Medical Genetics Commons^™

Poly(A) Probe Hcr Rna-Fish Specifically Marks Pyriform Nurse Cells In The Brown Anole Lizard Ovary, Zoe B Griffin, Bonnie K Kircher, Richard R Behringer

Faculty, Staff and Student Publications

Hybridization chain reaction RNA-fluorescent in situ hybridization (HCR RNA-FISH) is a powerful and increasingly used method for visualizing gene expression in cells and tissues. A probe set against polyadenylated RNA (poly(A)) is often used as a positive control for RNA integrity and staining quality. While optimizing this technique in the ovary of the brown anole lizard (Anolis sagrei), we found that the poly(A) probe produced a strikingly specific and intense signal in pyriform cells, a specialized lizard-specific nurse cell type. This staining pattern was found in both whole-mount samples and paraffin sections, suggesting that poly(A) signal intensity can serve as …

Wnt4 Deficiency Impacts Heart, Diaphragm, And Palate Development: Insights From Human Genetics, Machine Learning, And Mouse Models, Andrés Hernández-García, Bum Jun Kim, David Chitayat, Patrick Shannon, Stephanie Hedges, Maria Al Bandari, Maria J Guillen Sacoto, Emily Anne Bates, Yunus H Ozekin, Victor Faundes, Pamela N Luna, Chad A Shaw, Tara L Rasmussen, Chih-Wei Hsu, Daryl A Scott

Faculty, Staff and Students Publications

WNT4 is a secreted protein that plays a critical role in the regulation of cell fate and embryogenesis. Biallelic variants in WNT4 have been linked to SERKAL syndrome, an autosomal recessive disorder characterized by 46,XX sex reversal and dysgenesis of the kidneys, adrenals, and lungs. SERKAL syndrome has only been described in a single consanguineous kindred with four affected fetuses. Additional features seen in a subset of affected fetuses included ventricular septal defect (VSD), congenital diaphragmatic hernia (CDH), and orofacial clefting (OFC). To determine if these additional features were likely to be caused by WNT4 deficiency, we used machine learning …

Alternative Polyadenylation Signatures Distinguish Maladaptive Right Ventricular Remodeling In Pulmonary Hypertension: Implications For Rna-Based Diagnostics And Therapeutics, Janani Subramaniam, Venkata Jonnakuti, Scott D Collum, Sandra Martineau, Kai-Lieh Huang, Sandra Breuils-Bonnet, Andrea L Frump, Bindu H Akkanti, Jayeshkumar A Patel, Manish K Patel, Ismael Salas De Armas, Isabella N Lefebvre, Rajko Radovancevic, Elvin Blanco, Eric J Wagner, Igor Gregoric, Sriram Nathan, Biswajit Kar, Steeve Provencher, Sebastien Bonnet, François Potus, Hari Krishna Yalamanchili, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

Increased pulmonary vascular pressures due to vascular remodeling, elevated vascular resistance, and vasoconstriction characterize Pulmonary Arterial Hypertension (PAH). The narrowing of the pulmonary arteries and obstruction of blood flow increase the Right Ventricular (RV) afterload, forcing the RV to undergo structural and functional changes. While adaptive remodeling leads to RV compensation by maintaining function, maladaptive remodeling leads to RV decompensation, characterized by worsening function and eventual failure. At present, there is no effective treatment for these patients as therapies for left ventricular failure are ineffectual, and there are no therapies specifically targeting the RV. Therefore, there is a clear need …

Organ Chips And Translational Research: Identifying And Examining New Ethical Issues, Melanie Jeske

Center for Medical Ethics and Health Policy Staff Publications

Organ chips, also known as organ-on-a-chip devices, tissue chips, or microphysiological systems, have emerged over the last decade as a promising translational technology amidst growing concern about the translational crisis between laboratory research and patient bedside. Pointing to high rates of failure between nonhuman animal models and safety and efficacy in humans, organ chips and similar new approach methods have attracted substantial public and private investment. As human-cell-based alternatives to animal models, organ chips promise more predictive, efficient, and ethical platforms for pharmaceutical and toxicity testing. Engineered cultivation systems that enable cells to assemble into tissue-like structures (e.g. kidney, brain, …

Sex Differences In Bile Acid Homeostasis And Excretion Underlie The Disparity In Liver Cancer Incidence Between Males And Females, Megan E Patton, Sherwin Kelekar, Lauren J Taylor, Angela E Dean, Qianying Zuo, Rhishikesh N Thakare, Sung Hwan Lee, Emily C Gentry, Morgan Panitchpakdi, Pieter Dorrestein, Yazen Alnouti, Zeynep Madak-Erdogan, Ju-Seog Lee, Milton J Finegold, Sayeepriyadarshini Anakk

Faculty, Staff and Student Publications

Hepatocellular carcinoma (HCC), the common liver cancer, exhibits higher incidence in males. Here, we report that mice lacking bile acid (BA) regulators, Farnesoid X Receptor (FXR also termed NR1H4) and Small Heterodimer Partner (SHP also termed NR0B2), recapitulate the sex difference in liver cancer risk. Since few therapeutic options are available, we focused on understanding the intrinsic protection afforded to female livers. Transcriptomic analysis in control and NR1H4 and NR0B2 double knockout livers identified female-specific changes in metabolism, including amino acids, lipids, and steroids. To assess translational relevance, we examined if transcriptomic signatures obtained from this murine HCC model correlate …

Batf2 Is A Glutamine-Responsive Tumour Suppressor Required For Type-I Interferon-Dependent Anti-Tumour Immunity, Wang Gong, Hülya F Taner, Yuesong Wu, Yumin He, Xingwu Zhou, Zaiye Li, Xin Hu, Charisse Ursin, Kala Chand Debnath, Kohei Okuyama, Qiang Hu, Christopher R Donnelly, Felipe Nör, Chamila D Perera, Emily Bellile, Arash Yunesi, Zhiqian Zhai, Mei Zhao, Wanqing Cheng, Zackary R Fitzsimonds, Luke Broses, Jiaqian Li, Shadmehr Demehri, Deepak Nagrath, Gregory T Wolf, Andrew G Sikora, Yanbao Yu, Haitao Wen, Lei Wei, Steven B Chinn, Jeffrey N Myers, Shizuo Akira, Yuying Xie, James J Moon, Yu Leo Lei

Faculty, Staff and Student Publications

Recent evidence highlights the significance of a new type of tumour suppressors, which are not frequently mutated but inhibited by metabolic cues in cancers. Here, we identify BATF2 as a tumour suppressor whose expression is epigenetically silenced by glutamine in Head and Neck Squamous Cell Carcinomas (HNSCC). BATF2 correlates with type-I interferon and Th1 signatures in human HNSCC, with correlation coefficients even stronger than those of the positive control, STING. The phosphorylation of BATF2 at serine 227 promotes the oligomerization of STING. BATF2 deficiency or high glutamine levels result in higher oxygen consumption rates and metabolic profiles unfavorable for …

Sox11 Modulates Bcr Signaling Through The Pax5/Cd19 Axis For Therapeutic Targeting In Btk-Resistant Mantle Cell Lymphoma, Rudra Prasad Dutta, Heng-Huan Lee, Violetta V Leshchenko, Ravi Prakash Shukla, Fangfang Yan, Yang Liu, H Ümit Kaniskan, Xing Qiu, Jian Jin, Lapo Alinari, Michael Wang, Samir Parekh

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is an incurable subtype of B-cell non-Hodgkin lymphoma. Despite multiple approved Bruton tyrosine kinase inhibitors (BTKis), resistance to BTKi continues to pose a major clinical challenge. The transcription factor sex determining region Y-box 11 (SOX11) is expressed in most patients with MCL and is associated with poor outcomes. We have previously demonstrated SOX11-dependent B-cell receptor (BCR) signaling in transgenic models of MCL. Here, we report that SOX11 drives BCR signaling via the transcriptional activation of the PAX5/CD19 axis. The translational potential of these results is significant as single-cell RNA sequencing data show that SOX11 is overexpressed …

Coordinated Changes In Stromal And Hematopoietic Cells That Define The Perinatal To Juvenile Transition In The Mouse Thymus, Anusha Vasudev, Colin R Moore, Aparna Calindi, Seung Woo Kang, Bryan R Helm, Jayashree Srinivasan, Siddhartha Shah, Erin Baker, Ruiting Zong, Nandini Singarapu, Scott Casey, Andrew N Macintyre, Ken S Lau, Laura P Hale, Qi Liu, Nancy R Manley, Lauren I R Ehrlich, Ellen R Richie

Faculty, Staff and Student Publications

Perinatal T cells have distinctive phenotypes and functions that may be due in part to age-associated features of stromal cells in the perinatal thymus. We identify age-associated changes in mouse thymic epithelial cells, mesenchyme, endothelium, and hematopoietic antigen-presenting cells from birth to one month of age using single-cell transcriptional profiling, flow cytometry, and imaging. Coordinated cellular and molecular changes occur at 7-14 days of age, designated "transitional ages," as thymus growth switches to homeostasis. E2F target gene expression declines, and the expression of type I interferon response genes increases across diverse cell types at transitional ages. Alterations in thymic stromal …

Metabolomic Profiling Reveals Brain Lipid Alterations In Pex7-Deficient Models Of Rhizomelic Chondrodysplasia Punctata, Riya Sankhe, Meredith I Williams, Wedad Fallatah, Laura Mackay, Mary Layne Brown, Pranjali Bhagwat, Sarah H Elsea, Nancy Braverman, Michael F Wangler

Duncan NRI Faculty and Staff Publications

Rhizomelic chondrodysplasia punctata type 1 (RCDP1) is a peroxisomal disorder characterized by skeletal shortening, intellectual disability, seizures, cataracts, and reduced lifespans. RCDP1 is caused by biallelic loss-of-function variants in PEX7, which encodes a protein required for importing select enzymes into the peroxisome matrix, including those essential for ether lipid synthesis (e.g., plasmalogens) and the branched-chain fatty acid catabolism. Plasmalogen deficiency is a hallmark of RCDP1 and other peroxisomal disorders, including RCDP types 2-5 (RCDP2-5) and Zellweger spectrum disorders (ZSD). Here, we performed comprehensive metabolomic profiling of clinical samples from RCDP patients and Pex7-deficient mouse models. We identified profound …

Vesicle-Mediated Mitochondrial Clearance Presents An Actionable Metabolic Vulnerability In Triple-Negative Breast Cancer, Jody Vykoukal, Yihui Chen, Mingxin Zuo, Riccardo Ballarò, Monica J Hong, Hansini Krishna, Daniela B Rodriquez-Perera, Hiroyuki Katayama, Ehsan Irajizad, Ranran Wu, Ricardo A León-Letelier, Jennifer B Dennison, Angelica M Gutierrez, Adriana Paulucci-Holthauzen, Timothy C Thompson, Leona Rusling, Yining Cai, Fu Chung Hsiao, Soyoung Park, Banu Arun, Samir Hanash, Johannes F Fahrmann

Faculty, Staff and Student Publications

Selective autophagy of mitochondria is known to promote cancer cell survival and progression, including in triple-negative breast cancer (TNBC). Here, we apply an integrated multi-omics approach together with functional experimental analyses to investigate metabolic adaptations that support mitochondrial quality control in TNBC. We detail a mitochondrial quality control mechanism, complementary to mitophagy, that is enabled by a program of heightened extracellular sphingomyelin salvaging in TNBC coupled with extracellular vesicle-mediated intracellular clearance of mitochondrial damage. Targeting of this onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase, results in ceramide-mediated compensatory mitophagy and cancer cell death …

Lung Adenocarcinoma Surfaceome Remodeling With Egfr Inhibitors Uncovers Placental Alkaline Phosphatase As A Target For Combination Therapy, Yihui Chen, Rongzhang Dou, Monica J Hong, Hanwen Xu, Jody Vykoukal, Ricardo A León-Letelier, Yining Cai, Soyoung Park, Ehsan Irajizad, Fu Chung Hsiao, Jennifer B Dennison, Edwin J Ostrin, Johannes F Fahrmann, Hiroyuki Katayama, Samir M Hanash

Faculty, Staff and Student Publications

Treatment of lung adenocarcinomas (LUADs) that exhibit activated epidermal growth factor receptor (EGFR) with EGFR tyrosine kinase inhibitors (TKIs) has limited efficacy. Assessment of the impact of EGFR TKI on the LUAD surfaceome remodeling reveals potential therapeutic targets. We identify placental type alkaline phosphatase (ALPP), which has restricted expression in normal tissues, among upregulated surface proteins following EGFR TKI treatment of both TKI sensitive as well as resistant cells. EGF treatment represses ALPP expression, whereas EGFR TKIs upregulate its expression through dephosphorylation and activation of FoxO3a, a transcriptional regulator that binds to the promoter region of ALPP. The combination of …

Low-Dimensional Signatures Of Neuronal Activity Associated With Long-Term Operant Conditioning In Aplysia, Sara Vanaki, Nicholas O Gonzalez, Curtis L Neveu, Yuto Momohara, Behnaam Aazhang, John H Byrne

Faculty, Staff and Student Publications

Operant conditioning is a form of learning in which a behavior is reinforced by reward. Operant conditioning has multiple temporal domains, ranging from short-term, lasting a few minutes, to long-term, persisting for at least 24 h. The extent to which short- and long-term operant conditioning memories rely on shared or separate neural mechanisms is poorly understood. Voltage-sensitive dye (VSD) imaging has been used previously to record the activity of a large number of neurons simultaneously in the buccal ganglion to measure changes in neuronal activity during short-term operant conditioning. We examined neuronal activity using VSD 24 h after operant conditioning …

Targeting Kinesin Family Member 20a Sensitizes Stem-Like Triple-Negative Breast Cancer Cells To Standard Chemotherapy, Yayoi Adachi, Weilong Chen, Cheng Zhang, Tao Wang, Nina Gildor, Rachel Shi, Haoyong Fu, Masashi Takeda, Qian Liang, Fangzhou Zhao, Hongyi Liu, Jun Fang, Jin Zhou, Hongwei Yao, Lianxin Hu, Shina Li, Lei Guo, Lin Xu, Ling Xie, Xian Chen, Chengheng Liao, Qing Zhang

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC), being both aggressive and highly lethal, poses a major clinical challenge in terms of treatment. Its heterogeneity and lack of hormone receptors or HER2 expression further restrict the availability of targeted therapy. Breast cancer stem cells (BCSCs), known to fuel TNBC malignancy, are now being exploited as a vulnerability for TNBC treatment. Here, we dissected the transcriptome of BCSCs and identified kinesin family member 20A (KIF20A) as a key regulator of BCSC survival and TNBC tumorigenesis. Genetic depletion or pharmacological inhibition of KIF20A impairs BCSC viability and tumor initiation and development in vitro and in vivo. …

Agpat2 Acts At The Crossroads Of Lipid Biosynthesis And Drp1-Mediated Er Morphogenesis, Yoshihiro Adachi, Mauricio Torres, Allen H Hunter, Woo Jung Cho, Meixia Pan, Xianlin Han, Guangwei Du, Ling Qi, Miho Iijima, Hiromi Sesaki

Faculty, Staff and Student Publications

The morphology of the endoplasmic reticulum (ER), characterized by central sheets and peripheral tubules, is controlled by membrane-shaping proteins. However, the role of lipids in ER morphogenesis remains elusive, despite the ER being the major site for lipid synthesis. Here, by examining the role of eighteen phosphatidic acid (PA)-generating enzymes in ER morphology, we identify lysophosphatidic acid acyltransferase 2 (AGPAT2) as a critical factor in mouse and human cells. AGPAT2 produces PA in the glycerophospholipid/triacylglycerol biosynthesis pathway, and its mutations cause congenital generalized lipodystrophy. We find that AGPAT2-generated PA drives ER tubulation through gene knockout, 3D structural analysis by FIB-SEM, …

Actin Dysregulation Induces Neuroendocrine Plasticity And Immune Evasion: A Vulnerability Of Small Cell Lung Cancer, Yoojeong Seo, Shengzhe Zhang, Jinho Jang, Kyung-Pil Ko, Kee-Beom Kim, Yuanjian Huang, Dong-Wook Kim, Bongjun Kim, Gengyi Zou, Jie Zhang, Sohee Jun, Wonhong Chu, Nicole A Kirk, Ye Eun Hwang, Young Ho Ban, Shilpa S Dhar, Joseph M Chan, Min Gyu Lee, Charles M Rudin, Kwon-Sik Park, Jae-Il Park

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. Capping protein inhibiting regulator of actin dynamics (CRACD) that promotes actin polymerization, is frequently inactivated in SCLC. However, the role of CRACD loss in SCLC is unknown. Here we show that CRACD depletion drives neuroendocrine (NE) cell plasticity and immune evasion in SCLC. Mechanistically, CRACD inactivation disrupts actin organization, leading to suppression of Yap1-NOTCH signaling and subsequent NE gene upregulation. Simultaneously, CRACD loss drives EZH2-mediated histone methylation via nuclear actin disruption, leading to repression of MHC-I genes and depletion of CD8⁺ T cells. Consequently, CRACD-downregulated tumors exhibit …

Fgf13 Regulates Vgsc-Independent Cardiomyocyte Impulse Propagation Via Cx43 Trafficking, Lala Tanmoy Das, Mattia Malvezzi, Aravind R Gade, Maiko Matsui, Margaret Mckay, Eric Q Wei, Matea J Zelich, Keon Mazdisnian, Jared Kushner, Bi-Xing Chen, Isabella Distefano, Daniel Roybal, Lin Yang, Lisa Stoll, James C Lo, Marian Kalocsay, Fadi G Akar, Steven O Marx, Geoffrey S Pitt

Faculty, Staff and Student Publications

Background: FHF (fibroblast growth factor homologous factor) variants associate with arrhythmias. Although FHFs are best characterized as regulators of voltage-gated sodium channel (VGSC) gating, recent studies suggest broader, non-VGSC-related functions, including regulation of Cx43 (connexin 43) gap junctions and hemichannels, mechanisms that have generally been understudied or disregarded.

Methods: We assessed cardiac conduction and cardiomyocyte action potentials in mice with constitutive cardiac-specific Fgf13 ablation (cFgf13KO) while targeting Cx43 gap junctions and hemichannels pharmacologically. We characterized FGF13 regulation of Cx43 abundance and subcellular distribution. With proximity labeling proteomics, we investigated novel candidate mechanisms underlying FGF13 regulation of Cx43. …

Hif-2-Dependent Regulation Of Pthrp And Paraneoplastic Hypercalcemia In Aggressive Clear-Cell Renal Cell Carcinoma, Arijit Mal, Bingqing Xie, Zane Gray, Charlotte Small, Susmita G Ramanand, Yunpeng Gao, Vanina Toffessi Tcheuyap, Sashi Debnath, Alana Christie, Jeffrey Miyata, Brooklyn Jackson, Hua Zhong, Boning Gao, Jay Lohrey, Naim M Maalouf, Sangeetha M Reddy, John D Minna, Ivan Pedrosa, Xiankai Sun, Ram S Mani, Payal Kapur, James Brugarolas

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) patients with hypercalcemia (HC) have worse outcomes. HC often involves PTHrP, and the role of HIF-2 is incompletely understood. Leveraging RCC tumorgraft (TG) models of HC, which were characterized by tumor cell autonomous inflamatory/immune signatures, we show that HIF-2 inhibition with PT2399 frequently normalized calcium, downregulated circulating PTHrP and reduced HIF-2 binding to the PTHLH (PTHrP) promoter. Likely contributing to the selective induction of PTHrP in a subset of HIF-2-dependent tumors, the PTHLH locus was generally more accessible in TG(HC). However, PTHLH chromatin accessibility was grossly unaffected by PT2399, unlike elsewhere (including EPO locus in a …

Tumor Intrinsic Mettl5 Modulates Atf4 Translation To Prevent T Cell-Induced Ferroptosis In Ovarian Cancer, Jiakai Hou, Cheng-Wei Ju, Nicholas A Egan, Yanjun Wei, Yunfei Wang, Minghao Dang, Tianyi Zhou, Leilei Shi, Ningbo Zheng, Si Chen, Ashley M Guerrero, Xiaofang Liang, Wanfu Wu, Areej Akhtar, Chitra Dhiman, Debanwita Roy Burman, Andro E Gerges, Mason D Flores, Han Li, Li-Sheng Zhang, Marleen Kok, Xiaobo Mao, Linghua Wang, Qin Feng, Yiwen Chen, Sanghoon Lee, Daniel J Mcgrail, Nidhi Sahni, Chuan He, Amir A Jazaeri, Weiyi Peng

Faculty, Staff and Student Publications

Poor clinical responses to immune checkpoint blockade (ICB) observed in ovarian cancer (OC) highlight an unmet need to understand the mechanisms driving immune evasion in this disease. To address this, an integrative analysis is conducted by combining in vitro genome‐wide immune screens, in vivo ICB screens, and clinical data mining, and METTL5 is identified as a crucial OC‐intrinsic factor that promotes immune resistance. Immunologically “cold” OC tumors and poor responders to ICB exhibit elevated METTL5 expression. Mechanistically, knocking out (KO) METTL5 in OC disrupts ATF4 translation by altering 18S rRNA m6A levels, leading to the downregulation of SLC7A11 and SLC3A2 …

Kras Inhibition Activates An Actionable Cd24 "Do Not Eat Me" Signal In Pancreatic Cancer, Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Zhenzhen Xun, Phuoc T Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Ching-Fei Li, Madelaine S Theardy, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Elizabeth M Park, David H Peng, Yong Zhou, Hong Zhao, Timothy P Heffernan, Andrea Viale, Huamin Wang, Stephanie S Watowich, Han Liang, Dan Zhao, Ronald A Depinho, Wantong Yao, Haoqiang Ying

Faculty, Staff and Student Publications

KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared to the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a ‘hot’ tumor immune microenvironment. Immunoprofiling revealed that CD24, a ‘don’t eat me’ signal, is significantly upregulated on cancer …

Evidence For Improved Dna Repair In The Long-Lived Bowhead Whale, Denis Firsanov, Max Zacher, Xiao Tian, Todd L Sformo, Yang Zhao, Gregory Tombline, J Yuyang Lu, Zhizhong Zheng, Luigi Perelli, Enrico Gurreri, Li Zhang, Jing Guo, Anatoly Korotkov, Valentin Volobaev, Seyed Ali Biashad, Zhihui Zhang, Johanna Heid, Alexander Y Maslov, Shixiang Sun, Zhuoer Wu, Jonathan Gigas, Eric C Hillpot, John C Martinez, Minseon Lee, Alyssa Williams, Abbey Gilman, Nicholas Hamilton, Ekaterina Strelkova, Ena Haseljic, Avnee Patel, Maggie E Straight, Nalani Miller, Julia Ablaeva, Lok Ming Tam, Chloé Couderc, Michael R Hoopmann, Robert L Moritz, Shingo Fujii, Amandine Pelletier, Dan J Hayman, Hongrui Liu, Yuxuan Cai, Anthony K L Leung, Zhengdong Zhang, C Bradley Nelson, Lisa M Abegglen, Joshua D Schiffman, Vadim N Gladyshev, Carlo C Maley, Mauro Modesti, Giannicola Genovese, Mirre J P Simons, Jan Vijg, Andrei Seluanov, Vera Gorbunova

Faculty, Staff and Student Publications

At more than 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth1, reaching over 80,000 kg. Despite its very large number of cells and long lifespan, the bowhead is not highly cancer-prone, an incongruity termed Peto’s paradox2. Here, to understand the mechanisms that underlie the cancer resistance of the bowhead whale, we examined the number of oncogenic hits required for malignant transformation of whale primary fibroblasts. Unexpectedly, bowhead whale fibroblasts required fewer oncogenic hits to undergo malignant transformation than human fibroblasts. …

Periostin Promotes Sarcoma Growth By Promoting Tumor-Associated Macrophage Migration And Differentiation, Jin-Fen Xiao, Kristin Ishaya, Emily Y Ko, Annaliese Fowler, Marina T Broz, Jlenia Guarnerio

Faculty, Staff and Student Publications

Soft-tissue sarcomas (STS) are characterized by abundant extracellular matrix (ECM) deposition, yet the functional contribution of specific ECM components remains poorly understood. In this study, we identify periostin (POSTN), a matricellular protein, as a regulator of sarcoma progression and the tumor immune microenvironment. Analysis of human sarcoma datasets revealed that high POSTN expression correlates with poor prognosis and elevated expression of ECM-related and myeloid cell–associated genes. In murine genetic models of sarcoma, tumors expressing high levels of Postn displayed enhanced expression of ECM genes and monocyte-recruiting cytokines. Functional silencing of Postnin vivo reduced tumor growth without altering tumor cell …

Reviewing Vascular Influences On Neuronal Migration, Cortical Development, And Neurodevelopmental Disorders: Focus On Autism, Adhd And Schizophrenia, Lalit K Ahirwar, Spiros L Blackburn, Devin W Mcbride, Peeyush Kumar T

Faculty, Staff and Student Publications

During cortical development, newly born neurons migrate radially or tangentially from their origin to expand the cortex. Simultaneously, neuron-derived factors support angiogenesis, and an elaborate network of blood cerebral vessels develops in the cortex. Traditionally, blood cerebral vessels were considered to support the growing cortex or migrating neurons by providing nutrients and oxygen. However, recent studies have shed light on Endothelial cells' influence on cortical development; they guide neuronal migration by providing molecular cues and structural support. Here, we review the current understanding of how CNS cerebral vessels support neurogenesis, neuronal migration, and the formation of the six-layer cortical structure …

Smart Spatial Omics (S2-Omics) Optimizes Region Of Interest Selection To Capture Molecular Heterogeneity In Diverse Tissues, Musu Yuan, Kaitian Jin, Hanying Yan, Amelia Schroeder, Chunyu Luo, Sicong Yao, Bernhard Dumoulin, Jonathan Levinsohn, Tianhao Luo, Jean R Clemenceau, Inyeop Jang, Minji Kim, Yunhe Liu, Minghua Deng, Emma E Furth, Parker Wilson, Anupma Nayak, Idania Lubo, Luisa Maren Solis Soto, Linghua Wang, Jeong Hwan Park, Katalin Susztak, Tae Hyun Hwang, Mingyao Li

Faculty, Staff and Student Publications

Spatial omics technologies have transformed biomedical research by enabling high-resolution molecular profiling while preserving the native tissue architecture. These advances provide unprecedented insights into tissue structure and function. However, the high cost and time-intensive nature of spatial omics experiments necessitate careful experimental design, particularly in selecting regions of interest (ROIs) from large tissue sections. Currently, ROI selection is performed manually, which introduces subjectivity, inconsistency and a lack of reproducibility. Previous studies have shown strong correlations between spatial molecular patterns and histological features, suggesting that readily available and cost-effective histology images can be leveraged to guide spatial omics experiments. Here we …

Differential Effects Of Murine Stroke Models On Dopaminergic Neurons, Glial Responses, And Neurobehavioral Outcomes, Sidra Tabassum, Heng Hu, Silin Wu, Shuning Huang, Bosco Seong Kyu Yang, Chang-Hun Lee, Aaron W Gusdon, Xuefang S Ren

Faculty, Staff and Student Publications

Stroke is a leading cause of disability worldwide, often resulting in persistent motor, cognitive, and emotional impairments. While the hippocampus and amygdala play critical roles in post-stroke behavioral changes, specific neuronal alterations and prolonged glial responses within these regions across different stroke types remain unclear. This study investigates the behavioral, neuronal, and glial effects of subarachnoid hemorrhage (SAH), transient middle cerebral artery occlusion (tMCAO), and photothrombotic stimulation (PTS) in mice. SAH and tMCAO models exhibited significant motor deficits, spatial and recognition memory impairments, and increased anxiety- and depressive-like behaviors, whereas the PTS model showed similar motor and cognitive impairments but …

Inhibiting Monocyte Migration Reduces Arterial Thrombosis And Facilitates Thrombolysis, Hee Jeong Jang, Jiwon Kim, Ha Kim, Taesu Kim, Jinyong Chung, Sebastian Cremer, Marvin Krohn-Grimberghe, Eo Jin Kim, Dawid Schellingerhout, Matthias Nahrendorf, Dong-Eog Kim

Faculty, Staff and Student Publications

Background: Monocytes contribute to the initiation and propagation of venous thrombosis. Little is known about the roles monocytes play in arterial thrombosis, the cause of stroke and myocardial infarction.

Methods: We investigated how CCR2 (CC chemokine receptor 2) knockout (-/-)-mediated monocyte deficiency affects platelet function, blood coagulation, thrombus volume, and thrombolytic susceptibility in 666 male mice with FeCl3-mediated carotid arterial thrombosis, including 365 C57BL/6 wild type (WT) mice, 295 CCR2-/- mice, and 6 CX3CR1-GFP (CX3C chemokine receptor 1-green fluorescent protein) mice.

Results: Intravital microscopy and flow cytometry showed that both neutrophils and monocytes were recruited to the acute arterial thrombus, …

Profiling The Preclinical Pharmacokinetics And Biodistribution Of A Platinum(Iv)-Based Oxaliplatin Prodrug Oxalitex And Their Significance To Antitumor Response, Guangan He, Gregory D Thiabaud, Kathryn A Shelton, Luke J Segura, Jonathan F Arambula, Jonathan L Sessler, Rick A Finch, Zahid H Siddik

Faculty, Staff and Student Publications

OxaliTEX (NOVO-111) is a novel gadolinium(III) texaphyrin-platinum(IV) complex that is under development for clinical trials. It was designed as a prodrug of oxaliplatin (1,2-diaminocyclohexane-platinum(II) oxalate) tethered to a tumor-affinic texaphyrin moiety to improve drug delivery to the tumor. However, oxaliTEX was not only more effective as an antitumor agent but also better tolerated in mice. To appreciate this higher therapeutic index and advance its preclinical development, studies were undertaken to profile its plasma pharmacokinetics, distribution to tumor and normal tissues, and pharmacodynamics of the p53/p21 molecular pathway. Nude mice, with or without a subcutaneous colorectal HCT-116 xenograft harboring a phenotypically …

Decoding Fibrosis In Nonresolvable Covid-19: A Role For Myeloid-Specific Hif1a Deletion, Kemly Philip, Hannah P Thompson, Scott D Collum, Isabella Lefebvre, Bindu Akkanti, Bihong Zhao, Rahat Hussain, Manish Patel, Michael R Blackburn, Tingting W Mills, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

A complication of viral lung infections is the development of pulmonary fibrosis. This phenomenon is most evident in patients with COVID-19, where in its most aggressive form patients developed nonresolvable (NR) COVID-19 requiring lung transplantation. NR-COVID-19 was characterized by the presentation of a fulminant fibrotic lung injury that progressed rapidly, even in patients with limited comorbidities. However, the mechanisms that led to this rapidly progressing form of fibrosis are not fully understood. A common clinical manifestation in the most severe cases of COVID-19 was the presence of "silent" hypoxemia. Thus, we hypothesized that a dysfunctional hypoxic response may result in …

The Role Of Neutrophils In Vasospasm And Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: Is It Time For A Sah Clinical Trial Targeting Neutrophils?, William W Wroe, Hussein A Zeineddine, Spiros L Blackburn, Jaroslaw Aronowski, Devin W Mcbride

Faculty, Staff and Student Publications

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating neurological disease, and one of the primary drivers of morbidity after aneurysm rupture is the phenomenon of delayed cerebral ischemia (DCI). Significant knowledge has been gained over the past two decades of the impact of neuroinflammation in DCI; and neutrophils are now believed to play a major role. There is significant human subject data showing the rise of neutrophil related inflammatory markers and neutrophil's association with poor outcome after aSAH, but as of yet no trials involving human subjects have been done specifically targeting neutrophils. There is however a growing body of evidence …

A Review Of Engraftment Assessments Following Fecal Microbiota Transplant, Chloe Herman, Bridget M Barker, Thais F Bartelli, Vidhi Chandra, Rosa Krajmalnik-Brown, Mary Jewell, Le Li, Chen Liao, Florencia Mcallister, Khemlal Nirmalkar, Joao B Xavier, J Gregory Caporaso

Faculty, Staff and Student Publications

Fecal Microbiota Transplant (FMT) is a treatment for recurrent Clostridium difficile infections and is being explored for other clinical applications, from alleviating digestive and neurological disorders, to restoring microbiomes impacted by cancer treatment. Quantifying the extent of engraftment following an FMT is important in understanding a recipient's response to treatment. Engraftment and clinical response need to be investigated independently to evaluate an FMT's role (or lack thereof) in achieving a clinical response. Standardized bioinformatics methodologies for quantifying engraftment extent would not only improve assessment and understanding of FMT outcomes, but also facilitate comparison of FMT results and protocols across studies. …

Impact Of Peripheral Circadian Misalignment And Alcohol On The Resiliency Of Intestinal Barrier And Microbiota, Laura Tran, Maliha Shaikh, Phillip A Engen, Ankur Naqib, Dulce M Frausto, Vivian Ramirez, Malia Gasteier, Zlata Bogin, Kristi Lawrence, Lijuan Zhang, Shiwen Song, Stefan J Green, Faraz Bishehsari, Christopher B Forsyth, Ali Keshavarzian, Garth R Swanson

Faculty, Staff and Student Publications

Circadian organization is involved in many gastrointestinal tract (GIT) functions such as the maintenance of intestinal barrier integrity. There is compelling evidence that perturbation of the circadian clock decreases intestinal epithelial cells' resiliency to alcohol-induced injury. One of the most common causes of circadian misalignment is wrong-time eating (largest meal at dinner) in modern societies. Yet, few studies have examined the importance of peripheral circadian rhythms of the GIT to alcohol consumption. Eating patterns during physiologic rest time, defined as wrong-time eating (WTE), misalign the peripheral circadian clock of the GIT and the body's central clock. This study aims to …