Biomedical Informatics Commons^™

A Small Secreted Protein Nicol Regulates Lumicrine-Mediated Sperm Maturation And Male Fertility, Daiji Kiyozumi, Kentaro Shimada, Michael Chalick, Chihiro Emori, Mayo Kodani, Seiya Oura, Taichi Noda, Tsutomu Endo, Martin M Matzuk, Daniel H Wreschner, Masahito Ikawa

Faculty, Staff and Students Publications

The mammalian spermatozoa produced in the testis require functional maturation in the epididymis for their full competence. Epididymal sperm maturation is regulated by lumicrine signalling pathways in which testis-derived secreted signals relocate to the epididymis lumen and promote functional differentiation. However, the detailed mechanisms of lumicrine regulation are unclear. Herein, we demonstrate that a small secreted protein, NELL2-interacting cofactor for lumicrine signalling (NICOL), plays a crucial role in lumicrine signalling in mice. NICOL is expressed in male reproductive organs, including the testis, and forms a complex with the testis-secreted protein NELL2, which is transported transluminally from the testis to the …

Synthetic Errα/Β/Γ Agonist Induces An Errα-Dependent Acute Aerobic Exercise Response And Enhances Exercise Capacity, Cyrielle Billon, Sadichha Sitaula, Subhashis Banerjee, Ryan Welch, Bahaa Elgendy, Lamees Hegazy, Tae Gyu Oh, Melissa Kazantzis, Arindam Chatterjee, John Chrivia, Matthew E Hayes, Weiyi Xu, Angelica Hamilton, Janice M Huss, Lilei Zhang, John K Walker, Michael Downes, Ronald M Evans, Thomas P Burris

Faculty, Staff and Students Publications

Repetitive physical exercise induces physiological adaptations in skeletal muscle that improves exercise performance and is effective for the prevention and treatment of several diseases. Genetic evidence indicates that the orphan nuclear receptors estrogen receptor-related receptors (ERRs) play an important role in skeletal muscle exercise capacity. Three ERR subtypes exist (ERRα, β, and γ), and although ERRβ/γ agonists have been designed, there have been significant difficulties in designing compounds with ERRα agonist activity. Additionally, there are limited synthetic agonists that can be used to target ERRs in vivo. Here, we report the …

Distinct Astrocytic Modulatory Roles In Sensory Transmission During Sleep, Wakefulness, And Arousal States In Freely Moving Mice, Fushun Wang, Wei Wang, Simeng Gu, Dan Qi, Nathan A Smith, Weiguo Peng, Wei Dong, Jiajin Yuan, Binbin Zhao, Ying Mao, Peng Cao, Qing Richard Lu, Lee A Shapiro, S Stephen Yi, Erxi Wu, Jason H Huang

Faculty, Staff and Student Publications

Despite extensive research on astrocytic Ca2+ in synaptic transmission, its contribution to the modulation of sensory transmission during different brain states remains largely unknown. Here, by using two-photon microscopy and whole-cell recordings, we show two distinct astrocytic Ca2+ signals in the murine barrel cortex: a small, long-lasting Ca2+ increase during sleep and a large, widespread but short-lasting Ca2+ spike when aroused. The large Ca2+ wave in aroused mice was inositol trisphosphate (IP3)-dependent, evoked by the locus coeruleus-norepinephrine system, and enhanced sensory input, contributing to reliable sensory transmission. However, the small Ca2+ transient was IP3-independent and contributed to decreased extracellular K+, …

The Melanocortin Action Is Biased Toward Protection From Weight Loss In Mice, Hongli Li, Yuanzhong Xu, Yanyan Jiang, Zhiying Jiang, Joshua Otiz-Guzman, Jessie C Morrill, Jing Cai, Zhengmei Mao, Yong Xu, Benjamin R Arenkiel, Cheng Huang, Qingchun Tong

Faculty, Staff and Student Publications

The melanocortin action is well perceived for its ability to regulate body weight bidirectionally with its gain of function reducing body weight and loss of function promoting obesity. However, this notion cannot explain the difficulty in identifying effective therapeutics toward treating general obesity via activation of the melanocortin action. Here, we provide evidence that altered melanocortin action is only able to cause one-directional obesity development. We demonstrate that chronic inhibition of arcuate neurons expressing proopiomelanocortin (POMC) or paraventricular hypothalamic neurons expressing melanocortin receptor 4 (MC4R) causes massive obesity. However, chronic activation of these neuronal populations failed to reduce body weight. …

Development Of A Corticosteroid-Immunosuppressed Mouse Model To Study The Pathogenesis And Therapy Of Influenza-Associated Pulmonary Aspergillosis, Sebastian Wurster, Jezreel Pantaleón García, Nathaniel D Albert, Ying Jiang, Keerthi Bhoda, Vikram V Kulkarni, Yongxing Wang, Thomas J Walsh, Scott Evans, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Influenza-associated pulmonary aspergillosis (IAPA) is a feared complication in patients with influenza tracheobronchitis, especially those receiving corticosteroids. Herein, we established a novel IAPA mouse model with low-inoculum Aspergillus infection and compared outcomes in mice with and without cortisone acetate (CA) immunosuppression. CA was an independent predictor of increased morbidity/mortality in mice with IAPA. Early antifungal treatment with liposomal amphotericin B was pivotal to improve IAPA outcomes in CA-immunosuppressed mice, even after prior antiviral therapy with oseltamivir. In summary, our model recapitulates key clinical features of IAPA and provides a robust preclinical platform to study the pathogenesis and treatment of IAPA.

Foxi3 Pathogenic Variants Cause One Form Of Craniofacial Microsomia, Ke Mao, Christelle Borel, Muhammad Ansar, Angad Jolly, Periklis Makrythanasis, Christine Froehlich, Justyna Iwaszkiewicz, Bingqing Wang, Xiaopeng Xu, Qiang Li, Xavier Blanc, Hao Zhu, Qi Chen, Fujun Jin, Harinarayana Ankamreddy, Sunita Singh, Hongyuan Zhang, Xiaogang Wang, Peiwei Chen, Emmanuelle Ranza, Sohail Aziz Paracha, Syed Fahim Shah, Valentina Guida, Francesca Piceci-Sparascio, Daniela Melis, Bruno Dallapiccola, Maria Cristina Digilio, Antonio Novelli, Monia Magliozzi, Maria Teresa Fadda, Haley Streff, Keren Machol, Richard A Lewis, Vincent Zoete, Gabriella Maria Squeo, Paolo Prontera, Giorgia Mancano, Giulia Gori, Milena Mariani, Angelo Selicorni, Stavroula Psoni, Helen Fryssira, Sofia Douzgou, Sandrine Marlin, Saskia Biskup, Alessandro De Luca, Giuseppe Merla, Shouqin Zhao, Timothy C Cox, Andrew K Groves, James R Lupski, Qingguo Zhang, Yong-Biao Zhang, Stylianos E Antonarakis

Faculty, Staff and Students Publications

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in …

Mapping The Metabolic Reprogramming Induced By Sodium-Glucose Cotransporter 2 Inhibition, Aviram Kogot-Levin, Yael Riahi, Ifat Abramovich, Ofri Mosenzon, Bella Agranovich, Liat Kadosh, Rachel Ben-Haroush Schyr, Doron Kleiman, Liad Hinden, Erol Cerasi, Danny Ben-Zvi, Ernesto Bernal-Mizrachi, Joseph Tam, Eyal Gottlieb, Gil Leibowitz

Faculty, Staff and Student Publications

Diabetes is associated with increased risk for kidney disease, heart failure, and mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent these adverse outcomes; however, the mechanisms involved are not clear. We generated a roadmap of the metabolic alterations that occur in different organs in diabetes and in response to SGLT2i. In vivo metabolic labeling with 13C-glucose in normoglycemic and diabetic mice treated with or without dapagliflozin, followed by metabolomics and metabolic flux analyses, showed that, in diabetes, glycolysis and glucose oxidation are impaired in the kidney, liver, and heart. Treatment with dapagliflozin failed to rescue glycolysis. SGLT2 inhibition increased glucose oxidation …

Targeting The Mevalonate Pathway Suppresses Arid1a-Inactivated Cancers By Promoting Pyroptosis, Wei Zhou, Heng Liu, Zhe Yuan, Joseph Zundell, Martina Towers, Jianhuang Lin, Simona Lombardi, Hao Nie, Brennah Murphy, Tyler Yang, Chen Wang, Liping Liao, Aaron R Goldman, Toshitha Kannan, Andrew V Kossenkov, Ronny Drapkin, Luis J Montaner, Daniel T Claiborne, Nan Zhang, Shuai Wu, Rugang Zhang

Faculty, Staff and Student Publications

ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC …

Bi-Allelic Variants In The Esam Tight-Junction Gene Cause A Neurodevelopmental Disorder Associated With Fetal Intracranial Hemorrhage, Mauro Lecca, Davut Pehlivan, Damià Heine Suñer, Karin Weiss, Thibault Coste, Markus Zweier, Yavuz Oktay, Nada Danial-Farran, Vittorio Rosti, Maria Paola Bonasoni, Alessandro Malara, Gianluca Contrò, Roberta Zuntini, Marzia Pollazzon, Rosario Pascarella, Alberto Neri, Carlo Fusco, Dana Marafi, Tadahiro Mitani, Jennifer Ellen Posey, Sadik Etka Bayramoglu, Alper Gezdirici, Jessica Hernandez-Rodriguez, Emilia Amengual Cladera, Elena Miravet, Jorge Roldan-Busto, María Angeles Ruiz, Cristofol Vives Bauzá, Liat Ben-Sira, Sabine Sigaudy, Anaïs Begemann, Sheila Unger, Serdal Güngör, Semra Hiz, Ece Sonmezler, Yoav Zehavi, Michael Jerdev, Alessandra Balduini, Orsetta Zuffardi, Rita Horvath, Hanns Lochmüller, Anita Rauch, Livia Garavelli, Elisabeth Tournier-Lasserve, Ronen Spiegel, James R Lupski, Edoardo Errichiello

Faculty, Staff and Students Publications

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in …

Pattern Dynamics And Stochasticity Of The Brain Rhythms, Clarissa Hoffman, Jingheng Cheng, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Student Publications

Our current understanding of brain rhythms is based on quantifying their instantaneous or time-averaged characteristics. What remains unexplored is the actual structure of the waves-their shapes and patterns over finite timescales. Here, we study brain wave patterning in different physiological contexts using two independent approaches: The first is based on quantifying stochasticity relative to the underlying mean behavior, and the second assesses "orderliness" of the waves' features. The corresponding measures capture the waves' characteristics and abnormal behaviors, such as atypical periodicity or excessive clustering, and demonstrate coupling between the patterns' dynamics and the animal's location, speed, and acceleration. Specifically, we …

Il6 Mediates Suppression Of T- And Nk-Cell Function In Emt-Associated Tki-Resistant Egfr-Mutant Nsclc, Sonia A Patel, Monique B Nilsson, Yan Yang, Xiuning Le, Hai T Tran, Yasir Y Elamin, Xiaoxing Yu, Fahao Zhang, Alissa Poteete, Xiaoyang Ren, Li Shen, Jing Wang, Seyed Javad Moghaddam, Tina Cascone, Michael Curran, Don L Gibbons, John V Heymach

Faculty, Staff and Student Publications

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype.

Experimental design: We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and …

Inhibition Of Stat6 With Antisense Oligonucleotides Enhances The Systemic Antitumor Effects Of Radiotherapy And Anti-Pd-1 In Metastatic Non-Small Cell Lung Cancer, Kewen He, Hampartsoum B Barsoumian, Nahum Puebla-Osorio, Yun Hu, Duygu Sezen, Mark D Wasley, Genevieve Bertolet, Jie Zhang, Carola Leuschner, Liangpeng Yang, Claudia S Kettlun Leyton, Natalie Wall Fowlkes, Morgan Maureen Green, Lisa Hettrick, Dawei Chen, Fatemeh Masrorpour, Meidi Gu, Hadi Maazi, Alexey S Revenko, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells-such as M2 tumor-associated macrophages (TAM)-thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung …

Dysregulation And Epigenetic Reprogramming Of Nrf2 Signaling Axis Promote Acquisition Of Cisplatin Resistance And Metastasis In Head And Neck Squamous Cell Carcinoma, Abdullah A Osman, Emre Arslan, Mason Bartels, Chieko Michikawa, Antje Lindemann, Katarzyna Tomczak, Wangjie Yu, Vlad Sandulache, Wencai Ma, Li Shen, Jing Wang, Anand K Singh, Mitchell J Frederick, Nakia D Spencer, Jeffery Kovacs, Timothy Heffernan, William F Symmans, Kunal Rai, Jeffrey N Myers

Faculty, Staff and Student Publications

PURPOSE: Cisplatin (CDDP)-based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCC), despite a high rate of treatment failures, acquired resistance, and subsequent aggressive behavior. The purpose of this study was to study the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC.

EXPERIMENTAL DESIGN: Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF2 …

Consensus-Based Evaluation Of Outcome Measures In Pediatric Stroke Care: A Toolkit, Samantha J Feldman, Lauren A Beslow, Ryan J Felling, Laura A Malone, Michaela Waak, Stuart Fraser, Nihal Bakeer, Jo Ellen M Lee, Victoria Sherman, Melissa M Howard, Beth Anne Cavanaugh, Robyn Westmacott, Lori C Jordan

Faculty, Staff and Student Publications

Following a pediatric stroke, outcome measures selected for monitoring functional recovery and development vary widely. We sought to develop a toolkit of outcome measures that are currently available to clinicians, possess strong psychometric properties, and are feasible for use within clinical settings. A multidisciplinary group of clinicians and scientists from the International Pediatric Stroke Organization comprehensively reviewed the quality of measures in multiple domains described in pediatric stroke populations including global performance, motor and cognitive function, language, quality of life, and behavior and adaptive functioning. The quality of each measure was evaluated using guidelines focused on responsiveness and sensitivity, reliability, …

De Novo Mutations Disturb Early Brain Development More Frequently Than Common Variants In Schizophrenia, Toshiyuki Itai, Peilin Jia, Yulin Dai, Jingchun Chen, Xiangning Chen, Zhongming Zhao

Faculty, Staff and Student Publications

Investigating functional, temporal, and cell-type expression features of mutations is important for understanding a complex disease. Here, we collected and analyzed common variants and de novo mutations (DNMs) in schizophrenia (SCZ). We collected 2,636 missense and loss-of-function (LoF) DNMs in 2,263 genes across 3,477 SCZ patients (SCZ-DNMs). We curated three gene lists: (a) SCZ-neuroGenes (159 genes), which are intolerant to LoF and missense DNMs and are neurologically important, (b) SCZ-moduleGenes (52 genes), which were derived from network analyses of SCZ-DNMs, and (c) SCZ-commonGenes (120 genes) from a recent GWAS as reference. To compare temporal gene expression, we used the BrainSpan …

The Glycoprotein Cd147 Defines Mirna-Enriched Extracellular Vesicles That Derive From Cancer Cells, Song Yi Ko, Wonjae Lee, Melanie Weigert, Eric Jonasch, Ernst Lengyel, Honami Naora

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) are ideal for liquid biopsy, but distinguishing cancer cell‐derived EVs and subpopulations of biomarker‐containing EVs in body fluids has been challenging. Here, we identified that the glycoproteins CD147 and CD98 define subpopulations of EVs that are distinct from classical tetraspanin+ EVs in their biogenesis. Notably, we identified that CD147+ EVs have substantially higher microRNA (miRNA) content than tetraspanin+ EVs and are selectively enriched in miRNA through the interaction of CD147 with heterogeneous nuclear ribonucleoprotein A2/B1. Studies using mouse xenograft models showed that CD147+ EVs predominantly derive from cancer cells, whereas the majority of tetraspanin+ EVs are not …

Temporal Single-Cell Atlas Of Non-Neuronal Retinal Cells Reveals Dynamic, Coordinated Multicellular Responses To Central Nervous System Injury, Inbal Benhar, Jiarui Ding, Wenjun Yan, Irene E Whitney, Anne Jacobi, Malika Sud, Grace Burgin, Karthik Shekhar, Nicholas M Tran, Chen Wang, Zhigang He, Joshua R Sanes, Aviv Regev

Faculty, Staff and Students Publications

Non-neuronal cells are key to the complex cellular interplay that follows central nervous system insult. To understand this interplay, we generated a single-cell atlas of immune, glial and retinal pigment epithelial cells from adult mouse retina before and at multiple time points after axonal transection. We identified rare subsets in naive retina, including interferon (IFN)-response glia and border-associated macrophages, and delineated injury-induced changes in cell composition, expression programs and interactions. Computational analysis charted a three-phase multicellular inflammatory cascade after injury. In the early phase, retinal macroglia and microglia were reactivated, providing chemotactic signals concurrent with infiltration of CCR2+ monocytes from …

Loss Of Neuron Navigator 2 Impairs Brain And Cerebellar Development, Andrea Accogli, Shenzhao Lu, Ilaria Musante, Paolo Scudieri, Jill A Rosenfeld, Mariasavina Severino, Simona Baldassari, Michele Iacomino, Antonella Riva, Ganna Balagura, Gianluca Piccolo, Carlo Minetti, Denis Roberto, Fan Xia, Razaali Razak, Emily Lawrence, Mohamed Hussein, Emmanuel Yih-Herng Chang, Michelle Holick, Elisa Calì, Emanuela Aliberto, Rosalba De-Sarro, Antonio Gambardella, Undiagnosed Diseases Network, Synaps Study Group, Lisa Emrick, Peter J A Mccaffery, Margaret Clagett-Dame, Paul C Marcogliese, Hugo J Bellen, Seema R Lalani, Federico Zara, Pasquale Striano, Vincenzo Salpietro

Faculty, Staff and Students Publications

Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. In …

Dnmt3a-Coordinated Splicing Governs The Stem State Switch Towards Differentiation In Embryonic And Haematopoietic Stem Cells, Raghav Ramabadran, Jarey H Wang, Jaime M Reyes, Anna G Guzman, Sinjini Gupta, Carina Rosas, Lorenzo Brunetti, Michael C Gundry, Ayala Tovy, Hali Long, Tianpeng Gu, Sean M Cullen, Siddhartha Tyagi, Danielle Rux, Jean J Kim, Steven M Kornblau, Michael Kyba, Fabio Stossi, Rachel E Rau, Koichi Takahashi, Thomas F Westbrook, Margaret A Goodell

Faculty, Staff and Student Publications

Upon stimulation by extrinsic stimuli, stem cells initiate a programme that enables differentiation or self-renewal. Disruption of the stem state exit has catastrophic consequences for embryogenesis and can lead to cancer. While some elements of this stem state switch are known, major regulatory mechanisms remain unclear. Here we show that this switch involves a global increase in splicing efficiency coordinated by DNA methyltransferase 3α (DNMT3A), an enzyme typically involved in DNA methylation. Proper activation of murine and human embryonic and haematopoietic stem cells depends on messenger RNA processing, influenced by DNMT3A in response to stimuli. DNMT3A coordinates splicing through recruitment …

Wwox P47t Partial Loss-Of-Function Mutation Induces Epilepsy, Progressive Neuroinflammation, And Cerebellar Degeneration In Mice Phenocopying Human Scar12, Tabish Hussain, Kevin Sanchez, Jennifer Crayton, Dhurjhoti Saha, Collene Jeter, Yue Lu, Martin Abba, Ryan Seo, Jeffrey L Noebels, Laura Fonken, C Marcelo Aldaz

Faculty, Staff and Student Publications

WWOX gene loss-of-function (LoF) has been associated with neuropathologies resulting in developmental, epileptic, and ataxic phenotypes of varying severity based on the level of WWOX dysfunction. WWOX gene biallelic germline variant p.Pro47Thr (P47T) has been causally associated with a new form of autosomal recessive cerebellar ataxia with epilepsy and intellectual disability (SCAR12, MIM:614322). This mutation affecting the WW1 protein binding domain of WWOX, impairs its interaction with canonical proline-proline-X-tyrosine motifs in partner proteins. We generated a mutant knock-in mouse model of Wwox P47T mutation that phenocopies human SCAR12. Wwox

Rational Design Of A Self-Assembling High Performance Organic Nanofluorophore For Intraoperative Nir-Ii Image-Guided Tumor Resection Of Oral Cancer, Xianwei Sun, Praveen Kumar Chintakunta, Andrew A Badachhape, Rohan Bhavane, Huan-Jui Lee, David S Yang, Zbigniew Starosolski, Ketan B Ghaghada, Peter G Vekilov, Ananth V Annapragada, Eric A Tanifum

Faculty, Staff and Students Publications

The first line of treatment for most solid tumors is surgical resection of the primary tumor with adequate negative margins. Incomplete tumor resections with positive margins account for over 75% of local recurrences and the development of distant metastases. In cases of oral cavity squamous cell carcinoma (OSCC), the rate of successful tumor removal with adequate margins is just 50–75%. Advanced real‐time imaging methods that improve the detection of tumor margins can help improve success rates,overall safety, and reduce the cost. Fluorescence imaging in the second near‐infrared (NIR‐II) window has the potential to revolutionize the field due to its high …

Hsc-Independent Definitive Hematopoiesis Persists Into Adult Life, Michihiro Kobayashi, Haichao Wei, Takashi Yamanashi, Nathalia Azevedo Portilho, Samuel Cornelius, Noemi Valiente, Chika Nishida, Haizi Cheng, Augusto Latorre, W Jim Zheng, Joonsoo Kang, Jun Seita, David J Shih, Jia Qian Wu, Momoko Yoshimoto

Faculty, Staff and Student Publications

It is widely believed that hematopoiesis after birth is established by hematopoietic stem cells (HSCs) in the bone marrow and that HSC-independent hematopoiesis is limited only to primitive erythro-myeloid cells and tissue-resident innate immune cells arising in the embryo. Here, surprisingly, we find that significant percentages of lymphocytes are not derived from HSCs, even in 1-year-old mice. Instead, multiple waves of hematopoiesis occur from embryonic day 7.5 (E7.5) to E11.5 endothelial cells, which simultaneously produce HSCs and lymphoid progenitors that constitute many layers of adaptive T and B lymphocytes in adult mice. Additionally, HSC lineage tracing reveals that the contribution …

Convergent Deployment Of Ancestral Functions During The Evolution Of Mammalian Flight Membranes, Charles Y Feigin, Jorge A Moreno, Raul Ramos, Sarah A Mereby, Ares Alivisatos, Wei Wang, Renée Van Amerongen, Jasmin Camacho, John J Rasweiler, Richard R Behringer, Bruce Ostrow, Maksim V Plikus, Ricardo Mallarino

Faculty, Staff and Student Publications

Lateral flight membranes, or patagia, have evolved repeatedly in diverse mammalian lineages. While little is known about patagium development, its recurrent evolution may suggest a shared molecular basis. By combining transcriptomics, developmental experiments, and mouse transgenics, we demonstrate that lateral Wnt5a expression in the marsupial sugar glider (Petaurus breviceps) promotes the differentiation of its patagium primordium. We further show that this function of Wnt5a reprises ancestral roles in skin morphogenesis predating mammalian flight and has been convergently used during patagium evolution in eutherian bats. Moreover, we find that many genes involved in limb development have been redeployed during …

A First-In-Human Phase I Study Of Milademetan, An Mdm2 Inhibitor, In Patients With Advanced Liposarcoma, Solid Tumors, Or Lymphomas, Mrinal M Gounder, Todd M Bauer, Gary K Schwartz, Amy M Weise, Patricia Lorusso, Prasanna Kumar, Ben Tao, Ying Hong, Parul Patel, Yasong Lu, Arnaud Lesegretain, Vijaya G Tirunagaru, Feng Xu, Robert C Doebele, David S Hong

Faculty, Staff and Student Publications

Purpose: This study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of milademetan, a small-molecule murine double minute-2 (MDM2) inhibitor, in patients with advanced cancers.

Patients and methods: In this first-in-human phase I study, patients with advanced solid tumors or lymphomas received milademetan orally once daily as extended/continuous (days 1-21 or 1-28 every 28 days) or intermittent (days 1-7, or days 1-3 and 15-17 every 28 days) schedules. The primary objective was to determine the recommended phase II dose and schedule. Secondary objectives included tumor response according to standard evaluation criteria. Predefined analyses by tumor type were performed. Safety and …

A Mast Cell-Thermoregulatory Neuron Circuit Axis Regulates Hypothermia In Anaphylaxis, Chunjing Bao, Ouyang Chen, Huaxin Sheng, Jeffrey Zhang, Yikai Luo, Byron W Hayes, Han Liang, Wolfgang Liedtke, Ru-Rong Ji, Soman N Abraham

Faculty, Staff and Student Publications

IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body's thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1+ …

Animal Models And Their Role In Imaging-Assisted Co-Clinical Trials, Donna M Peehl, Cristian T Badea, Thomas L Chenevert, Heike E Daldrup-Link, Li Ding, Lacey E Dobrolecki, A Mcgarry Houghton, Paul E Kinahan, John Kurhanewicz, Michael T Lewis, Shunqiang Li, Gary D Luker, Cynthia X Ma, H Charles Manning, Yvonne M Mowery, Peter J O'Dwyer, Robia G Pautler, Mark A Rosen, Raheleh Roudi, Brian D Ross, Kooresh I Shoghi, Renuka Sriram, Moshe Talpaz, Richard L Wahl, Rong Zhou

Faculty, Staff and Student Publications

The availability of high-fidelity animal models for oncology research has grown enormously in recent years, enabling preclinical studies relevant to prevention, diagnosis, and treatment of cancer to be undertaken. This has led to increased opportunities to conduct co-clinical trials, which are studies on patients that are carried out parallel to or sequentially with animal models of cancer that mirror the biology of the patients' tumors. Patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) are considered to be the models that best represent human disease and have high translational value. Notably, one element of co-clinical trials that still needs significant …

The Alpha7 Integrin Subunit In Astrocytes Promotes Endothelial Blood-Brain Barrier Integrity, Zhihua Chen, Jack R Kelly, John E Morales, Raymond C Sun, Arpan De, Dean J Burkin, Joseph H Mccarty

Faculty, Staff and Student Publications

The blood-brain barrier (BBB) is a vascular endothelial cell boundary that partitions the circulation from the central nervous system to promote normal brain health. We have a limited understanding of how the BBB is formed during development and maintained in adulthood. We used quantitative transcriptional profiling to investigate whether specific adhesion molecules are involved in BBB functions, with an emphasis on understanding how astrocytes interact with endothelial cells. Our results reveal a striking enrichment of multiple genes encoding laminin subunits as well as the laminin receptor gene Itga7, which encodes the alpha7 integrin subunit, in astrocytes. Genetic ablation of Itga7 …

Tsks Localizes To Nuage In Spermatids And Regulates Cytoplasmic Elimination During Spermiation, Keisuke Shimada, Soojin Park, Seiya Oura, Taichi Noda, Akane Morohoshi, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Spermatozoa have a streamlined shape to swim through the oviduct to fertilize oocytes. To become svelte spermatozoa, spermatid cytoplasm must be eliminated in several steps including sperm release, which is part of spermiation. Although this process has been well observed, the molecular mechanisms that underlie it remain unclear. In male germ cells, there are membraneless organelles called nuage, which are observed by electron microscopy in various forms of dense material. Reticulated body (RB) and chromatoid body remnant (CR) are two types of nuage in spermatids, but the functions of both are unknown. Using CRISPR/Cas9 technology, we deleted the entire coding …

Hypomorphic Brca2 And Rad51c Double Mutant Mice Display Fanconi Anemia, Cancer And Polygenic Replication Stress, Karl-Heinz Tomaszowski, Sunetra Roy, Carolina Guerrero, Poojan Shukla, Caezaan Keshvani, Yue Chen, Martina Ott, Xiaogang Wu, Jianhua Zhang, Courtney D Dinardo, Detlev Schindler, Katharina Schlacher

Faculty, Staff and Student Publications

The prototypic cancer-predisposition disease Fanconi Anemia (FA) is identified by biallelic mutations in any one of twenty-three FANC genes. Puzzlingly, inactivation of one Fanc gene alone in mice fails to faithfully model the pleiotropic human disease without additional external stress. Here we find that FA patients frequently display FANC co-mutations. Combining exemplary homozygous hypomorphic Brca2/Fancd1 and Rad51c/Fanco mutations in mice phenocopies human FA with bone marrow failure, rapid death by cancer, cellular cancer-drug hypersensitivity and severe replication instability. These grave phenotypes contrast the unremarkable phenotypes seen in mice with single gene-function inactivation, revealing an unexpected synergism between Fanc mutations. Beyond …

Towards A Biomarker For Acute Arterial Thrombosis Using Complete Blood Count And White Blood Cell Differential Parameters In Mice, Hee Jeong Jang, Dawid Schellingerhout, Jiwon Kim, Jinyong Chung, Dong-Eog Kim

Faculty, Staff and Student Publications

There is no blood biomarker diagnostic of arterial thrombosis. We investigated if arterial thrombosis per se was associated with alterations in complete blood count (CBC) and white blood cell (WBC) differential count in mice. Twelve-week-old C57Bl/6 mice were used for FeCl3-mediated carotid thrombosis (n = 72), sham-operation (n = 79), or non-operation (n = 26). Monocyte count (/µL) at 30-min after thrombosis (median 160 [interquartile range 140-280]) was ~ 1.3-fold higher than at 30-min after sham-operation (120 [77.5-170]), and twofold higher than in non-operated mice (80 [47.5-92.5]). At day-1 and -4 post-thrombosis, compared with 30-min, monocyte count decreased by about …