Medical Molecular Biology Commons^™

Expression Spectrum Of Te-Driven Transcripts In Human Adult Tissues, Benpeng Miao, Xinlong Luo, Amina Ademovic, Yushan Yang, Tao P Wu, Bo A Zhang

Faculty, Staff and Students Publications

Background

Transposable elements (TEs) are vital components of eukaryotic genomes and have played a critical role in genome evolution. Although most TEs are silenced in the mammalian genome, increasing evidence suggests that certain TEs are actively involved in gene regulation during early developmental stages. However, the extent to which human TEs drive gene transcription in adult tissues remains largely unexplored.

Results

In this study, we systematically analyze 17,329 human transcriptomes to investigate how TEs influence gene transcription across 47 adult tissues. Our findings reveal that TE-driven transcripts are broadly expressed in human tissues, contributing to both housekeeping functions and tissue-specific …

De Novo Variants In The Splicing Factor Gene Sf3b1 Are Associated With Neurodevelopmental Disorders, Kevin Uguen, Tiffany Bergot, Marie-Pier Scott-Boyer, Solène Chapalain, Camille Desdouets, Séverine Commet, Changlian Zhu, Yiran Xu, Yangong Wang, Tony Roscioli, Frederic Tran-Mau-Them, Laurence Faivre, Julien Maraval, Julian Delanne, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Céline Jost, Marc Planes, Susan Hiatt, Patricia Wheeler, Claudia Gonzaga-Jauregui, Heng Wang, Baozhong Xin, Valerie Sency, Michael C Kruer, Somayeh Bakhtiari, Patrick Sulem, Cynthia Curry, Trine Prescott, Gertrud Strobl-Wildemann, Theresa Brunet, Martine Doco Fenzy, Thomas Courtin, Céline Poirsier, Trine Bjørg Hammer, Christina D Fenger, Melissa Macpherson, Kosuke Izumi, Jacqueline Leonard, Dong Li, Elaine H Zackai, Ian A Glass, Scott Ward, Philippe M Campeau, Maria Carla Hermida Borroto, Laurence Le Moigno, Hilde Van Esch, Liesbeth De Waele, Daniel G Calame, James R Lupski, Giulia Barcia, Cristina Peduto, Pauline Planté-Bordeneuve, Lucie Dupuis, Roberto Mendoza-Londono, Dimitri J Stavropoulos, Jennifer Gillibert-Duplantier, Thomas Besnard, Laura Do Souto Ferreira, Benjamin Cogné, Stéphane Bézieau, Arnaud Droit, Laurent Corcos, Eric Lippert, Claude Férec, Sebastien Küry, Delphine G Bernard

Faculty, Staff and Students Publications

SF3B1 is an essential and ubiquitous splicing factor that plays a pivotal role in the early steps of pre-mRNA splicing. Recurrent somatic missense mutations in SF3B1 are frequent in cancers, but no constitutional variant has been reported so far. We describe here a cohort of 26 individuals with neurodevelopmental disorders, harbouring SF3B1 constitutional heterozygous variants that appeared mostly de novo. Patients present with a global developmental delay, associated with variable neurological and facial dysmorphic traits. A dichotomy may emerge between patients harbouring predicted loss of function (n = 9) and missense variants (n = 17), the latter being associated with …

Gh Alters Lymphatic Vessels In Female Mice And Stat5 Phosphorylation In Human Lymphatic Endothelial Cells, Christopher Walsh, Emily Scott, Elise Wagner, Jerome Walsh, Shashank Reddy, Arshad Ahmad, Reetobrata Basu, Eva Sevick-Muraca, Rich Brody, Uday Sandbhor, Sebastian Neggers, John J Kopchick

The Brown Foundation: Institute of Molecular Medicine

Disruption of lymphatic function underlies a broad spectrum of inflammatory and metabolic disorders, yet the hormonal pathways that regulate lymphatic biology remain poorly defined. GH, which is implicated in similar disease states, has an unclear role in lymphatic homeostasis. To address this gap, we investigated how chronic alterations in GH signaling alter lymphatic structure and function. Using transgenic mouse lines with increased, decreased, or absent GH action, we quantified the effect of GH on lymphatic pumping rate and lymphangiogenic remodeling during wound healing using near-infrared fluorescent imaging. We also measured markers of lymphatic endothelial cells using Western blot and immunohistochemistry …

Pathways, Outputs And Impact Of Nih-Supported Bioinformatics And Genomics Graduate Trainees In Africa, Daudi Jjingo, Andrew Walakira, Suhaila Hashim, Cisse Cheickna, Ronald Galiwango, Caleb Kibet, Florence N Kivunike, Gerald Mboowa, Fredrick Elishama Kakembo, Babajide Ayodele, Jean-Baka Domelevo Entfellner, Santie De Villiers, Karen Wambui, Segun Fatumo, Tinashe Chikowore, John Mukisa, Alfred Ssekagiri, Nicholas Bbosa, Julius Mulindwa, Samuel Kyobe, Mike Nsubuga, Grace Kebirungi, Eric Katagirya, Savannah Mwesigwa, Ibra Lujumba, Rogers Kamulegeya, Samuel Kirimunda, Stephen Kanyerezi, Shahiid Kiyaga, Ivan Sserwadda, Davis Kiberu, Bernard S Bagaya, Julius Okwir, Patricia Nabisubi, Grace Nabakooza, Mugume Twinamatsiko Atwine, Ricard Sserunjogi, Rolanda Julius, Mariam Quiñones, Meghan Mccarthy, Phillip Cruz, Karlynn Noble, Christopher J Whalen, Darrell Hurt, Maria Y Giovanni, Michael Tartakovsky, Deogratius Ssemwanga, John M Kitayimbwa, Steven J Reynolds, Christopher C Whalen, Andrew Kambugu, Neil A Hanchard, Li Jian, Peter Amoako-Yirenkyi, Graeme Mardon, I King Jordan, Samson Pandam Salifu, Mamadou Wele, Ezekiel Adebiyi, Jeffrey G Shaffer, Seydou Doumbia, David Patrick Kateete, Michelle Skelton, Nicola Mulder, Jonathan K Kayondo, Daniel Masiga, H3africa Consortium

Faculty, Staff and Students Publications

Global biomedical and health research is increasingly relying on genomic and computational approaches, largely driven by the increasing volumes of nucleic acid sequencing. Concurrently, epidemiological studies and clinical records are generating enormous amounts of data amenable to disease modeling, machine learning, and artificial intelligence techniques. Bioinformatics and data science expertise is therefore essential for improved population health. Accordingly, in 2012, the US National Institutes of Health (NIH) in partnership with the Wellcome Trust, and with support from the African Society for Human Genetics, initiated the H3Africa (Human Heredity and Health in Africa) consortium. One of its key goals was to …

Anti-Csf-1r Therapy With Combined Immuno-Chemotherapy Coordinate An Adaptive Immune Response To Eliminate Macrophage Enriched Triple Negative Breast Cancers, Diego A Pedroza, Xueying Yuan, Fengshuo Liu, Hilda L Chan, Christina Zhang, William Bowie, Alex J Smith, Sebastian J Calderon, Nadia Lieu, Weiguo Wu, Paul Porter, Poonam Sarkar, Na Zhao, Constanze V Oehler, Ondrej Peller, M Waleed Gaber, Qian Zhu, Charles M Perou, Xiang H-F Zhang, Jeffrey M Rosen

Faculty, Staff and Students Publications

Women diagnosed with metastatic triple negative breast cancer (mTNBC) have limited treatment options, are more prone to develop resistance and are associated with high mortality. A cold tumor immune microenvironment (TIME) characterized by low T cells and high tumor associated macrophages (TAMs) in mTNBC is associated with the failure of standard-of-care chemotherapy and immune checkpoint blockade (ICB) treatment. We demonstrate that the combination of immunomodulatory low-dose Cyclophosphamide (CTX) coupled with anti-CSF-1R antibody targeted therapy (SNDX-ms6352) and anti-PD-1 (ICB), was highly effective against aggressive metastatic Trp53 null TNBC transplantable syngeneic models that present with high macrophage infiltration. Mechanistically, CSF-1R inhibition along …

The Role Of Bacteriophage In The Rgg1-Mediated Virulence Control Of Streptococcus Pyogenes, Yuan Tian

Dissertations and Theses

In Streptococcus pyogenes, bacteriophages and other horizontally transmissible elements (HTEs) comprise approximately 10% of the genome, and each clinical isolate carries a unique combination of these elements, contributing to genetic diversity, virulence, antibiotic resistance, and immune evasion. Previously, our laboratory identified binding sites of the transcriptional regulator Rgg1 in the clinical isolate NZ131 and demonstrated that Rgg1 influences genome-wide gene expression, including bacteriophage genes. In the clinical isolate SF370, the prophage SpyCIM1, positioned in the chromosome between the mutL and mutS genes, controls DNA mismatch repair through excision and reintegration into the chromosome. In the integrated form, the prophage displaces …

Corticotropin-Releasing Factor Neurons In The Bed Nucleus Of The Stria Terminalis Modulate Avoidance Behaviors And Feeding, Juan Manuel Romero, Shae-Marie Stafford-Trujillo, Mitzy Mendoza, Pey-Shyuan Chin, Snigdha Srivastava, Mikhail Kochukov, Qingchun Tong, Benjamin Russell Arenkiel

The Brown Foundation: Institute of Molecular Medicine

Introduction: Animals rely on defensive avoidance of exposed or potentially threatening environments as a fundamental survival strategy, often expressing this behavior as thigmotaxis, or a preference for the periphery of an open space. However, researchers still do not understand how neural circuits coordinate avoidance behavior with competing physiological drives such as feeding. In this study, we investigate how corticotropin-releasing factor (CRF)-expressing neurons in the bed nucleus of the stria terminalis (BNST) integrate environmental avoidance and feeding behavior.

Methods: We used adult male and female mice and applied fiber photometry to monitor BNST CRF neuronal activity in vivo. We performed both …

From Fog To Function: An Occupational Therapist's Guide To Evaluating And Treating Cancer-Related Cognitive Impairments, Lauren E. Toner

Entry-Level Occupational Therapy Doctorate - Doctoral Capstone Symposium

Cancer – related cognitive impairment (CRCI) is a common side effect of cancer treatment that interferes with cancer survivors’ occupational performance, independence, and quality of life. Despite its high prevalence, CRCI remains under recognized and inconsistently addressed within oncology care. About 70% of individuals diagnosed with cancer report cognitive changes during or after treatment, yet many do not receive treatment. Occupational therapists are clinically trained to evaluate and treat functional cognition, activities of daily activities, instrumental activities of daily living, and client centered goals, positioning them as key providers in addressing CRCI. However, limited occupational therapy specific resources have hindered …

Sexually Dimorphic Effects Of Gpnmb Modulation On Vertebral Bone Mass Regulation And Intravertebral Disc Health, Hakem Altawil, Fayez Safadi

Williams Honors College, Honors Research Projects

Osteoporosis and vertebral degeneration are major contributors to musculoskeletal morbidity, yet the molecular mechanisms regulating vertebral bone and intervertebral disc (IVD) homeostasis remain incompletely understood. GPNMB (osteoactivin) has been identified as a regulator of bone remodeling, though its role in spine health is unclear. This study evaluated the effects of GPNMB deficiency on lumbar vertebral bone microarchitecture and IVD integrity in a sex-dependent context.

Six-month-old male and female wild-type (WT) and GPNMB knockout (KO) mice were analyzed using micro–computed tomography (µCT) of lumbar vertebrae (L4–L6) and histological assessment of the L5–L6 IVD. KO males exhibited increased bone volume fraction, bone …

Unlocking The Power Of Cxcr2 Inhibition To Overcome Gemcitabine Resistance In Pancreatic Cancer, Caitlin Molczyk, Reegan Sturgeon, Sugandha Saxena, Esther Johnson, Rakesh Bhatia, Namita Bhyravbhatla, Sushil Kumar, Surinder K. Batra, Rakesh K. Singh

Journal Articles: Biochemistry & Molecular Biology

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related mortality, characterized by intrinsic resistance to conventional therapies and limited effective treatment options. In this study, we investigated the role of the CXCR2 axis in PDAC therapy resistance. CXCR2, a chemokine receptor, is actively involved in inflammation, tumor angiogenesis, and metastasis. Our working hypothesis is that CXCR2 contributes to PDAC chemotherapy resistance. To test this, we generated gemcitabine-resistant (GemR) lines using T3M4 and CD18/HPAF (CD18) cell lines. Baseline expression of CXCL1, CXCL5, and CXCL8 ligands was higher in GemR cells compared to parental cells. Upon gemcitabine treatment, parental cells …

Midkine (Mdk) As A Central Regulator Of The Tumor Microenvironment: From Developmental Cytokine To Therapeutic Target, Hareesh B. Nair, Ajay Nair, Ya-Guang Liu, Dileep K. Vijayan, Ramadevi Subramani, Rajkumar Lakshmanaswamy, Suryavathi Viswanadhapalli, Gangadhara R. Sareddy, Surinder K. Batra, Ratna K. Vadlamudi

Journal Articles: Biochemistry & Molecular Biology

Midkine (MDK) is an oncofetal, heparin-binding cytokine that is re-expressed across diverse cancers and correlates with aggressive disease and treatment resistance. This review synthesizes current evidence on MDK as a coordinator of tumor-intrinsic signaling and microenvironmental remodeling. We summarize MDK structural features, extracellular matrix interactions, and receptor systems that mediate MDK signaling, highlighting LRP1 and PTPRZ1 with context-dependent participation of ALK, nucleolin and integrins. Downstream, MDK engages MAPK, PI3K-AKT, STAT3 and NF-κB pathways to promote tumor cell survival, epithelial-mesenchymal plasticity, and therapeutic stress tolerance. We then focus on tumor microenvironment (TME) programs shaped by MDK, including angiogenesis, fibroblast activation and …

Tick Lipocalin Triggers Mammalian Igfbp-3-Mediated Apoptosis In Macrophages And Keratinocytes, Krittika Nandy, P. P. Mahesh, Lichao Liu, Daniel E. Sonenshine, Hameeda Sultana, Girish Neelakanta

Biological Sciences Faculty Publications

Ticks secrete several molecules, including lipocalins, in their saliva during blood feeding on a vertebrate host. In this study, we provide novel evidence on the role of Ornithodoros turicata americanus tick lipocalin (Otlip) in modulating cytokine expression and in triggering apoptosis in mammalian macrophages and keratinocytes. The cytokine array analysis revealed significantly increased secretion of insulin-like growth factor-binding protein 3 (IGFBP3) from murine macrophage cell line upon treatment with recombinant Otlip protein (rGST-Otlip) when compared to the secretion noted from cells treated with a control protein (rGST). Similar observation with cytokine protein array analysis was noted when murine macrophages were …

The Influence, Dependency, And Targeting Of Fatty Acid Uptake In Er+ Breast Cancer, Abigail E. Goen

Dartmouth College Ph.D Dissertations

Estrogen Receptor-positive/ Human Epidermal Growth Factor 2-negative, breast cancer (ER+/HER2- BC) is the most prevalent subtype of BC, impacting millions of individuals. Although early screening and treatment with endocrine therapy has greatly enhanced survival, this subtype sustains a steady increase of risk for recurrent disease for decades after diagnosis, indicating the persistence of residual cancer cells that are capable of maintaining dormancy for >20 years prior to metastatic outgrowth. Dormant cells reprogram metabolic pathways which can be profoundly influenced by the tumor microenvironment in promoting quiescence or proliferation. Fatty acid oxidation dependency has been noted as a hallmark of drug …

Manuka Honey Modulates Oxidative Stress In Neuro2-A Cells Through Mitochondrial Regulation, Rachel Abramovici

Honors Undergraduate Theses

Manuka honey is known for its vital usage in wound healing, being an agonist towards fighting infections, and is an acting antioxidant [32]. Its main constituents are flavonoids and phenolic compounds, with methyl syringate (MSYR) being a major active ingredient. The specific compounds responsible for these antioxidant effects, particularly in the CNS, remain unclear. It is hypothesized that pre-treatment of mouse neuroblastoma cells with MSYR followed by hydrogen peroxide exposure will activate the AMPK/SIRT1/PGC-1a pathway, due to MSYR’s phenolic structure, and thus reduce oxidative stress and improve mitochondrial biogenesis. Hydrogen peroxide is a standard reactive oxygen species (ROS) treatment to …

Endometriosis From Initiation To Innovation: Immune Microenvironments, Clonal Lesion Biology, And The Emerging Therapeutic Pipeline, Bindu Santhamma, Jessica Chacon, Eva Deemer, Dorota Stary, Shayla A. Hernandez, Ramadevi Subramani, Rajkumar Lakshmanaswamy, Klaus J. Nickisch, Surinder K. Batra, Hareesh B. Nair

Journal Articles: Biochemistry & Molecular Biology

Endometriosis is a chronic, estrogen-dependent inflammatory disease that, despite its benign histology, displays several cancer-relevant features, including clonal expansion, somatic alteration-associated lesion evolution, tissue invasion, apoptosis resistance, immune evasion, angiogenesis, fibrosis, and metabolic adaptation. These features are particularly important in ovarian endometriosis, where recurrent hemorrhage, iron-driven oxidative stress, and chronic inflammatory remodeling may promote malignant transformation. This review examines endometriosis through an oncologic framework by integrating current evidence on disease initiation, clonal lesion evolution, and the peritoneal, ovarian, and deep-infiltrating microenvironments. We discuss how epithelial, stromal, immune, endothelial, mesothelial, and neural components cooperate to support lesion survival, dissemination, vascularization, fibrosis, …

Slc22a3/Oct3 Drives Serotonin-Mediated Stemness In Pancreatic Cancer, Nivedeta Krishna Kumar, Venkatesh Varadharaj, Neelanjana Gayen, Annant Bir Kaur, Kirtana Arikath, Ashu Shah, Poompozhil Mathivanan, Palanisamy Nallasamy, Zahraa Wajih Alsafwani, Bhuvaneshwari Seshadri, Pratima Raut, Sanchita Rauth, Jimmie Persinger, Sandipan Brahma, Micah Schott, Rebecca E. Oberley-Deegan, Geoffrey A. Talmon, Jesse L. Cox, Surinder K. Batra, Moorthy P. Ponnusamy

Journal Articles: Biochemistry & Molecular Biology

Pancreatic cancer (PC) is a highly aggressive malignancy, with cancer stem cells (CSCs) playing a critical role in metastasis, therapy resistance, and recurrence, thereby presenting significant treatment challenges. Emerging evidence suggests that normal embryonic and adult progenitor stem cells share common gene signatures with CSCs. However, the early pluripotency-associated factors and stemness programs that become aberrantly reactivated during oncogenic transformation remain poorly defined. Here, we identify SLC22A3/OCT3 (Solute Carrier Family 22 Member 3) as a reactivated embryonic-associated signature that regulates PC stemness. SLC22A3 is markedly upregulated in CSC-enriched populations, and its silencing in PC cells grown in both 2D cultures …

Rac1 Gtpase Regulates The Scfβtrcp-Mediated Degradation Of Claspin And The Cellular Response Of Pancreatic Cancer Cells To Gamma Rays, Neha Chaudhary, Tabbatha N. Somers, Surinder K. Batra, Ying Yan, Michel M. Ouellette

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND/OBJECTIVES: Pancreatic ductal adenocarcinomas (PDACs) are lethal tumors exhibiting resistance to most cancer therapeutics, particularly DNA-damaging agents. The

METHODS: Western blot analyses were used to assess the impacts of Rac1 inhibition on the components of the ATR/Chk1 cascade.

RESULTS: Here, we show that Rac1 inhibition disrupts ATR/Chk1 signaling by promoting degradation of Claspin, a key component of the fork protection complex needed for the Ser345-phosphorylation of Chk1 by ATR. In PDACs and normal pancreatic ductal cells, Rac1 inhibition (via inhibitors or siRNA) decreased Claspin protein levels without affecting its mRNA, reflecting a >3-fold reduction in Claspin's half-life. Claspin contains a …

Extracellular Vesicles In Prostate Cancer: Current Understanding And Future Perspectives, Balaji Perumalsamy, Parthasarathy Seshacharyulu, Raghupathy Vengoji, Nicole Shonka, Benjamin A. Teply, Surinder K. Batra, Sakthivel Muniyan

Journal Articles: Biochemistry & Molecular Biology

Exosomes are nanoscale, lipid bilayer extracellular vesicles (EVs) actively secreted by cells under both physiological and pathological conditions. As key mediators of intercellular communication, exosomes carry a diverse array of molecular cargo, including nucleic acids, proteins, lipids, and metabolites, which can influence the function of recipient cells. Based on evidence from 2016–2025 across PubMed, Embase, the Cochrane Library, and clinicaltrials.org, this review consolidates current understanding of exosome biology in prostate cancer (PCa). We discuss exosome biogenesis, molecular cargo composition, and their functional roles in tumor progression, angiogenesis, immune evasion, metastasis, and therapy resistance of PCa. We emphasize the biomarker potential …

The Underexplored Complexity Of Pancreatic Cancer: Early Dissemination And Quiescence, Nivedeta Krishna Kumar, Annant Bir Kaur, Surinder K. Batra, Moorthy P. Ponnusamy

Journal Articles: Biochemistry & Molecular Biology

Pancreatic cancer has been renowned for its aggressive nature and occasionally manifests periods of dormancy, presenting a perplexing challenge in studying disease progression. Despite surgery, many patients relapse due to dormancy and chemoresistance, resulting in recurrence and death within a few years. Studies also suggest that pancreatic cancer disseminates early on, spreading to secondary organs with no evidence of disease. The lingering question is: how, where, and when does pancreatic cancer recur and spread? Herein, we explore evidence for clinically dormant pancreatic cancer cells, examining the roles of quiescence and stemness populations and their interactions with the tumor microenvironment. Understanding …

Mucin 5ac Modulates Cancer-Associated Fibroblast Heterogeneity Through Epigenetic Reprogramming Of Precursor Cells, Rachel J. Kehrberg, Namita Bhyravbhatla, Zahraa Wajih Alsafwani, Xiaoqi Li, Gopalakrishnan Natarajan, Imran Khan, Randall E. Brand, Maneesh Jain, Surinder K. Batra, Sushil Kumar

Journal Articles: Biochemistry & Molecular Biology

Pancreatic cancer (PC) is characterized by extensive desmoplasia, with heterogeneous cancer-associated fibroblasts (CAFs) as a major component. However, the contribution of distinct precursor cells to CAF heterogeneity remains poorly defined. This study investigated the role of Muc5ac in modulating CAF heterogeneity by maturing precursor cells, including adipose-derived mesenchymal stem cells (AD-MSCs), bone marrow-derived MSCs (BM-MSCs), and pancreatic stellate cells (PSCs), into different CAF subsets. RNA sequencing of precursor cells treated with conditioned media from Muc5ac-proficient or -deficient cancer cells revealed distinct transcriptional profiles. Muc5ac significantly modulated the expression of Dnmts and Tets in AD-MSCs, promoting the acquisition of extracellular matrix …