety of two escalating SPECT-based functional liver volumetric dose constraints. Dose-limiting toxicities (DLTs), liver segment volumes, and MRI functional liver imaging score, relative liver enhancement, and elastography were assessed.

Results: Thirteen patients were enrolled from 2018 to 2021. Median reRT gross tumor volume was 61 cm3 (range 1-677 …

Cdk2 Inhibitor Blu-222 Synergizes With Cdk4/6 Inhibitors In Drug Resistant Breast Cancers Through P21/P27 Induction, Linjie Luo, Yan Wang, Tuyen Bui, Xiaoting Jiang, Mei-Kuang Chen, Xiayu Rao, Sepideh Mohammadhosseinpour, Mi Li, Serena Kim, Rachel Y Kim, Saba Kamaliasl, Carmen W Ulizio, Spyros Tsavachidis, Juliana Navarro-Yepes, Nicole M Kettner, Hannah Wingate, Funda Meric-Bernstam, Kelly K Hunt, Jing Wang, Kerrie Faia, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are the standard first-line treatment for hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer, but resistance inevitably develops. In triple-negative breast cancer (TNBC), the efficacy of CDK4/6i remains uncertain. Our study shows that the selective CDK2 inhibitor BLU-222, while effective alone, enhances synergistic activity when combined with CDK4/6i in resistant HR+/HER2- and TNBC models, leading to increased apoptosis and cell cycle arrest. In vivo, combining BLU-222 with palbociclib or ribociclib produced significant antitumor activity across eight resistant models, driving durable tumor regression and prolonged survival. Mechanistically, BLU-222, alone or with palbociclib, upregulated …

Low Intensity Vibration With Zoledronate Reduces Musculoskeletal Weakness And Adiposity In Estrogen Deprived Female Mice, Gabriel M Pagnotti, Trupti Trivedi, Laura E Wright, Sutha K John, Sreemala Murthy, Ryan R Pattyn, Monte S Willis, Yun She, Sukanya Suresh, Aji F Touray, William R Thompson, Clinton T Rubin, Khalid S Mohammad, Theresa A Guise

Faculty, Staff and Student Publications

Aromatase inhibitors are widely used in the treatment of hormone-sensitive breast cancer, but their suppression of estrogen production accelerates bone loss, increases fracture risk, and negatively impacts muscle and fat metabolism. Here, we demonstrate that daily low intensity vibration, serving as a non-drug mimetic for exercise, protects musculoskeletal health in skeletally immature, female mice under complete estrogen deprivation. Subsequent improvements in vertebral bone density are paralleled by greater and leaner skeletal muscle mass and function alongside reduced fat accretion and circulating metabolites. In mature, estrogen deprived mice, vibration enhances weekly bisphosphonate treatment, improving bone density, cortical thickness, and mechanical resistance …

Genomics Define Malignant Transformation In Myeloma Precursor Conditions, Francesco Maura, P Leif Bergsagel, Bachisio Ziccheddu, Shaji Kumar, Kylee Maclachlan, Andriy Derkach, Juan-Jose Garces, Ross Firestone, Esteban Braggio, Yan Asmann, Michael Durante, Benjamin T Diamond, Marios Papadimitriou, Malin Hultcrantz, Alessio Marella, Giancarlo Castellano, Akihiro Maeda, Marta Lionetti, Antonio Matera, Stefania Pioggia, Matteo Claudio Da Vià, Claudio De Magistris, Daniel Leongamornlert, Danny Deavila, Praneeth Reddy Sudalagunta, Rafael Renatino Canevarolo, Erin M Siegel, Phaedra Agius, Jamie Teer, Andrew Mcpherson, Yusuke Yamashita, Ariosto S Silva, Patrick Blaney, Rachid Baz, Krina K Patel, Peter Campbell, Gareth Morgan, Rafael Fonseca, Ola Landgren, Robert Z Orlowski, Kenneth H Shain, Niccolo Bolli, Saad Usmani, S Vincent Rajkumar

Faculty, Staff and Student Publications

Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). While these precursor conditions are asymptomatic, they are not entirely benign and carry a lifelong risk of progression to MM. Unlike other cancers defined by pathology, malignant transformation from MGUS or SMM to MM has so far relied on demonstration of clinical end-organ damage as morphology and cytogenetics cannot reliably distinguish them. In this study, using genomic data from 374 patients with MGUS or SMM (277 training, 97 validation), to our knowledge, we demonstrate for the first time the ability to identify …

Simulated Complex Cells Contribute To Object Recognition Through Representational Untangling, Mitchell B Slapik, Harel Z Shouval

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The visual system performs a remarkable feat: it takes complex retinal activation patterns and decodes them for object recognition. This operation, termed "representational untangling," organizes neural representations by clustering similar objects together while separating different categories of objects. While representational untangling is usually associated with higher-order visual areas like the inferior temporal cortex, it remains unclear how the early visual system contributes to this process-whether through highly selective neurons or high-dimensional population codes. This article investigates how a computational model of early vision contributes to representational untangling. Using a computational visual hierarchy and two different data sets consisting of numerals …

Comprehensive Metabolic Profiling Across Five Lifespan Stages In Murine Hippocampus And Cortex Reveals Sex-Related Variation In Age-Related Cognitive Decline, Xi Long, Wuping Liu, Changhan Chen, Qi Guo, Yidan Wang, Fang Yu, Yujin Zhang, Rodney E Kellems, Yang Xia

Faculty, Staff and Student Publications

This study employs Barnes maze behavioral assessments, untargeted liquid chromatography-mass spectrometry metabolomics, and 13C6-glucose isotopic tracing to systematically investigate cognitive function and metabolic profiles in hippocampal and cortical tissues of male and female mice across five distinct age-ranges. Behavioral analyses reveal significant cognitive decline in both sexes by 16-months-of-age, with females exhibiting more severe impairment by 23-months, demonstrating a sex-related variation. 13C6-glucose tracing analyses reveals that glucose is rapidly and preferentially metabolized toward the Tricarboxylic acid cycle over glycolysis and the pentose phosphate pathway (PPP), with metabolism rates increasing from juvenility to meet developmental demands and maintaining homeostasis into pre-elderly. …

Radionuclide-Stimulated Dynamic Therapy Induces Complementary Immunogenic Necroptosis And Apoptosis Cancer Cell Death Pathways, Christopher Egbulefu, Kvar Black, Xinming Su, Partha Karmakar, Lemoyne Habimana-Griffin, Gail Sudlow, Julie Prior, Ezugo Onejeme, Alex Zheleznyak, Baogang Xu, Yalin Xu, Alison Esser, Matthew Mixdorf, Evan Moss, Brad Manion, Cody Hongsermeier, Nisha Gamadia, Nicole Blasi, Luke Stallings, Chidube Alagbaoso, Nathan Reed, Matthew M Gubin, Chieh-Yu Lin, Robert Schreiber, Katherine Weilbaecher, Samuel Achilefu

Faculty, Staff and Student Publications

Radionuclide-stimulated dynamic therapy (RaST) utilizes Cerenkov-radiating radiopharmaceuticals to activate light-sensitive drugs and materials, generating reactive oxygen species (ROS) that inhibit cancer progression. However, the underlying cell death mechanisms are not fully understood. Using ROS-regenerative nanophotosensitizers coated with a tumor-targeting transferrin-titanocene complex and radiolabeled 2-fluorodeoxyglucose, we found that RaST induced apoptosis and necroptosis, characterized by the activation of RIPK-1, RIPK-3, nuclear factor kappa B, and mixed lineage kinase domain-like pseudokinase, leading to membrane permeabilization, cytokine release, and the expression of immunogenic damage-associated molecular patterns. In immune-deficient breast tumor-bearing mice with adequate stroma and growth factors, RaST did not prevent tumor growth …

Foxo1 Inhibition And Fadd Knockdown Have Opposing Effects On Anticancer Drug-Induced Cytotoxicity And P21 Expression In Osteosarcoma Cells, Danielle Walker, Antanay Hall, Alexis Bonwell, Nancy Gordon, Danielle Robinson, Mario G Hollomon

Faculty, Staff and Student Publications

Forkhead box class O1 (FOXO1) and fas-associated death domain (FADD) regulate cell death pathways and homeostatic processes such as cell cycle progression and apoptosis. FADD phosphorylation promotes nuclear localization of FOXO1, and FOXO1 regulates FADD expression. Therefore, it is plausible that FOXO1 and FADD have synergistic or antagonistic effects on cell cycle regulation and the response to anticancer drug treatment in cancer cells. In the present study, we report that AS1842856-mediated inhibition of FOXO1 reverses anticancer drug-induced cytotoxicity, while FADD knockdown increases anticancer drug-induced cytotoxicity in osteosarcoma (OS). Reversed anticancer drug-induced cytotoxicity was accompanied by G2/M cell cycle arrest and …

Premature Aging In Serious Mental Illness, Breno S Diniz, Gabriel R Fries, Chia-Ling Kuo, Ming Xu, Eric J Lenze

Faculty, Staff and Student Publications

Serious mental illnesses (SMIs), including major depressive disorder, bipolar disorder, and schizophrenia, have long been linked to cognitive decline, multiple chronic medical conditions, and premature mortality. These factors significantly contribute to the severe disability seen in SMIs, extending beyond the severity of psychopathology and indicating a premature aging phenotype associated with these conditions. The mechanisms that underlie the relationship between SMIs and the premature aging phenotype are not well understood, but recent evidence suggests that individuals with SMIs may exhibit accelerated biological aging. In this review, we present a comprehensive analysis of the current literature, demonstrating the potential association of …

Glutamatergic Projection Neurons In The Basal Forebrain Underlie Learned Olfactory Associational Valence Assignments, Pey-Shyuan Chin, Zhuokun Ding, Mikhail Kochukov, Snigdha Srivastava, Elizabeth H Moss, Qingchun Tong, Benjamin R Arenkiel

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Sensory perception is shaped by experience, giving stimuli behavioral significance. Basal forebrain (BF) cholinergic neurons in mice, which are crucial for arousal and motivation, also regulate sensory processing. Within BF nuclei, glutamatergic (vGlut2BF) neurons receive cholinergic input and modulate behaviors, but their roles in encoding sensory significance remain unclear. Using in vivo calcium imaging, we found that vGlut2BF neurons initially poorly encoded odor identity. However, their response to conditioned odors increased following associative learning, and their population activity more distinctly encoded paired stimuli, reflecting emergent value representation. Furthermore, pairing stimulation or inhibition of vGlut2BF neurons with specific odors altered odor …

Integrative Spatial Multi-Omics Reveal Niche-Specific Inflammatory Signaling And Differentiation Hierarchies In Aml, Enes Dasdemir, Ivo Veletic, Christopher P Ly, Andres E Quesada, Christopher D Pacheco, Fatima Z Jelloul, Pamella Borges, Sreyashi Basu, Sonali Jindal, Zhiqiang Wang, Alexander Lazar, Khalida M Wani, Dinler A Antunes, Patrick K Reville, Preethi H Gunaratne, Robert J Tower, Padmanee Sharma, Hussein A Abbas

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) is a clonal disorder characterized by immature blasts and arrested differentiation that primarily affects the bone marrow (BM) and occasionally presents as extramedullary (EM) disease. EM manifestations highlight AML's adaptability to distinct microenvironments, which we examined using spatial analyses of medullary and EM tissues. We describe a workflow for Visium-based spatial transcriptomics in medullary and EM AML, revealing insights into cell-cell communication and the spatial organization of AML hierarchies. In BM, monocytes and granulocyte-monocyte progenitors colocalized with leukemic populations, sharing molecular signatures with those in EM sample. CXCL12-CXCR4-mediated communication correlated with PI3K/AKT/mTOR signaling in inflammatory niches.

Loss Of Payload Sensitivity And Other Mechanisms Of Resistance To T-Dxd In Her2-Mutant Nsclc: Implications For Subsequent Responsiveness To Her2 Tkis, Monique B Nilsson, Xiuning Le, Alissa Poteete, Xiaoxing Yu, Junqin He, Qian Huang, Yuji Shibata, Ximeng Liu, Cesar Moran, Ash A Alizadeh, Maximilian Diehn, Heather Wakelee, Diego Almanza, Scott Soltys, Takeshi Sugio, Jurik Mutter, Xiaoman Kang, Rui Wang, Soyeong Jun, Mohammad Shahrokh Esfahani, Hai Tran, Yuanxin Xi, Lingzhi Hong, Xiaofang Huo, Ashwani Kumar, Xiaoyang Ren, Kei Oguchi, Kazuhisa Minamiguchi, Caroline M Weipert, Jing Wang, Ralf Kittler, John V Heymach

Faculty, Staff and Student Publications

Introduction: Effective therapies are needed for patients with NSCLC with HER2-mutant tumors who progress on the HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), a standard-of-care treatment. A greater understanding of mechanisms mediating acquired T-DXd resistance and whether these tumors could benefit from HER2 tyrosine kinase inhibitors (TKIs) is needed.

Methods: Using preclinical models of acquired T-DXd resistance, LentiMutate scanning mutagenesis, and clinical analyses, we investigated mechanisms mediating acquired resistance to T-DXd and assessed the impact of each of these resistance mechanisms on cross-resistance to alternative HER2-targeting approaches.

Results: We determined that acquired resistance to T-DXd could occur through multiple mechanisms including …

Emt-Induced Stem Cell And Mesenchymal Programs Can Be Decoupled Via Cell Division And Esrp1-Dependent Mechanisms, Petra Den Hollander, Maria Castaneda, Suhas V Vasaikar, Joanna Joyce Maddela, Claire Gould, Breanna R Demestichas, Robiya Joseph, Shivangi Agarwal, Abhijeet P Deshmukh, Alvina Zia, Shruti Shah, Tieling Zhou, Geraldine Raja, Paul Allegakoen, Nick A Kuburich, Mika Pietila, Chunxiao Fu, Jeffrey Chang, Chad J Creighton, William F Symmans, Rama Soundararajan, Sendurai A Mani

Faculty, Staff and Student Publications

Epithelial-to-mesenchymal transition (EMT) is known to induce both stemness and mesenchymal properties, and our findings reveal that these two programs can be uncoupled. During EMT, epithelial cells transition from symmetric divisions producing differentiated daughter cells to self-renewing daughter cells. When we block cell division and induce EMT, cells gain mesenchymal properties but not stemness, suggesting the importance of cell division for gaining stemness. We identified ESRP1 as a key regulator of EMT-driven stemness, which get downregulated during EMT in a cell division-dependent manner. Overexpression of ESRP1 prevents the gain of stemness without affecting the mesenchymal program. Only the stemness and …

Aberrant Cd25 And Increased Cd123 Expression Are Common In Acute Myeloid Leukemia With Kmt2a Partial Tandem Duplication And Are Associated With Flt3 Internal Tandem Duplication, Qing Wei, Guilin Tang, Shaoying Li, Sa A Wang, Pei Lin, Wei Wang, Sanam Loghavi, Wei J Wang, L Jeffrey Medeiros, Jie Xu

Faculty, Staff and Student Publications

Background: KMT2A partial tandem duplication (PTD) occurs in approximately 5-10% of acute myeloid leukemia (AML) cases and is associated with poor prognosis. While its cytogenetic and molecular features are well described, the immunophenotypic characteristics of AML with KMT2A-PTD remain incompletely defined.

Methods: We identified 47 cases of AML with KMT2A-PTD by optical genome mapping. All cases underwent flow cytometric immunophenotypic analysis and next-generation sequencing using an 81-gene panel.

Results: The cohort included 32 men and 15 women with a median age of 67 years (range, 19-87). Thirty-eight cases were de novo AML, and nine were secondary to myelodysplastic …

Advances In Targeting Her2 Across Cancer Subtypes: A Pan-Tumor Approach, Taiwo Adesoye, Ecaterina E Dumbrava, Kanwal P S Raghav, Aysegul A Sahin, Hui Chen, Sunyoung S Lee, Milind M Javle, Shubham Pant, Omar Alhalabi, Xiuning Le, Vicente Valero, Paula R Pohlmann, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Human epidermal growth factor receptor 2 (HER2) is an established therapeutic target in multiple solid tumors, particularly breast and gastric cancers. Significant advancements have been made in the development of HER2-targeted therapies, including monoclonal antibodies, tyrosine kinase inhibitors, antibody-drug conjugates (ADC), and novel bispecific antibodies. These agents have revolutionized the treatment landscape for HER2-positive metastatic cancers, resulting in improved progression-free and overall survival, and quality of life for patients. Beyond breast and gastric cancers, HER2 expression/amplification has been observed in other solid tumors, such as colorectal, lung, bladder, ovarian, and biliary tract cancers, offering new opportunities for personalized therapy in …

Role Of The Etv5/P38 Signaling Axis In Aggressive Thyroid Cancer Cells, Jerry H Houl, Rozita Bagheri-Yarmand, Muthusamy Kunnimalaiyaan, Paola Miranda Mendez, Joseph L Kidd, Ali Dadbin, Andrea Ruiz-Jurado, Parag A Parekh, Ying C Henderson, Nikhil S Chari, Aatish Thennavan, Reid T Powell, Clifford C Stephan, Xiao Zhao, Anastasios Maniakas, Roza Nurieva, Naifa L Busaidy, Maria E Cabanillas, Ramona Dadu, Mark Zafereo, Jennifer R Wang, Stephen Y Lai, Marie-Claude Hofmann

Faculty, Staff and Student Publications

Patients with poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) face a much poorer prognosis than those with differentiated thyroid cancers. Around 25% of PDTCs and 35% of ATCs carry the BRAFV600E mutation, which constitutively activates the MAPK pathway, a key driver of cell growth. Although combining BRAF and MEK inhibitors can shrink tumors, resistance often develops. The exact cause of this resistance remains unclear. We previously found that in PDTC and ATC cells, the BRAFV600E mutation is strongly linked to the expression of ETV5, a transcription factor downstream of the MAPK pathway. In the current study, we …

Bdcd: A Comprehensive Brain Disease Cell-Cell Communication Database, Xinyi Liu, Citu Citu, Gang Qu, Wendao Liu, Nitesh Enduru, Andi Liu, Chia-Hao Tung, Zhongming Zhao

Faculty, Staff and Student Publications

Dysregulated cell–cell communication (CCC) is increasingly recognized as a driver of brain disease pathology, contributing to neuroinflammation, synaptic dysfunction, and neurodegeneration. Nevertheless, existing resources remain limited in brain specificity, regional coverage, and functional annotation. To address this gap, we develop the Brain Disease Cell-cell communication Database (BDCD), the first comprehensive resource focused on CCC networks across major brain diseases. BDCD integrates 38 manually curated datasets, comprising 8 519 425 single cells from single-cell RNA-seq studies and 140 744 spots from spatial transcriptomic maps, spanning 14 brain regions and 13 canonical cell types covering Alzheimer’s disease, Parkinson’s disease, schizophrenia, bipolar disorder, …

Bridging Hypoxia And Vision Loss: The Emerging Role Of Connexins In Local And Systemic Eye Diseases, Xianping Zhang, Yalong Cheng, Jean X Jiang, Yuting Li

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Hypoxic eye diseases represent a pivotal yet often underappreciated contributor to the onset and progression of many retinal disorders. When hypoxia persists or exceeds the tissue's compensatory capacity, it triggers pathological retinal neovascularization, blood-retinal barrier disruption, and neuronal apoptosis, ultimately resulting in irreversible visual impairment. Connexins (Cxs) form gap junction channels and hemichannels and regulate retinal cell proliferation, differentiation, and survival, thereby playing a central regulatory role in the pathogenesis of hypoxic ocular diseases. In addition to gap junctions, Cx hemichannels promote transmission of molecules between intra- and extracellular environments, further influencing retinal homeostasis under hypoxic stress. This review synthesizes …

Epigenome-Wide Association Study Meta-Analysis Of Bmi In African Americans, Kendra Ferrier, Mariaelisa Graff, Iain R Konigsberg, Maggie Stanislawski, Heather M Highland, Laura M Raffield, April P Carson, Eric Boerwinkle, Jill M Norris, Chris R Gignoux, Audrey E Hendricks, Sridharan Raghavan, Kari E North, Kristin L Young, Anne E Justice, Matthew A Allison, Mathew J Budoff, Silva Kasela, François Aguet, Joshua J Joseph, Charles Kooperberg, Stephen S Rich, Jerome I Rotter, Ethan M Lange, Leslie A Lange

Faculty, Staff and Student Publications

Despite considerable advances in identifying risk factors for obesity, gaps remain in our understanding about its etiology. Genetic variants explain only a small portion of variation in obesity-related traits such as body mass index (BMI). Epigenetic regulation, which controls gene expression and is influenced by environmental and genetic factors, may account for additional variability in BMI. Epigenetic studies of BMI have largely been conducted in European ancestry populations, despite the disproportionate burden of obesity in African Americans (AAs). We conducted a sex-stratified BMI epigenome-wide association study meta-analysis in AA participants from the Jackson Heart Study (n = 1,604) and …

Dna Methyltransferase Inhibitors In Hematological Malignancies And Solid Tumors, Valentin Wenger, Guillermo Garcia-Manero, Robert Zeiser, Michael Lübbert

Faculty, Staff and Student Publications

Epigenetic modifications such as DNA methylation play a fundamental role in oncogenesis and the progression of neoplasms neoplasias. DNA methyltransferase inhibitors (DNMTi) constitute a family of therapeutic agents that impede the methylation at the 5-position on cytosine nucleotides, thereby modulating the epigenetic regulation of tumor suppressor genes, oncogenes, and other key regulatory genes. The first-generation DNMTi azacitidine and decitabine have demonstrated substantial efficacy in the treatment of medically non-fit, older patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy (IC), by virtue of their favorable safety profile. Despite these clinical achievements, however, single-agent DNMTi treatment …

C Elegans As A Tractable Infection Model For The Emerging Fungal Pathogen Candida Auris, Melissa Martinez, Melissa R Cruz, Danielle A Garsin, Michael C Lorenz

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Candida auris is an emerging multidrug-resistant fungal pathogen. The genetic factors contributing to the virulence, drug resistance, and stress-tolerant nature of C. auris are mostly unknown. Additional animal models of virulence are needed, especially those amenable to high-throughput analysis. The nematode Caenorhabditis elegans has been validated as an effective tool for studying multiple fungal and bacterial pathogens. We describe here a C. elegans infection model in which exposure to C. auris is lethal to worms with kinetics similar to killing by Candida albicans; in contrast to C. albicans, C. auris does not form hyphae, indicating distinct virulence mechanisms. …

Autograft Enlargement After The Ross Procedure In Pediatric Patients: Somatic Growth Or Pathologic Dilatation?, Ioannis Zoupas, Alexander C Mills, Scott D Olson, Damien J Lapar

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Purpose of ReviewPulmonary autograft autotransplantation represents a popular surgical approach for pediatric patients requiring aortic valve replacement due to the potential for autograft enlargement to accommodate somatic growth. Nevertheless, autograft dilatation and the subsequent need for reintervention are quite common. Published data suggest that autograft enlargement may result from pathological passive remodeling rather than active somatic growth and vice versa. The present review serves to comprehensively evaluate available evidence related to the fate of the pulmonary autograft after the Ross procedure as it relates to the etiology, risk factors and patterns of autograft failure.ResultsStudies present conflicting results supporting both pathological …

Understanding The Compatibility Of Fluoride-Based Radiopharmaceutical Reaction Solutions And Pdms, Mark Mc Veigh, Charles Frech, Mai Lin, Robert Ta, H Charles Manning, Leon M Bellan

Faculty, Staff and Student Publications

Microfluidic devices offer unique and exciting benefits when applied to radiopharmaceutical manufacturing, and these platforms are now starting to be integrated into commercial products. The field has strayed away from the use of polydimethylsiloxane (PDMS), the most common microfluidic device material, due to its suspected incompatibility with 18F, the most commonly used radionuclide. However, existing literature provides conflicting conclusions as to the existence and extent of this incompatibility. In this study, we use several analytical instruments to uncover the underlying interaction between fluoride and PDMS. SEM imaging and profilometry confirm the reactive relationship between the two materials and suggest that …

Diet-Responsive Genetic Determinants Of Intestinal Colonization In The Yeast Candida Albicans, Musfirat Shubaita, Mazen Oneissi, Elena Lindemann-Pérez, Cecilia Fadhel Alvarez, Anne-Marie Krachler, Diana M Proctor, J Christian Pérez

Faculty, Staff and Student Publications

Dietary components influence microbial composition in the digestive tract. Although often viewed as energy sources, dietary components are likely to shape microbial determinants of intestinal colonization beyond metabolism. Here, we report that a dietary long-chain fatty acid enhances the yeast Candida albicans colonization of the murine gut partly by eliciting modifications to the fungal cell surface. Mice fed an oleic acid-rich diet were readily colonized by C. albicans and exhibited higher fungal load in feces compared with rodents fed an isocaloric control diet. Surprisingly, β-oxidation, a catabolic process to break down fatty acids for energy production, was dispensable for C. …

Prevalence And Outcomes Of Her2-Low Versus Her2-0 Status In Patients With Metastatic Breast Cancer, Akshara Singareeka Raghavendra, Diane D Liu, Senthil Damodaran, Sarah Pasyar, Yu Shen, Jason A Mouabbi, Carlos H Barcenas, Kelly K Hunt, Debu Tripathy

Faculty, Staff and Student Publications

Background: HER2-low breast cancer (HER2 immunohistochemical [IHC] score 1+, or IHC 2+ without HER2 gene amplification) is distinct from HER2-positive and HER2-0 breast cancer (IHC 0), with a differing prognosis and specific therapeutic options. The DESTINY-Breast04 trial demonstrated notable efficacy of the HER2 antibody-drug conjugate trastuzumab deruxtecan over standard chemotherapy in patients with metastatic breast cancer (MBC) defined as HER2-low. More recently, the DESTINY-Breast06 trial confirmed this benefit in hormone receptor-positive and HER2-ultralow (less than 1+, but with ≤10% of infiltrating cancer cells showing incomplete and faint/weak membrane staining) cases, prompting re-evaluation of HER2 diagnostic thresholds and treatment strategies.

Methods …

Genome-Wide Gene By Sleepiness Interaction Analysis For Sleep Apnea, Pavithra Nagarajan, Nuzulul Kurniansyah, Jiwon Lee, Sina A Gharib, Yushan Xu, Yiyan Zhang, Brian Spitzer, Tariq Faquih, Hufeng Zhou, Eric Boerwinkle, Han Chen, Daniel J Gottlieb, Xiuqing Guo, Nancy L Heard-Costa, Bertha A Hidalgo, Daniel Levy, Peter Y Liu, Hao Mei, Rebecca Montalvan, Sutapa Mukherjee, Kari E North, George T O'Connor, Lyle J Palmer, Sanjay R Patel, Bruce M Psaty, Shaun M Purcell, Laura M Raffield, Stephen S Rich, Jerome I Rotter, Richa Saxena, Albert V Smith, Katie L Stone, Xiaofeng Zhu, Topmed Sleep Trait Working Group, Brian E Cade, Tamar Sofer, Susan Redline, Heming Wang

Faculty, Staff and Student Publications

Study objectives: Excessive daytime sleepiness (EDS), influenced by environmental and social-behavioral factors, is reported by a subset of patients with sleep apnea-a group that may be at elevated cardiovascular risk. However, it is unclear whether sleep apnea with and without EDS have distinct genetic underpinnings. In this study, we perform gene-by-EDS interaction analyses for apnea hypopnea index, a diagnostic marker of sleep apnea severity, to understand EDS's influence on its underlying genetic risk.

Methods: Discovery interaction analyses for common variants and gene-based rare variants were conducted respectively using multi-ethnic Trans-Omics for Precision Medicine (N = 11 619) data, followed by …

Workflow Improvements From Automated Large Vessel Occlusion Detection Algorithms Are Dependent On Care Team Engagement, Emmanuel C Ebirim, Ngoc Mai Le, Joseph N Samaha, Hussain Azeem, Ananya Iyyangar, Anjan N Ballekere, Saagar Dhanjani, Luca Giancardo, Eunyoung Lee, Sunil A Sheth

Faculty, Staff and Student Publications

Background: Automated machine learning (ML)-based large vessel occlusion (LVO) detection algorithms have been shown to improve in-hospital workflow metrics including door-to-groin time (DTG). The degree to which care team engagement and interaction are required for these benefits remains incompletely characterized.

Methods: This analysis was conducted as a pre-planned post-hoc analysis of a randomized prospective clinical trial. ML-based LVO detection software was implemented at four comprehensive stroke centers (CSCs) from January 1, 2021, to February 27, 2022. Patients were included if they underwent endovascular thrombectomy for LVO acute ischemic stroke. ML software utilization was quantified as the total number of active …

Mini-Hyper-Cvd Plus Venetoclax And Navitoclax For Relapsed/Refractory Acute Lymphoblastic Leukemia, Nicholas J Short, Hagop Kantarjian, Nitin Jain, Tapan M Kadia, Jayastu Senapati, Fadi G Haddad, Manuel M Maroun, Koji Sasaki, Lianchun Xiao, Xuelin Huang, Omer Karrar, Regina Abramova, Min Zhao, Rebecca Garris, Marina Konopleva, Farhad Ravandi, Elias Jabbour

Faculty, Staff and Student Publications

No abstract provided.