Medical Cell Biology Commons^™

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …

Osteoprogenitor-Gmp Crosstalk Underpins Solid Tumor-Induced Systemic Immunosuppression And Persists After Tumor Removal, Xiaoxin Hao, Yichao Shen, Nan Chen, Weijie Zhang, Elizabeth Valverde, Ling Wu, Hilda L Chan, Zhan Xu, Liqun Yu, Yang Gao, Igor Bado, Laura Natalee Michie, Charlotte Helena Rivas, Luis Becerra Dominguez, Sergio Aguirre, Bradley C Pingel, Yi-Hsuan Wu, Fengshuo Liu, Yunfeng Ding, David G Edwards, Jun Liu, Angela Alexander, Naoto T Ueno, Po-Ren Hsueh, Chih-Yen Tu, Liang-Chih Liu, Shu-Hsia Chen, Mien-Chie Hung, Bora Lim, Xiang H-F Zhang

Faculty, Staff and Students Publications

Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitors (OPs) expansion, hematopoietic stem cell dislocation and CD41− granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41− GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in hematopoietic program. Importantly, these effects persist …

Sexual Dimorphism In Bidirectional Sr-Mitochondria Crosstalk In Ventricular Cardiomyocytes, Richard T Clements, Radmila Terentyeva, Shanna Hamilton, Paul M L Janssen, Karim Roder, Benjamin Y Martin, Fruzsina Perger, Timothy G Schneider, Zuzana Nichtova, Anindhya S Das, Roland Veress, Beth S Lee, Do-Gyoon Kim, Gideon Koren, Matthew S Stratton, György Csordás, Federica Accornero, Andriy E Belevych, Sandor Gyorke, Dmitry Terentyev

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Calcium transfer into the mitochondrial matrix during sarcoplasmic reticulum (SR) Ca²⁺ release is essential to boost energy production in ventricular cardiomyocytes (VCMs) and match increased metabolic demand. Mitochondria from female hearts exhibit lower mito-[Ca²⁺] and produce less reactive oxygen species (ROS) compared to males, without change in respiration capacity. We hypothesized that in female VCMs, more efficient electron transport chain (ETC) organization into supercomplexes offsets the deficit in mito-Ca²⁺ accumulation, thereby reducing ROS production and stress-induced intracellular Ca²⁺ mishandling. Experiments using mitochondria-targeted biosensors confirmed lower mito-ROS and mito-[Ca²⁺] in female rat VCMs challenged …

The Impact Of The American Association For Thoracic Surgery On National Institutes Of Health Grant Funding For Cardiothoracic Surgeons, J Hunter Mehaffey, Hanjay Wang, Adishesh K Narahari, Simar S Bajaj, Anirudha S Chandrabhatla, Alexander S Krupnick, Frank W Sellke, Todd K Rosengart, Y Joseph Woo

Faculty, Staff and Students Publications

Objectives: The American Association for Thoracic Surgery, through its annual meeting, pilot grant funding, Scientific Affairs and Government Relations Committee activity, and academic development programs (Grant Writing Workshop, Clinical Trials Course, Innovation Summit), has aimed to develop the research careers of cardiothoracic surgeons. We hypothesized that American Association for Thoracic Surgery activities have helped increase National Institutes of Health grants awarded to cardiothoracic surgeons.

Methods: A database of 1869 academic cardiothoracic surgeons in the United States was created in December 2020. National Institutes of Health grant records from 1985 to 2020 were obtained for each surgeon using National Institutes of …

Direct Cardiac Reprogramming: A New Technology For Cardiac Repair, Paige E Brlecic, Clark A Bonham, Todd K Rosengart, Megumi Mathison

Faculty, Staff and Students Publications

Cardiovascular disease is one of the leading causes of morbidity and mortality worldwide, with myocardial infarctions being amongst the deadliest manifestations. Reduced blood flow to the heart can result in the death of cardiac tissue, leaving affected patients susceptible to further complications and recurrent disease. Further, contemporary management typically involves a pharmacopeia to manage the metabolic conditions contributing to atherosclerotic and hypertensive heart disease, rather than regeneration of the damaged myocardium. With modern healthcare extending lifespan, a larger demographic will be at risk for heart disease, driving the need for novel therapeutics that surpass those currently available in efficacy. Transdifferentiation …

Apoptotic Cell Death In Disease-Current Understanding Of The Nccd 2023, Ilio Vitale, Federico Pietrocola, Emma Guilbaud, Stuart A Aaronson, John M Abrams, Dieter Adam, Massimiliano Agostini, Patrizia Agostinis, Emad S Alnemri, Lucia Altucci, Ivano Amelio, David W Andrews, Rami I Aqeilan, Eli Arama, Eric H Baehrecke, Siddharth Balachandran, Daniele Bano, Nickolai A Barlev, Jiri Bartek, Nicolas G Bazan, Christoph Becker, Francesca Bernassola, Mathieu J M Bertrand, Marco E Bianchi, Mikhail V Blagosklonny, J Magarian Blander, Giovanni Blandino, Klas Blomgren, Christoph Borner, Carl D Bortner, Pierluigi Bove, Patricia Boya, Catherine Brenner, Petr Broz, Thomas Brunner, Rune Busk Damgaard, George A Calin, Michelangelo Campanella, Eleonora Candi, Michele Carbone, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Guo-Qiang Chen, Quan Chen, Youhai H Chen, Emily H Cheng, Jerry E Chipuk, John A Cidlowski, Aaron Ciechanover, Gennaro Ciliberto, Marcus Conrad, Juan R Cubillos-Ruiz, Peter E Czabotar, Vincenzo D'Angiolella, Mads Daugaard, Ted M Dawson, Valina L Dawson, Ruggero De Maria, Bart De Strooper, Klaus-Michael Debatin, Ralph J Deberardinis, Alexei Degterev, Giannino Del Sal, Mohanish Deshmukh, Francesco Di Virgilio, Marc Diederich, Scott J Dixon, Brian D Dynlacht, Wafik S El-Deiry, John W Elrod, Kurt Engeland, Gian Maria Fimia, Claudia Galassi, Carlo Ganini, Ana J Garcia-Saez, Abhishek D Garg, Carmen Garrido, Evripidis Gavathiotis, Motti Gerlic, Sourav Ghosh, Douglas R Green, Lloyd A Greene, Hinrich Gronemeyer, Georg Häcker, György Hajnóczky, J Marie Hardwick, Ygal Haupt, Sudan He, David M Heery, Michael O Hengartner, Claudio Hetz, David A Hildeman, Hidenori Ichijo, Satoshi Inoue, Marja Jäättelä, Ana Janic, Bertrand Joseph, Philipp J Jost, Thirumala-Devi Kanneganti, Michael Karin, Hamid Kashkar, Thomas Kaufmann, Gemma L Kelly, Oliver Kepp, Adi Kimchi, Richard N Kitsis, Daniel J Klionsky, Ruth Kluck, Dmitri V Krysko, Dagmar Kulms, Sharad Kumar, Sergio Lavandero, Inna N Lavrik, John J Lemasters, Gianmaria Liccardi, Andreas Linkermann, Stuart A Lipton, Richard A Lockshin, Carlos López-Otín, Tom Luedde, Marion Macfarlane, Frank Madeo, Walter Malorni, Gwenola Manic, Roberto Mantovani, Saverio Marchi, Jean-Christophe Marine, Seamus J Martin, Jean-Claude Martinou, Pier G Mastroberardino, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Gerry Melino, Sonia Melino, Edward A Miao, Ute M Moll, Cristina Muñoz-Pinedo, Daniel J Murphy, Maria Victoria Niklison-Chirou, Flavia Novelli, Gabriel Núñez, Andrew Oberst, Dimitry Ofengeim, Joseph T Opferman, Moshe Oren, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M Penninger, Francesca Pentimalli, David M Pereira, Shazib Pervaiz, Marcus E Peter, Paolo Pinton, Giovanni Porta, Jochen H M Prehn, Hamsa Puthalakath, Gabriel A Rabinovich, Krishnaraj Rajalingam, Kodi S Ravichandran, Markus Rehm, Jean-Ehrland Ricci, Rosario Rizzuto, Nirmal Robinson, Cecilia M P Rodrigues, Barak Rotblat, Carla V Rothlin, David C Rubinsztein, Thomas Rudel, Alessandro Rufini, Kevin M Ryan, Kristopher A Sarosiek, Akira Sawa, Emre Sayan, Kate Schroder, Luca Scorrano, Federico Sesti, Feng Shao, Yufang Shi, Giuseppe S Sica, John Silke, Hans-Uwe Simon, Antonella Sistigu, Anastasis Stephanou, Brent R Stockwell, Flavie Strapazzon, Andreas Strasser, Liming Sun, Erwei Sun, Qiang Sun, Gyorgy Szabadkai, Stephen W G Tait, Daolin Tang, Nektarios Tavernarakis, Carol M Troy, Boris Turk, Nicoletta Urbano, Peter Vandenabeele, Tom Vanden Berghe, Matthew G Vander Heiden, Jacqueline L Vanderluit, Alexei Verkhratsky, Andreas Villunger, Silvia Von Karstedt, Anne K Voss, Karen H Vousden, Domagoj Vucic, Daniela Vuri, Erwin F Wagner, Henning Walczak, David Wallach, Ruoning Wang, Ying Wang, Achim Weber, Will Wood, Takahiro Yamazaki, Huang-Tian Yang, Zahra Zakeri, Joanna E Zawacka-Pankau, Lin Zhang, Haibing Zhang, Boris Zhivotovsky, Wenzhao Zhou, Mauro Piacentini, Guido Kroemer, Lorenzo Galluzzi

Faculty, Staff and Student Publications

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. …

Barriers To Care In Juvenile Localized And Systemic Scleroderma: An Exploratory Survey Study Of Caregivers’ Perspectives, Leigh A Stubbs, Andrew M Ferry, Danielle Guffey, Christina Loccke, Erin Moriarty Wade, Pamela Pour, Kaveh Ardalan, Peter Chira, Ingrid M Ganske, Daniel Glaser, Gloria Higgins, Nadia Luca, Katharine F Moore, Vidya Sivaraman, Katie Stewart, Natalia Vasquez-Canizares, Raegan D Hunt, Renata S Maricevich, Kathryn S Torok, Suzanne C Li, Childhood Arthritis, Rheumatology Research Alliance (Carra) Scleroderma Workgroup

Faculty, Staff and Students Publications

BACKGROUND: Juvenile localized scleroderma (LS) and systemic sclerosis (SSc) are rare pediatric conditions often associated with severe morbidities. Delays in diagnosis are common, increasing the risk for permanent damage and worse outcomes. This study explored caregiver perspectives on barriers they encountered while navigating diagnosis and care for their child's scleroderma.

METHODS: In this cross-sectional study, caregivers of juvenile LS or SSc patients were recruited from a virtual family scleroderma educational conference and a juvenile scleroderma online interest group. The survey queried respondents about their child's condition and factors affecting diagnosis and treatment.

RESULTS: The response rate was 61% (73/120), with …

Corneal Injury Is Associated With Stromal And Vascular Alterations Within Cranial Dura Mater, Olga V. Glinskii, Vladislav V. Glinsky, Leike Xie, Filiz Bunyak, Vladimir V. Glinskii, Sunilima Sinha, Suneel Gupta, Renato V. Iozzo, Rajiv R. Mohan

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The cornea and cranial dura mater share sensory innervation. This link raises the possibility that pathological impulses mediated by corneal injury may be transmitted to the cranial dura, trigger dural perivascular/connective tissue nociceptor responses, and induce vascular and stromal alterations affecting dura mater blood and lymphatic vessel functionality. In this study, using a mouse model, we demonstrate for the first time that two weeks after the initial insult, alkaline injury to the cornea leads to remote pathological changes within the coronal suture area of the dura mater. Specifically, we detected significant pro-fibrotic changes in the dural stroma, as well as …

Serinc5 Restricts Hiv Membrane Fusion By Altering Lipid Order And Heterogeneity In The Viral Membrane, Amanda E Ward, Daria Sokovikova, Melvin Neal Waxham, Frederick A Heberle, Ilya Levental, Kandice R Levental, Volker Kiessling, Judith M White, Lukas K Tamm

Faculty, Staff and Student Publications

The host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A body of work suggests that Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5's effects on HIV pseudoviral membranes. By measuring pseudoviral membrane thickness via cryo-electron microscopy and order via the fluorescent dye, …

Rank Is A Poor Prognosis Marker And A Therapeutic Target In Er-Negative Postmenopausal Breast Cancer, Marina Ciscar, Eva M Trinidad, Gema Perez-Chacon, Mansour Alsaleem, Maria Jimenez, Maria J Jimenez-Santos, Hector Perez-Montoyo, Adrian Sanz-Moreno, Andrea Vethencourt, Michael Toss, Anna Petit, Maria T Soler-Monso, Victor Lopez, Jorge Gomez-Miragaya, Clara Gomez-Aleza, Lacey E Dobrolecki, Michael T Lewis, Alejandra Bruna, Silvana Mouron, Miguel Quintela-Fandino, Fatima Al-Shahrour, Antonio Martinez-Aranda, Angels Sierra, Andrew R Green, Emad Rakha, Eva Gonzalez-Suarez

Faculty, Staff and Students Publications

Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER- ) from four independent cohorts. RANK protein expression was more frequent in ER- tumors, where it associated with poor outcome and poor response to chemotherapy. In ER- breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor …

Toward Practical Integration Of Omic And Imaging Data In Co-Clinical Trials, Emel Alkim, Heidi Dowst, Julie Dicarlo, Lacey E Dobrolecki, Anadulce Hernández-Herrera, David A Hormuth, Yuxing Liao, Apollo Mcowiti, Robia Pautler, Mothaffar Rimawi, Ashley Roark, Ramakrishnan Rajaram Srinivasan, Jack Virostko, Bing Zhang, Fei Zheng, Daniel L Rubin, Thomas E Yankeelov, Michael T Lewis

Faculty, Staff and Students Publications

Co-clinical trials are the concurrent or sequential evaluation of therapeutics in both patients clinically and patient-derived xenografts (PDX) pre-clinically, in a manner designed to match the pharmacokinetics and pharmacodynamics of the agent(s) used. The primary goal is to determine the degree to which PDX cohort responses recapitulate patient cohort responses at the phenotypic and molecular levels, such that pre-clinical and clinical trials can inform one another. A major issue is how to manage, integrate, and analyze the abundance of data generated across both spatial and temporal scales, as well as across species. To address this issue, we are developing MIRACCL …

Chemical Reprogramming Takes The Fast Lane, Emily J Park, Srikanth Kodali, Bruno Di Stefano

Faculty, Staff and Students Publications

Small molecule-induced cell fate transitions are characterized by low efficiency and slow kinetics. An optimized chemical reprogramming approach now facilitates the robust and rapid conversion of somatic cells to pluripotent stem cells, unlocking exciting avenues to study and manipulate human cell identity.

Parp Inhibitors For The Treatment Of Brca1/2-Mutated Metastatic Breast Cancer: A Systematic Review And Meta-Analysis, Ranju Kunwor, Daniel P. Silver, Maysa Abu-Khalaf

Kimmel Cancer Center Faculty Papers

BACKGROUND: The PARP inhibitors (PARPis) olaparib and talazoparib are currently approved for the treatment of deleterious germline BRCA1/2-mutated (gBRCA+) metastatic breast cancer (MBC). These approvals were based on improvements in progression-free survival (PFS) observed in two randomized controlled trials (RCTs). Other PARPis, such as veliparib and niraparib, have also been studied. We conducted this meta-analysis of RCTs to assess the PFS and overall survival (OS) benefits of PARPis in gBRCA + MBC.

METHODS: We performed a systematic search for RCTs using the Cochrane Library, PubMed, Embase, and Web of Science databases up to March 2021. Only phase II and III …

Swi/Snf Blockade Disrupts Pu1-Directed Enhancer Programs In Normal Hematopoietic Cells And Acute Myeloid Leukemia, Courtney Chambers, Katerina Cermakova, Yuen San Chan, Kristen Kurtz, Katharina Wohlan, Andrew Henry Lewis, Christiana Wang, Anh Pham, Milan Dejmek, Michal Sala, Mario Loeza Cabrera, Rogelio Aguilar, Radim Nencka, H Daniel Lacorazza, Rachel E Rau, H Courtney Hodges

Faculty, Staff and Students Publications

UNLABELLED: In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition …

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 …

Cigarette Smoke Condensate Induces Centrosome Clustering In Normal Lung Epithelial Cells, Jose Thaiparambil, Chandra S Amara, Subrata Sen, Nagireddy Putluri, Randa El-Zein

Faculty, Staff and Students Publications

BACKGROUND: Unlike normal cells, cancer cells frequently have multiple centrosomes that can cluster to form bipolar mitotic spindles and allow for successful cell division. Inhibiting centrosome clustering, therefore, holds therapeutic promise to promote cancer cell-specific cell death.

METHODS: We used confocal microscopy, real-time PCR, siRNA knockdown, and western blot to analyze centrosome clustering and declustering using normal lung bronchial epithelial and nonsmall-cell lung cancer (NSCLC) cell lines. Also, we used Ingenuity Pathway Analysis software to identify novel pathways associated with centrosome clustering.

RESULTS: In this study, we found that exposure to cigarette smoke condensate induces centrosome amplification and clustering in …

Opa1 Disease-Causing Mutants Have Domain-Specific Effects On Mitochondrial Ultrastructure And Fusion, Benjamín Cartes-Saavedra, Daniel Lagos, Josefa Macuada, Duxan Arancibia, Florence Burté, Marcela K. Sjöberg-Herrera, María Estela Andrés, Rita Horvath, Patrick Yu-Wai-Man, György Hajnóczky, Verónica Eisner

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Inner mitochondrial membrane fusion and cristae shape depend on optic atrophy protein 1, OPA1. Mutations in OPA1 lead to autosomal dominant optic atrophy (ADOA), an important cause of inherited blindness. The Guanosin Triphosphatase (GTPase) and GTPase effector domains (GEDs) of OPA1 are essential for mitochondrial fusion; yet, their specific roles remain elusive. Intriguingly, patients carrying OPA1 GTPase mutations have a higher risk of developing more severe multisystemic symptoms in addition to optic atrophy, suggesting pathogenic contributions for the GTPase and GED domains, respectively. We studied OPA1 GTPase and GED mutations to understand their domain-specific contribution to protein function by analyzing …

Renal Cell Carcinoma Unclassified With Medullary Phenotype In A Patient With Neurofibromatosis Type 2, Sanila Sarkar, Whitney Throckmorton, Racheal Bingham, Pavlos Msaouel, Giannicola Genovese, John Slopis, Priya Rao, Zsila Sadighi, Cynthia E Herzog

Faculty, Staff and Student Publications

We present, to our knowledge, the first reported case of germline neurofibromatosis Type 2 (NF2) associated with renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) with somatic loss by immunohistochemistry of the SMARCB1 tumor suppressor gene located centromeric to NF2 on chromosome 22q. Our patient is a 15-year-old with germline neurofibromatosis Type 2 (NF2) confirmed by pathogenic mutation of c.-854-??46+??deletion. Her NF2 history is positive for a right optic nerve sheath meningioma, CNIII schwannoma requiring radiation therapy and post gross total resection of right frontotemporal anaplastic meningioma followed by radiation. At age 15 she developed new onset weight loss and …

Hla Factors Versus Non-Hla Factors For Haploidentical Donor Selection, Rohtesh S Mehta, Kai Cao, Rima M Saliba, Gheath Al-Atrash, Amin M Alousi, Konstantinos Lontos, Curtis Marcoux, Yudith Carmazzi, Gabriela Rondon, Qaiser Bashir, Chitra M Hosing, Partow Kebriaei, Issa Khouri, David Marin, Yago Nieto, Betul Oran, Uday R Popat, Muzaffar H Qazilbash, Jeremy Ramdial, Katayoun Rezvani, Richard E Champlin, Elizabeth J Shpall

Faculty, Staff and Student Publications

When multiple haploidentical donors are available for transplantation, those of younger generations are generally selected over those of older generations. However, it is unclear who is the optimal donor when selecting candidates from within a generation, such as father versus mother, son versus daughter, or brother versus sister. Although traditionally male donors are favored over female donors, particularly for male recipients, and significant associations of individual HLA mis(matches) on outcomes are being increasingly recognized, the hierarchy of factors for donor selection is indeterminate. To assess whether HLA factors take precedence over non-HLA factors and to isolate the influence of specific …

The Tumor-Immune Ecosystem In Shaping Metastasis, Yang Gao, Jeffrey M Rosen, Xiang H-F Zhang

Faculty, Staff and Students Publications

A better understanding of the mechanisms regulating cancer metastasis is critical to develop new therapies and decrease mortality. Emerging evidence suggests that the interactions between tumor cells and the host immune system play important roles in establishing metastasis. Tumor cells are able to recruit immune cells, which in turn promotes tumor cell invasion, intravasation, survival in circulation, extravasation, and colonization in different organs. The tumor-host immunological interactions also generate a premetastatic niche in distant organs which facilitates metastasis. In this review, we summarize the recent findings on how tumor cells and immune cells regulate each other to coevolve and promote …

Actin Cytoskeleton Vulnerability To Disulfide Stress Mediates Disulfidptosi, Xiaoguang Liu, Litong Nie, Yilei Zhang, Yuelong Yan, Chao Wang, Medina Colic, Kellen Olszewski, Amber Horbath, Xiong Chen, Guang Lei, Chao Mao, Shiqi Wu, Li Zhuang, Masha V Poyurovsky, M James You, Traver Hart, Daniel D Billadeau, Junjie Chen, Boyi Gan

Faculty, Staff and Student Publications

SLC7A11-mediated cystine uptake suppresses ferroptosis yet promotes cell death under glucose starvation; the nature of the latter cell death remains unknown. Here, we show that aberrant accumulation of intracellular disulfides in SLC7A11high cells under glucose starvation induces a previously uncharacterized form of cell death distinct from apoptosis or ferroptosis. We term this cell death disulfidptosis. Chemical proteomics and cell biological analyses showed that glucose starvation in SLC7A11high cells induces aberrant disulfide bonds in actin cytoskeleton proteins and F-actin collapse in a SLC7A11-dependent manner. CRISPR screens and functional studies revealed that inactivation of the WAVE regulatory complex (WRC, which promotes actin …

Pyroptosis In Neutrophils: Multimodal Integration Of Inflammasome And Regulated Cell Death Signaling Pathways, George R Dubyak, Brandon A Miller, Eric Pearlman

Faculty, Staff and Student Publications

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which …

Ferroptosis In Life: To Be Or Not To Be, Ling Xu, Yu'e Liu, Xi Chen, Hua Zhong, Yi Wang

Faculty, Staff and Students Publications

Ferroptosis is a novel type of programmed cell death, characterized by a dysregulated iron metabolism and accumulation of lipid peroxides. It features the alteration of mitochondria and aberrant accumulation of excessive iron as well as loss of the cysteine-glutathione-GPX4 axis. Eventually, the accumulated lipid peroxides result in lethal damage to the cells. Ferroptosis is induced by the overloading of iron and the accumulation of ROS and can be inhibited by the activation of the GPX4 pathway, FS1-CoQ10 pathway, GCH1-BH4 pathway, and the DHODH pathway, it is also regulated by the oncogenes and tumor suppressors. Ferroptosis involves various physiological and pathological …

Deep Learning-Based Pathology Image Analysis Predicts Cancer Progression Risk In Patients With Oral Leukoplakia, Xinyi Zhang, Frederico O Gleber-Netto, Shidan Wang, Roberta Rayra Martins-Chaves, Ricardo Santiago Gomez, Nadarajah Vigneswaran, Arunangshu Sarkar, William N William, Vassiliki Papadimitrakopoulou, Michelle Williams, Diana Bell, Doreen Palsgrove, Justin Bishop, John V Heymach, Ann M Gillenwater, Jeffrey N Myers, Renata Ferrarotto, Scott M Lippman, Curtis Rg Pickering, Guanghua Xiao

Faculty, Staff and Student Publications

BACKGROUND: Oral leukoplakia (OL) is associated with an increased risk for oral cancer (OC) development. Prediction of OL cancer progression may contribute to decreased OC morbidity and mortality by favoring early intervention. Current OL progression risk assessment approaches face large interobserver variability and is weakly prognostic. We hypothesized that convolutional neural networks (CNN)-based histology image analyses could accelerate the discovery of better OC progression risk models.

METHODS: Our CNN-based oral mucosa risk stratification model (OMRS) was trained to classify a set of nondysplastic oral mucosa (OM) and a set of OC H&E slides. As a result, the OMRS model could …

Emerging Treatments For Myelodysplastic Syndromes: Biological Rationales And Clinical Translation, Juan Jose Rodriguez-Sevilla, Vera Adema, Guillermo Garcia-Manero, Simona Colla

Faculty, Staff and Student Publications

Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by myeloid dysplasia, peripheral blood cytopenias, and increased risk of progression to acute myeloid leukemia (AML). The standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, nearly 50% of patients have no response to the treatment. Patients with MDS in whom HMA therapy has failed have a dismal prognosis and no approved second-line therapy options, so enrollment in clinical trials of experimental agents represents these patients' only chance for improved outcomes. A better understanding of the molecular and biological mechanisms underpinning MDS …

Differential Regulation Of H3k9/H3k14 Acetylation By Small Molecules Drives Neuron-Fate-Induction Of Glioma Cell, Xincheng Liu, Cui Guo, Tiandong Leng, Zhen Fan, Jialuo Mai, Jiehong Chen, Jinhai Xu, Qianyi Li, Bin Jiang, Ke Sai, Wenzhuo Yang, Jiayu Gu, Jingyi Wang, Shuxin Sun, Zhijie Chen, Yingqian Zhong, Xuanming Liang, Chaoxin Chen, Jing Cai, Yuan Lin, Jiankai Liang, Jun Hu, Guangmei Yan, Wenbo Zhu, Wei Yin

Faculty, Staff and Student Publications

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple …

Estimated Impact Of Low Isolate Numbers On The Reliability Of Cumulative Antibiogram Data, Christian Tran, John Hargy, Bryan Hess, Matthew Pettengill

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Antibiograms are cumulative reports of antimicrobial susceptibility results that are used to guide the selection of empirical antibiotic therapy. Although Clinical and Laboratory Standards Institute (CLSI) guidelines recommend including only organisms that have at least 30 isolates in an antibiogram, previous studies demonstrated that adherence to this recommendation is highly variable. This paper aims to model the impact of small sample sizes on expected levels of error in cumulative antibiograms by comparing percent susceptibility results for random samples to those of the larger, entire data set. The results demonstrate relatively high error rates when utilizing low numbers of isolates in …

Optimizing Dna Extraction From Pediatric Stool For Diagnosis Of Tuberculosis And Use In Next-Generation Sequencing Applications, Tara E Ness, Lennard Meiwes, Alexander Kay, Rojelio Mejia, Christoph Lange, Maha Farhat, Anna Mandalakas, Andrew Dinardo

Faculty, Staff and Students Publications

The WHO has endorsed the use of stool samples for diagnosis of tuberculosis (TB) in children, and targeted next-generation sequencing (tNGS) of stool has been shown to support diagnosis and provide information about drug susceptibility (DS). Optimizing extraction of DNA from stool for sequencing is critical to ensure high diagnostic sensitivity and accurate DS information. Human stool samples were spiked with various concentrations of Mycobacterium bovis bacillus Calmette-Guérin (BCG), and DNA was extracted from the samples using four different DNA extraction kits. Each sample was subjected to quantitative PCR for identifying Mycobacterium tuberculosis complex bacteria and underwent further analysis to …

Bone Metastasis Initiation Is Coupled With Bone Remodeling Through Osteogenic Differentiation Of Ng2+ Cells, Weijie Zhang, Zhan Xu, Xiaoxin Hao, Tiancheng He, Jiasong Li, Yichao Shen, Kai Liu, Yang Gao, Jun Liu, David G Edwards, Aaron M Muscarella, Ling Wu, Liqun Yu, Longyong Xu, Xi Chen, Yi-Hsuan Wu, Igor L Bado, Yunfeng Ding, Sergio Aguirre, Hai Wang, Zbigniew Gugala, Robert L Satcher, Stephen T C Wong, Xiang H-F Zhang

Faculty, Staff and Students Publications

The bone microenvironment is dynamic and undergoes remodeling in normal and pathologic conditions. Whether such remodeling affects disseminated tumor cells (DTC) and bone metastasis remains poorly understood. Here, we demonstrated that pathologic fractures increase metastatic colonization around the injury. NG2+ cells are a common participant in bone metastasis initiation and bone remodeling in both homeostatic and fractured conditions. NG2+ bone mesenchymal stem/stromal cells (BMSC) often colocalize with DTCs in the perivascular niche. Both DTCs and NG2+ BMSCs are recruited to remodeling sites. Ablation of NG2+ lineage impaired bone remodeling and concurrently diminished metastatic colonization. In cocultures, NG2+ BMSCs, especially when …

Lef1 Drives A Central Memory Program And Supports Antitumor Activity Of Natural Killer T Cells, Ho Ngai, Gabriel A Barragan, Gengwen Tian, Julien C Balzeau, Chunchao Zhang, Amy N Courtney, Linjie Guo, Xin Xu, Michael S Wood, Janice M Drabek, Thorsten Demberg, Caroline M Sands, Cynthia N Chauvin-Fleurence, Erica J Di Pierro, Jeffrey M Rosen, Leonid S Metelitsa

Faculty, Staff and Students Publications

Vα24-invariant natural killer T cells (NKT) possess innate antitumor properties that can be exploited for cancer immunotherapy. We have shown previously that the CD62L+ central memory-like subset of these cells drives the in vivo antitumor activity of NKTs, but molecular mediators of NKT central memory differentiation remain unknown. Here, we demonstrate that relative to CD62L- cells, CD62L+ NKTs express a higher level of the gene encoding the Wnt/β-catenin transcription factor lymphoid enhancer binding factor 1 (LEF1) and maintain active Wnt/β-catenin signaling. CRISPR/Cas9-mediated LEF1 knockout reduced CD62L+ frequency after antigenic stimulation, whereas Wnt/β-catenin activator Wnt3a ligand increased CD62L+ frequency. LEF1 overexpression …