Medical Sciences Commons^™

Runx2 Cooperates With Srebp1 To Rewire Cancer Metabolism And Promote Aggressiveness, Emanuele Vitale, Mila Gugnoni, Veronica Manicardi, Silvia Muccioli, Federica Torricelli, Benedetta Donati, Simonetta Piana, Gloria Manzotti, Elisa Salviato, Francesca Reggiani, Cristian Ascione, Rebecca Vezzani, Moira Ragazzi, Mattia Forcato, Oriana Romano, Silvio Bicciato, Aaron Goldman, Marco Tigano, Alessia Ciarrocchi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Embryonic Transcription Factors (TFs) are often reactivated in cancer, driving developmental gene programs that support phenotypic plasticity. Metabolic adaptation fuels this plasticity by supplying energy and molecular building blocks for growth. RUNX2, the master regulator of bone morphogenesis, is ectopically expressed in epithelial cancer, promoting metastasis through trans-differentiation processes like Epithelial-to-Mesenchymal Transition (EMT) and osteomimicry. By combining omics data with functional validation, we demonstrated that RUNX2 drives cancer cell metabolic rewiring by repressing mitochondrial respiration while promoting anabolic processes. We showed that RUNX2 upregulates key genes of lipid biosynthesis by regulating and cooperating with SREBP1. In vivo expression analysis in …

Understanding The Effects Of Real-Time Head Position Feedback On Postural Sway In Terms Of Changes In Underlying Deterministic And Stochastic Dynamical Processes, Steven J. Harrison, Benjamin De Bari, Ryan Poutre, Jeffrey M. Kinsella-Shaw

College of Humanities and Sciences Faculty Papers

Our perceptual systems detect information about how our body is moving relative to the surrounding environment. Such information is essential to our ability to maintain upright standing balance. Real-time postural feedback systems are technologies that appear to enhance our ability to detect information about the movements of our body, and as a consequence improve our capacity to control the posture of our body. Here we examine a system in which real-time measurements of head position were "felt" as changes in the intensity of vibration of tactors in a headband. Using this system, participants were able to stabilize their body posture, …

Short Term Hemodynamic Effects Of Atrial Fibrillation In A Closed-Loop Human Cardiac-Baroreflex System, Oluwasanmi Adeodu, Michelle Gee, Babak Mahmoudi, Rajanikanth Vadigepalli, Mayuresh V. Kothare

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Atrial fibrillation (AF) remains the leading cardiac cause of stroke and AF-related death rate in the United States has been increasing for over twenty years. While the effect of standalone AF on heart rate is well established, there is a lack of clarity on its impact on other critical hemodynamic metrics. This is ostensibly due to interaction with other common comorbidities, especially hypertension. In addition, AF has a complex relationship with the state of the baroreflex. Evidence indicates that baroreflex sensitivity (BRS), the ability of the intrinsic cardiac control system to initiate parasympathetic response, is suppressed during AF. Therefore, a …

Effect Of Valemetostat On The Pharmacokinetics Of Midazolam And Digoxin: A Phase 1 Drug-Drug Interaction Study In Patients With Non-Hodgkin Lymphoma, Masaya Tachibana, Steven Horwitz, Eric Jacobsen, Francine Foss, Pamela Allen, Pierluigi Porcu, Tatyana Feldman, Jia Ruan, Jonathan Brammer, Jie Wang, Shinichi Inaba, Yuka Iko, Keiko Nakajima, Yasuyuki Kakurai, Noriaki Kitami, Yang Chen, Yvonne Lau

Department of Medicine Faculty Papers

Valemetostat tosylate (valemetostat) is an oral, potent, dual inhibitor of enhancer of zeste homolog (EZH)2/1, under investigation in non-Hodgkin lymphomas (NHLs) and solid tumors. In vitro, it inhibits cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp) when combined with sensitive CYP3A or P-gp substrates. This drug–drug interaction (DDI) sub-study is part of the phase 1 trial of valemetostat monotherapy (DS3201-A-J101; NCT02732275), assessing the effect of valemetostat on the pharmacokinetics (PK) of sensitive CYP3A and P-gp substrates midazolam and digoxin, respectively, in patients with relapsed or refractory NHL, and its safety and efficacy. Patients received two simultaneous single doses of midazolam and …

Setdb1 Is Critically Required For Uveal Melanoma Growth And Represents A Promising Therapeutic Target, Imène Krossa, Céline Pisibon, Yann Cheli, Karine Bille, Mélanie Dalmasso, Sabah Hamadat, Chrystel Husser, Marie Irondelle, Julien Cherfils-Vicini, Frédéric Soysouvanh, Sacha Nahon-Esteve, Arnaud Martel, Sandra Lassalle, Jean-Pierre Caujolle, Célia Maschi, Stéphanie Baillif, Dan Hasson, Saul Carcamo, Andrerw E. Aplin, Irwin Davidson, Emily Bernstein, Valeria Naim, Robert Ballotti, Corine Bertolotto, Thomas Strub

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Metastatic uveal melanomas are highly resistant to all existing treatments. To identify actionable vulnerabilities, we conducted a CRISPR-Cas9 knockout screen using a library composed of chromatin regulators. We revealed that the lysine methyltransferase, SETDB1, plays a critical role in metastatic uveal melanoma cell proliferation and survival. Functionally, SETDB1 deficiency induces a DNA damage response, senescence-like state and growth arrest. Knockdown of SETDB1 is associated with a decreased expression of genes related to replication and cell cycle. Moreover, deficiency in CDC6, an essential regulator of DNA replication, phenocopies SETDB1 inhibition. Using a pre-clinical model, we further demonstrated that anti-SETDB1 therapy impairs …

Rtx-303, An Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates Parp Inhibitors In Brca Mutant Tumors, Gurushankar Chandramouly, William Fried, John Gordon, Douglas Ralph, Channita Keuk, Sangeeta Kumari, Mercy Ramanjulu, William Auerbacher, Leonid Minakhin, Taylor Tredinnick, Bernadette Tiberi, George Morton, Robert Betsch, Kathy Q. Cai, Umeshkumar M Vekariya, Mrityunjay Tyagi, Tomasz Skorski, Sergey Karakashev, Neil Johnson, Wayne E. Childers, Xiaojiang S. Chen, Richard T. Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

DNA polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC50, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like …

Regorafenib Pulmonary Toxicity: A Case Of Cavitary Lung Disease And Ards Treated With Infliximab, Michael Dong, Mackenzie Kramer, Tanmay Gandhi, Gautam George

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

Regorafenib-induced pneumonitis and acute respiratory distress syndrome (ARDS) are rare and poorly characterized toxicities. We describe a 43-year-old male with metastatic colorectal cancer who developed hypoxic respiratory failure after two cycles of regorafenib. Imaging revealed cavitary lung lesions and diffuse ground glass opacities. Despite antibiotics and high-dose corticosteroids, his condition deteriorated, requiring ICU admission and mechanical ventilation. Bronchoalveolar lavage revealed bacterial pathogens, and he was treated for pneumonia. After multidisciplinary discussion, he was assessed to have regorafenib-induced pneumonitis as a major driver of his respiratory failure, and after limited steroid response, infliximab was administered with marked respiratory improvement. However, he …

Large Language Models As Information Providers For Appropriate Antimicrobial Use: Computational Text Analysis And Expert-Rated Comparison Of Chatgpt, Claude And Gemini, Marcello Di Pumpo, Maria Rosaria Gualano, Danilo Buonsenso, Francesca Raffaelli, Daniele Donà, Vittorio Maio, Patrizia Laurenti, Walter Ricciardi, Leonardo Villani

College of Population Health Faculty Papers

OBJECTIVES: Antimicrobial resistance is a critical public health threat. Large language models (LLMs) show great capability for providing health information. This study evaluates the effectiveness of LLMs in providing information on antibiotic use and infection management.

METHODS: Using a mixed-method approach, responses to healthcare expert-designed scenarios from ChatGPT 3.5, ChatGPT 4.0, Claude 2.0 and Gemini 1.0, in both Italian and English, were analysed. Computational text analysis assessed readability, lexical diversity and sentiment, while content quality was assessed by three experts via DISCERN tool.

RESULTS: 16 scenarios were developed. A total of 101 outputs and 5454 Likert-scale (1-5) scores were obtained …

Cerebellar Dysfunction In Glaucoma Patients, Anisha Kasi, Ji Won Bang, Vivek Trivedi, Jeannie Au, Ian Conner, Gadi Wollstein, Joel Schuman, Rakie Cham, Kevin Chan

Wills Eye Hospital Papers

Glaucoma patients often have higher injurious fall rates compared to healthy older adults. However, little is known about the underlying neural mechanisms. Recent evidence shows cerebral changes beyond the visual pathway of glaucoma patients, yet it remains unclear whether the cerebellum, which plays an important role in balance and motor control, is involved in glaucoma. In this study, we sought to investigate cerebellar functional connectivity changes in glaucoma by comparing 32 glaucoma subjects and 10 age-matched healthy control subjects who underwent resting-state functional magnetic resonance imaging at 3 Tesla with eyes closed. After conducting both regions-of-interest and seed-to-voxel analyses, we …

Role Of M6a Mrna Methylation In Plant Defense, Rakesh Srivastava, Niraj Lodhi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

N6-methyladenosine (m⁶A) is the most abundant and dynamic RNA modification in eukaryotic messenger and non-coding RNAs, playing a pivotal role in the post-transcriptional regulation of gene expression. The coordinated actions of m⁶A writers, erasers, and readers influence transcript stability, immune activation, and pathogen suppression. Growing evidence indicates that m⁶A fine-tunes the expression of defense-related genes, modulates RNA processing events, and is frequently hijacked by pathogens and pests to promote virulence. Notably, the dual role of m⁶A in enhancing plant defense and facilitating pathogen adaptation highlights its significance in the host–pathogen arms race. …

A Social Media Campaign And Web-Based Survey About Prostate Cancer Genetics: Mixed Methods Study, Amy Leader, Stacy Loeb, Preethi Selvan, Ashley Hunter, Rebecca Hartman, Scott Keith, Veda Giri

Department of Medical Oncology Faculty Papers

BACKGROUND: Germline genetic variants are important for prostate cancer (PCa) management and hereditary cancer risk assessment, but testing is underused. Furthermore, patients are often unaware of the genetic connections to PCa. Social media is increasingly serving as a source of awareness for health information and a method to gather data from a large population.

OBJECTIVE: There were three objectives: to (1) create and test social media messages related to PCa genetics and genetic testing, (2) determine which social media message was most engaging, and (3) assess knowledge of and attitudes toward PCa genetic testing through an online survey using the …

Organism-Specific Sequence Motifs Link Ribosomal Rnas To Brain Disorders, Isidore Rigoutsos, Stepan Nersisyan, Eric Londin, Iliza Nazeraj, Bonnie Dong, Anastasios Vourekas, Phillipe Loher

Computational Medicine Center Faculty Papers

We report that in humans, mice, fruit flies, and worms, the ribosomal RNAs and the transcribed spacers of 45S are densely packed with organism-specific sequence motifs that are primarily shared with nervous system genes. The human ribosomal RNAs and 45S spacers contain 1,723 such motifs. Specific combinations of these motifs are predominantly found in 3,430 human nervous system genes, of which 1,046 are genes associated with brain disorders, including autism spectrum disorder and schizophrenia. The sequences of the 1,723 motifs and their locations in the introns and exons of nervous system genes are unique to primates. Experimental evidence indicates that …

Neuronal Activity-Dependent Gene Dysregulation In C9orf72 I3neuronal Models Of Als/Ftd Pathogenesis, Layla T. Ghaffari, Emily A. Welebob, Sarah E. Bond Newton, Ashley V. Boehringer, Kelly L. Cyliax, Piera Pasinelli, Davide Trotti, Aaron R. Haeusler

Farber Institute for Neuroscience Faculty Papers

The GGGGCC nucleotide repeat expansion (NRE) mutation in the C9ORF72 (C9) gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Neuronal activity plays an essential role in shaping biological processes within both healthy and neurodegenerative disease scenarios. Here, we show that at baseline conditions, C9-NRE-induced pluripotent stem cell-cortical neurons display aberrations in several pathways, including synaptic signaling and transcriptional machinery, potentially priming diseased neurons for an altered response to neuronal stimulation. Indeed, exposure to two pathophysiologically relevant stimulation modes, prolonged membrane depolarization or a blockade of K⁺ channels, followed by RNA sequencing, induces …

Three-Dimensional Human Mucopolysaccharidosis Iva Chondrocyte Culture Reveals Significant Impairments In The Lysosomal-Mitochondrial Crosstalk, Andrés Felipe Leal, Sampurna Saikia, Shaukat A. Khan, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder (LSD) caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase enzyme. MPS IVA patients suffer from skeletal dysplasia due to the abnormal function of chondrocytes. Given the interactions of lysosomes with various intracellular organelles, it is not surprising that lysosomal dysfunction can lead to improper functioning of lysosome-interacting organelles such as mitochondria. Mitochondrial alterations have been evaluated in several LSDs; nevertheless, they have not been fully addressed in MPS IVA. In this study, we assessed the mitochondrial alterations in MPS IVA chondrocytes using a three-dimensional culture approach. Our findings revealed that MPS IVA …

Dynamic Rewiring Of Microrna Networks In The Brainstem Autonomic Control Circuits During Hypertension Development In The Female Spontaneously Hypertensive Rat, Alison Moss, Ankita Srivastava, Lakshmi Kuttippurathu, James S. Schwaber, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

We describe global microRNA (miRNA) changes in the central autonomic control circuits during the development of neurogenic hypertension. Using the female spontaneously hypertensive rat (SHR) and the normotensive Wistar Kyoto (WKY), we analyzed the dynamic miRNA expression changes in three brainstem regions-the nucleus of the solitary tract, caudal ventrolateral medulla, and rostral ventrolateral medulla-as a time series beginning at 8 wk of age before hypertension onset through to extended chronic hypertension. Our analysis yielded nine miRNAs that were significantly differentially regulated in all three regions between SHR and WKY over time. We collated computationally predicted gene targets of these nine …

Decorin Evokes A Pro-Lysosomal Pathway In Lymphatic Endothelial Cells, Gabriel J. Pascal, Dipon K. Mondal, Sadie Kim, Christopher Xie, Devanarayanan Siva Sankar, Jörn Dengjel, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The lymphatic system is critical to the body's immune and circulatory system, and lymphangiogenesis, the development of new lymphatic vessels from pre-existing ones, is a significant process capitalized upon by cancer during tumorigenesis. Decorin is a small leucine-rich proteoglycan which we have previously shown to be anti-tumorigenic and a suppressor of lymphangiogenesis. We have also shown that decorin exercises its anticancer properties through its ability to evoke autophagy. Through a comprehensive and unbiased proteomic analysis, we explored the implications of decorin exposure on protein expression within mouse lymphatic endothelial cells. We discovered that decorin enriches several protein pathways, notably proteasomal …

Association Of Estimated Plasma Volume Status With Invasive Hemodynamics And Adverse Clinical Outcomes In Patients With Pulmonary Hypertension And Chronic Kidney Disease, Andrew Geller, Jose Manuel Martinez Manzano, Esteban Kosak Lopez, Phuuwadith Wattanachayakul, John Malin, Raul Leguizamon, Tara John, Rasha Khan, Ian Mclaren, Alexander Prendergast, Simone Jarrett, Kevin Bryan Lo, Christian Witzke

Einstein Health Papers

Identifying noninvasive measures to assess intravascular volume status and risk stratify patients with pulmonary hypertension (PH) and chronic kidney disease (CKD) is needed. We assessed the predictive value of estimated plasma volume status (ePVS) using the Strauss-derived Duarte formula in PH-CKD patients. This single-center retrospective cohort analysis included patients with PH and CKD Stage 3b (CKD3b), Stage 4 (CKD4), or Stage 5 (CKD5) who underwent right heart catheterization from 2018 to 2023. Patients were categorized into low ePVS (< 6.2) and high ePVS (≥ 6.2) using Youden's J statistics. We used the Cox-proportional hazards model, adjusting for age, sex, and body mass index, to investigate the association between …

Comparison Of Authentic Urine N-Ethylpentedrone Metabolites To Predicted In Silico And In Vitro Human Hepatocyte Metabolism, Gloria Daziani, Omayema Taoussi, Diletta Berardinelli, Giulia Bambagiotti, Marilyn A. Huestis, Francesco P. Busardò, Jeremy Carlier

Institute of Emerging Health Professions Faculty Papers

Synthetic cathinones are the second most common class of substances belonging to the category of new psychoactive substances (NPS). N-ethylpentedrone (NEPD) self-administration was reported, making it important to elucidate its metabolic pathway to improve its detection. NEPD is often taken together with other substances; confidently identifying its intake is important for accurate toxicological analysis and understanding its toxicity. NEPD metabolism was studied following incubation with human hepatocytes and analysis by liquid chromatography-high-resolution mass spectrometry paired with Compound Discoverer software (Thermo Fisher Scientific). Prediction of possible metabolites was performed with the online software GLORYx. In vivo NEPD metabolism was evaluated by …

Trajectory Of Iron And Red Cell Parameters In Moderately Anemic Iron-Deficient Pregnant Women Receiving Daily Iron-Folic Acid Supplementation: A Prospective Cohort Study, J. P. Akshaykirthan, Manjunath S. Somannavar, S. Yogeshkumar, M. S. Deepthy, Umesh Charantimath, Amaresh Patil, Mrutyunjaya B. Bellad, Richard Derman, Shivaprasad S. Goudar

Global Health Articles

Background/Objectives: The objective is to study the trajectories of hematologic and biochemical markers in moderately anemic pregnant women receiving oral iron supplementation throughout pregnancy. Methods: This prospective cohort study was conducted from August 2021 to September 2023 involving 315 pregnant women from rural areas of Belgaum, Karnataka, India, with hemoglobin levels between 7.0 and 9.9 g/dL and serum ferritin < 30 ng/mL and/or TSAT < 20%. Participants received iron-folic acid supplementation (IFAS) as per Anaemia Mukt Bharat guidelines. Blood samples were collected to measure various hematologic and iron markers and compared across each visits. Results: We report a complete adherence rate of 95.3% for iron and 97.8% for folic acid supplementation throughout pregnancy and also observed significant improvements in hemoglobin (9.36 (8.55, 9.74) to 12.03 (11.49, 12.72)) g/dL, hematocrit (29.93 ± 2.87 to …

Er Stress Tolerance Is Regulated By Copper-Dependent Perk Kinase Activity., Sarah E. Bond Newton, Xinglong Shi, Noah R. Beratan, Julia Perhacs, Jitendra K. Arya, Margaret K. Bond, Tali Gidalevitz, Cagla Akay-Espinoza, Donita C. Brady, Kelly L. Jordan-Sciutto

Farber Institute for Neuroscience Faculty Papers

Pancreatic/PKR-like endoplasmic reticulum (ER) kinase (PERK) is a kinase that, in response to ER stress, mediates dual homeostatic and pro-apoptotic signaling. Thus, intricate regulation is required for physiological function. Attempts to modulate PERK activity have shown that the determinants of adaptive vs. maladaptive signaling remain ambiguous. Here, with purified protein, we provide evidence that PERK binds copper, identifies residues required for interaction, and demonstrates that copper is necessary for kinase activity. Furthermore, cellular PERK activity can be modulated via copper availability, and this regulatory relationship can be manipulated to dictate ER stress tolerance. Critically, these phenomena translate to phenotypes in …

The Impact Of Myopia On Regional Visual Field Loss And Progression In Glaucoma, Anagha Lokhande, Luo Song, Yueyin Pang, Yan Luo, Louis R. Pasquale, Sarah R. Wellik, Carlos G. De Moraes, Jonathan S. Myers, Mohammad Eslami, Tobias Elze, Lucy Q. Shen, Nazlee Zebardast, David S. Friedman, Michael V. Boland, Mengyu Wang

Wills Eye Hospital Papers

PURPOSE: The purpose of this study was to investigate the impact of myopia on regional visual field (VF) loss and progression in glaucoma.

METHODS: We included 112,633 24-2 VFs; longitudinal analyses comprised patients with at least 5 reliable VFs over 4 years. The degree of myopia was measured by spherical equivalent (SE) extracted from VF testing. Linear and Cox regressions determined the impact of myopia on regional VF loss and progression, respectively. We calculated three VF progression outcomes: (1) mean deviation (MD) progression: MD slope < 0; (2) total deviation (TD) pointwise progression: at least 3 TD locations with TD slope ≤-1 decibels (dB)/year; (3) MD fast progression: MD slope ≤-1 dB/year (P value < 0.05). Longitudinal analyses were conducted for all subjects and with exclusion of patients with high myopia (SE ≤-6.00 diopters [D]).

RESULTS: More negative SE values were associated with worse TD values in the paracentral VF …

Impact Of Tricuspid Regurgitation On The Clinical Outcomes Of Patients With Heart Failure, Muhammad U. Almani, Rasha Khan, Noor Fatima, Muhammad Yousuf, Aman Amanullah

Einstein Health Papers

BACKGROUND: Tricuspid regurgitation (TR) is a common occurrence in patients with heart failure (HF), and its role in disease progression has gained attention in recent years. Although TR can worsen clinical outcomes in HF patients, the impact of gender, racial, and socioeconomic factors remains largely unexplored. With growing evidence supporting the role of percutaneous interventions for the treatment of significant TR, understanding these disparities is more crucial than ever.

METHODS: Data were extracted from the National Inpatient and National Readmission 2016-2020 Databases. We used ICD-10 code I50 to identify the patients primarily admitted for HF and subdivided the cohort into …

Bard1: A Friend Or Foe In Pancreatic Ductal Adenocarcinoma?, Lily Zekavat, Aditi Jain

Department of Surgery Faculty Papers

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid malignancy with poor overall prognosis and limited response to standard treatments. Growing interest in the modulation of DNA repair mechanisms, including the homologous recombination (HR) repair pathway, has opened new avenues for therapeutic development. BARD1 (BRCA1-Associated RING Domain 1) plays a complex role in tumor biology, functioning either as a tumor suppressor or as an oncogenic driver, depending on isoform expression, cellular context, and regulatory environment. In this review, we examine the dual roles of BARD1, focusing on its regulation and paradoxical activities in PDAC. We summarize evidence that BARD1 and BARD1 …

Distinct Transcriptional Regulation Of The Wnt And Tgfβ Signaling Families Associated With Wound Healing And Fibrotic Outcomes To Lens Injury, Catherine Lalman, Kylie R. Stabler, Joshua Disatham, Lisa A. Brennan, Marc Kantorow, Janice L. Walker

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Posterior capsule opacification (PCO) is a fibrotic complication of cataract surgery caused by aberrant repair of residual lens cells. It remains unclear how the lens injury response shifts toward a pathological repair process. Here, we performed a transcriptional analysis of two major pro-fibrotic pathways, the TGF-β superfamily and Wnt signaling pathways to determine how they are differentially regulated during regenerative wound healing versus fibrosis in a lens injury model. For these studies, RNA sequencing was performed on an ex vivo lens explant system that models post-surgical healing within regenerative and fibrotic microenvironments, from 0 to 3 days post-injury. Fibrotic conditions …

The Colonic Crypt: Cellular Dynamics And Signaling Pathways In Homeostasis And Cancer, Anh L. Nguyen, Molly A. Lausten, Bruce M. Boman

College of Life Sciences Faculty Papers

The goal of this review is to expand our understanding of how the cellular organization of the normal colonic crypt is maintained and elucidate how this intricate architecture is disrupted during tumorigenesis. Additionally, it will focus on implications for new therapeutic strategies targeting Epithelial-Mesenchymal Transition (EMT). The colonic crypt is a highly structured epithelial unit that functions in maintaining homeostasis through a complex physiological function of diverse cell types: SCs, transit-amplifying (TA) progenitors, goblet cells, absorptive colonocytes, Paneth-like cells, M cells, tuft cells, and enteroendocrine cells. These cellular subpopulations are spatially organized and regulated by multiple crucial signaling pathways, including …

Cardiomyocyte Regeneration Therapy And Its Effect On Lvef And Scar Size- A Systematic Review And Meta-Analysis, Mahnoor Mahnoor, Syed Irtaza Hassan, Muhammad Bakhtiar, Salal Sharjeel, Roha Daneyal, Muhammad Ibrahim, Raheel Iftikhar

Kimmel Cancer Center Faculty Papers

BACKGROUND: Myocardial infarction (MI) results in loss of cardiomyocytes leading to heart failure. Despite advancements in pharmacotherapy and interventions such as revascularization, ischemic heart failure remains a challenge. Recent advancements in stem cell therapies, genetic engineering and bioengineering have shown to improve cardiac function and quality of life.

METHODOLOGY: Following PRISMA guidelines, randomized controlled trials clinical trials from last 12 years were systematically reviewed. All the patients included in these studies had ischemic heart failure and were subjected to different types of stem cell therapies. Protocol for this meta-analysis is registered on PROSPERO (Registration no: CRD42023399263). Data extraction and Quality …

Dynamics And Malleability Of Plant Dna Methylation During Abiotic Stresses, Niraj Lodhi, Rakesh Srivastava

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Epigenetic regulation, particularly DNA methylation, plays a crucial role in plant adaptation to environmental stresses by modulating gene expression without altering the underlying DNA sequence. In response to major abiotic stresses such as salinity, drought, heat, cold, and heavy metal toxicity, plants undergo dynamic changes in DNA methylation patterns. These modifications are orchestrated by DNA methyltransferases and demethylases with variations depending on plant species, genetic background, and ontogenic phase. DNA methylation affects the expression of key genes involved in cellular, physiological, and metabolic processes essential for stress tolerance. Furthermore, it contributes to the establishment of stress memory, which can be …

Astrocytes Expressing Mutant Hnrnpa1 Induce Non-Cell-Autonomous Motor Neuron Death, Qinxue Wu, Xionghao Liu, Tingting Zhang, Shiquan Cui, Bo Huang, Cao Huang, Qilin Cao, Xu-Gang Xia, Hongxia Zhou

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pathogenic mutation of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is causative to amyotrophic lateral sclerosis (ALS). Neuron death resulting from pathogenic hnRNPA1 may not require its presence across all pertinent cells types, including neurons, glia, and muscles. Rather, the exclusive presence of pathogenic hnRNPA1 in a specific cell type, such as astrocytes, may suffice to substantially alter cellular functions. Consequently, this alteration initiates abnormal interaction within intricate neuron-glia networks, culminating in non-cell-autonomous motor neuron death. To investigate the pivotal role of non-cell-autonomous neuron death in hnRNPA1-associated ALS, we developed transgenic rats overexpressing mutant hnRNPA1 in specifically astrocytes. The confined overexpression of …

Current Mechanobiological Pathways And Therapies Driving Spinal Health, Rahul Kumar, Kyle Sporn, Harlene Kaur, Akshay Khanna, Phani Paladugu, Nasif Zaman, Alireza Tavakkoli

SKMC Student Presentations and Publications

Spinal health depends on the dynamic interplay between mechanical forces, biochemical signaling, and cellular behavior. This review explores how key molecular pathways, including integrin, yeas-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), Piezo, and Wingless/Integrated (Wnt) with β-catenin, actively shape the structural and functional integrity of spinal tissues. These signaling mechanisms respond to physical cues and interact with inflammatory mediators such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), driving changes that lead to disc degeneration, vertebral fractures, spinal cord injury, and ligament failure. New research is emerging that shows scaffold designs that can …

Silvestrol Inhibits Nasopharyngeal Carcinoma Cells And Synergizes With Cx‑5461: Insights From A Proteomics Study, Maelinda Daker, Munirah Ahmad, Alan Khoo, Lu Ping Tan, Siok-Fong Chin, Siaw San Hwang, Paul Neilsen

Department of Medical Oncology Faculty Papers

Nasopharyngeal carcinoma (NPC) is a cancer arising from the epithelial cells of the nasopharynx, which is rare in Western countries but extremely prevalent in Borneo and the Southern China region. Present-day hurdles in NPC treatment that lead to poor quality of life and poor survival include distant metastasis and resistance to chemoradiotherapy. Silvestrol and its 5'''-epimer, episilvestrol, are compounds isolated from the plant Aglaia stellatopilosa, which is endemic to Borneo. Silvestrol, a protein synthesis inhibitor, preferentially inhibits the translation of cancer-associated mRNAs. CX-5461 is an inhibitor of RNA polymerase I that catalyzes rRNA synthesis. The present study sought to …