Digital Commons Network^™

Lowering Of Circulating Sclerostin May Increase Risk Of Atherosclerosis And Its Risk Factors: Evidence From A Genome-Wide Association Meta-Analysis Followed By Mendelian Randomization, Jie Zheng, Eleanor Wheeler, Maik Pietzner, Till F M Andlauer, Michelle S Yau, April E Hartley, Ben Michael Brumpton, Humaira Rasheed, John P Kemp, Monika Frysz, Jamie Robinson, Sjur Reppe, Vid Prijatelj, Kaare M Gautvik, Louise Falk, Winfried Maerz, Ingrid Gergei, Patricia A Peyser, Maryam Kavousi, Paul S De Vries, Clint L Miller, Maxime Bos, Sander W Van Der Laan, Rajeev Malhotra, Markus Herrmann, Hubert Scharnagl, Marcus Kleber, George Dedoussis, Eleftheria Zeggini, Maria Nethander, Claes Ohlsson, Mattias Lorentzon, Nick Wareham, Claudia Langenberg, Michael V Holmes, George Davey Smith, Jonathan H Tobias

Faculty, Staff and Student Publications

OBJECTIVE: In this study, we aimed to establish the causal effects of lowering sclerostin, target of the antiosteoporosis drug romosozumab, on atherosclerosis and its risk factors.

METHODS: A genome-wide association study meta-analysis was performed of circulating sclerostin levels in 33,961 European individuals. Mendelian randomization (MR) was used to predict the causal effects of sclerostin lowering on 15 atherosclerosis-related diseases and risk factors.

RESULTS: We found that 18 conditionally independent variants were associated with circulating sclerostin. Of these, 1 cis signal in SOST and 3 trans signals in B4GALNT3, RIN3, and SERPINA1 regions showed directionally opposite signals for sclerostin levels and …

Metabolomic Signatures Of Sedentary Behavior And Cardiometabolic Traits In Us Hispanics/Latinos: Results From Hchs/Sol, Jee-Young Moon, Jin Choul Chai, Bing Yu, Rebecca J Song, Guo-Chong Chen, Mariaelisa Graff, Martha L Daviglus, Queenie Chan, Bharat Thyagarajan, Sheila F Castaneda, Megan L Grove, Jianwen Cai, Xiaonan Xue, Yasmin Mossavar-Rahmani, Ramachandran S Vasan, Eric Boerwinkle, Robert C Kaplan, Qibin Qi

Faculty, Staff and Student Publications

PURPOSE: The aim of this study was to understand the serum metabolomic signatures of moderate-to-vigorous physical activity (MVPA) and sedentary behavior, and further associate their metabolomic signatures with incident cardiometabolic diseases.

METHODS: This analysis included 2711 US Hispanics/Latinos from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 yr (2008-2011). An untargeted, liquid chromatography-mass spectrometry was used to profile the serum metabolome. The associations of metabolites with accelerometer-measured MVPA and sedentary time were examined using survey linear regressions adjusting for covariates. The weighted correlation network analysis identified modules of correlated metabolites in relation to sedentary time, and the modules …

Multi-Ancestry Genome-Wide Study Identifies Effector Genes And Druggable Pathways For Coronary Artery Calcification, Maryam Kavousi, Maxime M Bos, Hanna J Barnes, Christian L Lino Cardenas, Doris Wong, Haojie Lu, Chani J Hodonsky, Lennart P L Landsmeer, Adam W Turner, Minjung Kho, Natalie R Hasbani, Paul S De Vries, Donald W Bowden, Sandesh Chopade, Joris Deelen, Ernest Diez Benavente, Xiuqing Guo, Edith Hofer, Shih-Jen Hwang, Sharon M Lutz, Leo-Pekka Lyytikäinen, Lotte Slenders, Albert V Smith, Maggie A Stanislawski, Jessica Van Setten, Quenna Wong, Lisa R Yanek, Diane M Becker, Marian Beekman, Matthew J Budoff, Mary F Feitosa, Chris Finan, Austin T Hilliard, Sharon L R Kardia, Jason C Kovacic, Brian G Kral, Carl D Langefeld, Lenore J Launer, Shaista Malik, Firdaus A A Mohamed Hoesein, Michal Mokry, Reinhold Schmidt, Jennifer A Smith, Kent D Taylor, James G Terry, Jeroen Van Der Grond, Joyce Van Meurs, Rozemarijn Vliegenthart, Jianzhao Xu, Kendra A Young, Nuno R Zilhão, Robert Zweiker, Themistocles L Assimes, Lewis C Becker, Daniel Bos, J Jeffrey Carr, L Adrienne Cupples, Dominique P V De Kleijn, Menno De Winther, Hester M Den Ruijter, Myriam Fornage, Barry I Freedman, Vilmundur Gudnason, Aroon D Hingorani, John E Hokanson, M Arfan Ikram, Ivana Išgum, David R Jacobs, Mika Kähönen, Leslie A Lange, Terho Lehtimäki, Gerard Pasterkamp, Olli T Raitakari, Helena Schmidt, P Eline Slagboom, André G Uitterlinden, Meike W Vernooij, Joshua C Bis, Nora Franceschini, Bruce M Psaty, Wendy S Post, Jerome I Rotter, Johan L M Björkegren, Christopher J O'Donnell, Lawrence F Bielak, Patricia A Peyser, Rajeev Malhotra, Sander W Van Der Laan, Clint L Miller

Faculty, Staff and Student Publications

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci …

Nuclear Receptors As Potential Therapeutic Targets In Peripheral Arterial Disease And Related Myopathy, Ashok Kumar, Vihang A Narkar

Faculty, Staff and Student Publications

Peripheral arterial disease (PAD) is a prevalent cardiovascular complication of limb vascular insufficiency, causing ischemic injury, mitochondrial metabolic damage and functional impairment in the skeletal muscle, and ultimately leading to immobility and mortality. While potential therapies have been mostly focussed on revascularization, none of the currently available pharmacological treatments are fully effective in PAD, often leading to amputations, particularly in chronic metabolic diseases. One major limitation of focussed angiogenesis and revascularization as a therapeutic strategy is a limited effect on metabolic restoration and muscle regeneration in the affected limb. Therefore, additional preclinical investigations are needed to discover novel treatment options …

Controversy And Consensus On The Management Of Elevated Sperm Dna Fragmentation In Male Infertility: A Global Survey, Current Guidelines, And Expert Recommendations, Ala'a Farkouh, Ashok Agarwal, Taha Abo-Almagd Abdel-Meguid Hamoda, Parviz Kavoussi, Ramadan Saleh, Armand Zini, Mohamed Arafa, Ahmed M Harraz, Murat Gul, Vilvapathy Senguttuvan Karthikeyan, Damayanthi Durairajanayagam, Amarnath Rambhatla, Florence Boitrelle, Eric Chung, Ponco Birowo, Tuncay Toprak, Ramy Abou Ghayda, Rossella Cannarella, Nguyen Ho Vinh Phuoc, Fotios Dimitriadis, Giorgio I Russo, Ioannis Sokolakis, Taymour Mostafa, Konstantinos Makarounis, Imad Ziouziou, Shinnosuke Kuroda, Marion Bendayan, Raneen Sawaid Kaiyal, Andrian Japari, Mara Simopoulou, Lucia Rocco, Nicolas Garrido, Nazim Gherabi, Kadir Bocu, Oguzhan Kahraman, Tan V Le, Christine Wyns, Kelton Tremellen, Selcuk Sarikaya, Sheena Lewis, Donald P Evenson, Edmund Ko, Aldo E Calogero, Fahmi Bahar, Marlon Martinez, Andrea Crafa, Quang Nguyen, Rafael F Ambar, Giovanni Colpi, Mustafa Emre Bakircioglu, Ralf Henkel, Hussein Kandil, Ege Can Serefoglu, Abdullah Alarbid, Akira Tsujimura, Alireza Kheradmand, Christina Anagnostopoulou, Angelo Marino, Aram Adamyan, Birute Zilaitiene, Cevahir Ozer, Edoardo Pescatori, Paraskevi Vogiatzi, Gian Maria Busetto, Giancarlo Balercia, Haitham Elbardisi, Hamed Akhavizadegan, Hesamoddin Sajadi, Hisanori Taniguchi, Hyun Jun Park, Israel Maldonado Rosas, Mohamed Al-Marhoon, Mohammad Ali Sadighi Gilani, Naif Alhathal, Germar-Michael Pinggera, Priyank Kothari, Nasser Mogharabian, Sava Micic, Sheryl Homa, Sara Darbandi, Tran Quang Tien Long, Wael Zohdy, Widi Atmoko, Marjan Sabbaghian, Wael Ibrahim, Ryan P Smith, Christopher Chee Kong Ho, Jean De La Rosette, Ahmed I El-Sakka, Mirko Preto, Cătălina Zenoaga-Barbăroșie, Saad Mohammed Abumelha, Aykut Baser, Kaan Aydos, Liliana Ramirez-Dominguez, Vijay Kumar, Teng Aik Ong, Tiago Cesar Mierzwa, Ricky Adriansjah, Saleem A Banihani, Kasonde Bowa, Shinichiro Fukuhara, Marcelo Rodriguez Peña, Mohamad Moussa, Umut Çağın Ari, Chak-Lam Cho, Nicholas N Tadros, Muhammet Rasit Ugur, Edouard Amar, Marco Falcone, Frederic Romain Santer, Arif Kalkanli, Keshab Kumar Karna, Kareim Khalafalla, Ranjit B Vishwakarma, Federica Finocchi, Carlo Giulioni, Erman Ceyhan, Gökhan Çeker, Chadi Yazbeck, Osvaldo Rajmil, Mehmet Yilmaz, Baris Altay, Trenton L Barrett, Kay Seong Ngoo, Shubhadeep Roychoudhury, Gianmaria Salvio, Haocheng Lin, Ates Kadioglu, Massimiliano Timpano, Tomer Avidor-Reiss, Lukman Hakim, Puneet Sindhwani, Giorgio Franco, Rajender Singh, Filippo Giacone, Mikhail Ruzaev, Raghavender Kosgi, Nikolaos Sofikitis, Ayad Palani, Gokhan Calik, Deniz Kulaksız, Davor Jezek, Manaf Al Hashmi, Panagiotis Drakopoulos, Huda Omran, Sofia Leonardi, Ciler Celik-Ozenci, Nur Dokuzeylül Güngör, Jonathan Ramsay, Toshiyasu Amano, Emrullah Sogutdelen, Gede Wirya Kusuma Duarsa, Koji Chiba, Sunil Jindal, Missy Savira, Luca Boeri, Edson Borges, Deepak Gupte, Fatih Gokalp, Guadalupe Hernández Hebrard, Suks Minhas, Rupin Shah, Global Andrology Forum

Faculty, Staff and Student Publications

Purpose: Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition.

Materials and methods: An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate …

Automated Cellular-Level Dual Global Fusion Of Whole-Slide Imaging For Lung Adenocarcinoma Prognosis, Songhui Diao, Pingjun Chen, Eman Showkatian, Rukhmini Bandyopadhyay, Frank R Rojas, Bo Zhu, Lingzhi Hong, Muhammad Aminu, Maliazurina B Saad, Morteza Salehjahromi, Amgad Muneer, Sheeba J Sujit, Carmen Behrens, Don L Gibbons, John V Heymach, Neda Kalhor, Ignacio I Wistuba, Luisa M Solis Soto, Jianjun Zhang, Wenjian Qin, Jia Wu

Faculty, Staff and Student Publications

Histopathologic whole-slide images (WSI) are generally considered the gold standard for cancer diagnosis and prognosis. Survival prediction based on WSI has recently attracted substantial attention. Nevertheless, it remains a central challenge owing to the inherent difficulties of predicting patient prognosis and effectively extracting informative survival-specific representations from WSI with highly compounded gigapixels. In this study, we present a fully automated cellular-level dual global fusion pipeline for survival prediction. Specifically, the proposed method first describes the composition of different cell populations on WSI. Then, it generates dimension-reduced WSI-embedded maps, allowing for efficient investigation of the tumor microenvironment. In addition, we introduce …

Correction To “Inhibition Of Hyaluronan Synthesis Attenuates Pulmonary Hypertension Associated With Lung Fibrosis”, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

No abstract provided.

New Insights Into The Neuraminidase-Mediated Hemagglutination Activity Of Influenza A(H3n2) Viruses, Rongyuan Gao, Philippe Noriel Q Pascua, Ha T Nguyen, Anton Chesnokov, Chloe Champion, Vasiliy P Mishin, Dave E Wentworth, Larisa V Gubareva

Faculty, Staff and Student Publications

Influenza virus neuraminidase (NA) can act as a receptor-binding protein, a role commonly attributed to hemagglutinin (HA). In influenza A(H3N2) viruses, three NA amino acid residues have previously been associated with NA-mediated hemagglutination: T148, D151, and more recently, H150. These residues are part of the 150-loop of the NA monomer. Substitutions at 148 and 151 arise from virus propagation in laboratory cell cultures, whereas changes at 150 occurred during virus evolution in the human host. In this study, we examined the effect of natural amino acid polymorphism at position 150 on NA-mediated hemagglutination. Using the A/Puerto Rico/8/34 backbone, we generated …

Kunitz-Type Protease Inhibitor Tfpi2 Remodels Stemness And Immunosuppressive Tumor Microenvironment In Glioblastoma, Lizhi Pang, Madeline Dunterman, Songlin Guo, Fatima Khan, Yang Liu, Erfan Taefi, Atousa Bahrami, Changiz Geula, Wen-Hao Hsu, Craig Horbinski, Charles David James, Peiwen Chen

Faculty, Staff and Student Publications

Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy …

The Concise Guide To Pharmacology 2023/24: Enzymes, Stephen P H Alexander, Doriano Fabbro, Eamonn Kelly, Alistair A Mathie, John A Peters, Emma L Veale, Jane F Armstrong, Elena Faccenda, Simon D Harding, Jamie A Davies, Stephanie Annett, Detlev Boison, Kathryn Elisa Burns, Carmen Dessauer, Jurg Gertsch, Nuala Ann Helsby, Angelo A Izzo, Rennolds Ostrom, Andreas Papapetropoulos, Nigel J Pyne, Susan Pyne, Tracy Robson, Roland Seifert, Johannes-Peter Stasch, Csaba Szabo, Mario Van Der Stelt, Albert Van Der Vliet, Val Watts, Szu Shen Wong

Faculty, Staff and Student Publications

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It …

The Emerging Importance Of Mitochondria In White Adipocytes: Neither Last Nor Least, Juan Cai, Fenfen Wang, Mengle Shao

Faculty, Staff and Student Publications

The growing recognition of mitochondria's crucial role in the regulation of white adipose tissue remodeling and energy balance underscores its significance. The marked metabolic diversity of mitochondria provides the molecular and cellular foundation for enabling adipose tissue plasticity in response to various metabolic cues. Effective control of mitochondrial function at the cellular level, not only in thermogenic brown and beige adipocytes but also in energy-storing white adipocytes, exerts a profound influence on adipose homeostasis. Furthermore, mitochondria play a pivotal role in intercellular communication within adipose tissue via production of metabolites with signaling properties. A more comprehensive understanding of mitochondrial regulation …

Clinical And Biological Significance Of Circulating Mirnas In Chronic Pancreatitis Patients Undergoing Total Pancreatectomy With Islet Autotransplantation, Srividya Vasu, Giovanna Saracino, Carly M Darden, Kenjiro Kumano, Yang Liu, Michael C Lawrence, Bashoo Naziruddin

Faculty, Staff and Student Publications

Background: Specific microRNAs (miRNAs) were elevated in chronic pancreatitis (CP) patients during islet infusion after total pancreatectomy (TPIAT). We aimed to identify circulating miRNA signatures of pancreatic damage, predict miRNA-mRNA networks to identify potential links to CP pathogenesis and identify islet isolation and transplantation functional outcomes.

Methods: Small RNA sequencing was performed to identify distinct circulating miRNA signatures in CP. Plasma miRNAs were measured using miRCURY LNA SYBR green quantitative real-time polymerase chain reaction assays. Correlation analyses were performed using R software. The miRNA target and disease interactions were determined using miRNet and the miRNA enrichment and annotation tool.

Results: …

Delivery Outcomes In A Cohort Of Pregnant Patients With Covid-19 With And Without Viral Pneumonia, Brianna Dubose, Yazmeen Tembunde, Katherine E Goodman, Lisa Pineles, Gita Nadimpalli, Jonathan D Baghdadi, Jacqueline G Parchem, Anthony D Harris, Beth L Pineles

Faculty, Staff and Student Publications

Background: Among pregnant people, COVID-19 can lead to adverse outcomes, but the specific pregnancy outcomes that are affected by the disease are unclear. In addition, the effect of the severity of COVID-19 on pregnancy outcomes has not been clearly identified.

Objective: This study aimed to evaluate the associations between COVID-19 with and without viral pneumonia and cesarean delivery, preterm delivery, preeclampsia, and stillbirth.

Study design: We conducted a retrospective cohort study (April 2020-May 2021) of deliveries between 20 and 42 weeks of gestation from US hospitals in the Premier Healthcare Database. The primary outcomes were cesarean delivery, preterm delivery, preeclampsia, …

Electrophysiological Responses To Emotional And Cocaine Cues Reveal Individual Neuroaffective Profiles In Cocaine Users, Heather E Webber, Constanza De Dios, Margaret C Wardle, Robert Suchting, Charles E Green, Joy M Schmitz, Scott D Lane, Francesco Versace

Faculty, Staff and Student Publications

Smokers with stronger neuroaffective responses to drug-related cues compared to non-drug-related pleasant images (C>P) are more vulnerable to compulsive smoking than individuals with the opposite brain reactivity profile (P>C). However, it is unknown if these neurobehavioral profiles exist in individuals abusing other drugs. We tested whether individuals with cocaine use disorder (CUD) show similar neuroaffective profiles to smokers. We also monitored eye movements to assess attentional bias toward cues and we further performed exploratory analyses on demographics, personality, and drug use between profiles. Participants with CUD (n=43) viewed pleasant, unpleasant, cocaine, and neutral images while we recorded electroencephalogram. …

Gwas Meta-Analysis Of Suicide Attempt: Identification Of 12 Genome-Wide Significant Loci And Implication Of Genetic Risks For Specific Health Factors, Anna R Docherty, Niamh Mullins, Allison E Ashley-Koch, Xuejun Qin, Jonathan R I Coleman, Andrey Shabalin, Jooeun Kang, Balasz Murnyak, Frank Wendt, Mark Adams, Adrian I Campos, Emily Diblasi, Janice M Fullerton, Henry R Kranzler, Amanda V Bakian, Eric T Monson, Miguel E Rentería, Consuelo Walss-Bass, Ole A Andreassen, Chittaranjan Behera, Cynthia M Bulik, Howard J Edenberg, Ronald C Kessler, J John Mann, John I Nurnberger, Giorgio Pistis, Fabian Streit, Robert J Ursano, Renato Polimanti, Michelle Dennis, Melanie Garrett, Lauren Hair, Philip Harvey, Elizabeth R Hauser, Michael A Hauser, Jennifer Huffman, Daniel Jacobson, Ravi Madduri, Benjamin Mcmahon, David W Oslin, Jodie Trafton, Swapnil Awasthi, Wade H Berrettini, Martin Bohus, Xiao Chang, Hsi-Chung Chen, Wei J Chen, Erik D Christensen, Scott Crow, Philibert Duriez, Alexis C Edwards, Fernando Fernández-Aranda, Hanga Galfalvy, Michael Gandal, Philip Gorwood, Yiran Guo, Jonathan D Hafferty, Hakon Hakonarson, Katherine A Halmi, Akitoyo Hishimoto, Sonia Jain, Stéphane Jamain, Susana Jiménez-Murcia, Craig Johnson, Allan S Kaplan, Walter H Kaye, Pamela K Keel, James L Kennedy, Minsoo Kim, Kelly L Klump, Daniel F Levey, Dong Li, Shih-Cheng Liao, Klaus Lieb, Lisa Lilenfeld, Christian R Marshall, James E Mitchell, Satoshi Okazaki, Ikuo Otsuka, Dalila Pinto, Abigail Powers, Nicolas Ramoz, Stephan Ripke, Stefan Roepke, Vsevolod Rozanov, Stephen W Scherer, Christian Schmahl, Marcus Sokolowski, Anna Starnawska, Michael Strober, Mei-Hsin Su, Laura M Thornton, Janet Treasure, Erin B Ware, Hunna J Watson, Stephanie H Witt, D Blake Woodside, Zeynep Yilmaz, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lars Alfredsson, Vivek Appadurai, María Soler Artigas, Sandra Van Der Auwera, M Helena Azevedo, Nicholas Bass, Claiton H D Bau, Bernhard T Baune, Frank Bellivier, Klaus Berger, Joanna M Biernacka, Tim B Bigdeli, Elisabeth B Binder, Michael Boehnke, Marco P Boks, David L Braff, Richard Bryant, Monika Budde, Enda M Byrne, Wiepke Cahn, Enrique Castelao, Jorge A Cervilla, Boris Chaumette, Aiden Corvin, Nicholas Craddock, Srdjan Djurovic, Jerome C Foo, Andreas J Forstner, Mark Frye, Justine M Gatt, Ina Giegling, Hans J Grabe, Melissa J Green, Eugenio H Grevet, Maria Grigoroiu-Serbanescu, Blanca Gutierrez, Jose Guzman-Parra, Marian L Hamshere, Annette M Hartmann, Joanna Hauser, Stefanie Heilmann-Heimbach, Per Hoffmann, Marcus Ising, Ian Jones, Lisa A Jones, Lina Jonsson, René S Kahn, John R Kelsoe, Kenneth S Kendler, Stefan Kloiber, Karestan C Koenen, Manolis Kogevinas, Marie-Odile Krebs, Mikael Landén, Marion Leboyer, Phil H Lee, Douglas F Levinson, Calwing Liao, Jolanta Lissowska, Fermin Mayoral, Susan L Mcelroy, Patrick Mcgrath, Peter Mcguffin, Andrew Mcquillin, Divya Mehta, Ingrid Melle, Philip B Mitchell, Esther Molina, Gunnar Morken, Caroline Nievergelt, Markus M Nöthen, Michael C O'Donovan, Roel A Ophoff, Michael J Owen, Carlos Pato, Michele T Pato, Brenda W J H Penninx, James B Potash, Robert A Power, Martin Preisig, Digby Quested, Josep Antoni Ramos-Quiroga, Andreas Reif, Marta Ribasés, Vanesa Richarte, Marcella Rietschel, Margarita Rivera, Andrea Roberts, Gloria Roberts, Guy A Rouleau, Diego L Rovaris, Alan R Sanders, Peter R Schofield, Thomas G Schulze, Laura J Scott, Alessandro Serretti, Jianxin Shi, Lea Sirignano, Pamela Sklar, Olav B Smeland, Jordan W Smoller, Edmund J S Sonuga-Barke, Maciej Trzaskowski, Ming T Tsuang, Gustavo Turecki, Laura Vilar-Ribó, John B Vincent, Henry Völzke, James T R Walters, Cynthia Shannon Weickert, Thomas W Weickert, Myrna M Weissman, Leanne M Williams, Naomi R Wray, Clement C Zai, Esben Agerbo, Anders D Børglum, Gerome Breen, Ditte Demontis, Annette Erlangsen, Joel Gelernter, Stephen J Glatt, David M Hougaard, Hai-Gwo Hwu, Po-Hsiu Kuo, Cathryn M Lewis, Qingqin S Li, Chih-Min Liu, Nicholas G Martin, Andrew M Mcintosh, Sarah E Medland, Ole Mors, Merete Nordentoft, Catherine M Olsen, David Porteous, Daniel J Smith, Eli A Stahl, Murray B Stein, Danuta Wasserman, Thomas Werge, David C Whiteman, Virginia Willour, Hilary Coon, Jean C Beckham, Nathan A Kimbrel, Douglas M Ruderfer

Faculty, Staff and Student Publications

OBJECTIVE: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.

METHODS: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, …

Joint Vestibular Schwannoma Enlargement Prediction And Segmentation Using A Deep Multi-Task Model, Kai Wang, Nicholas A George-Jones, Liyuan Chen, Jacob B Hunter, Jing Wang

Faculty, Staff and Student Publications

Objective: To develop a deep-learning-based multi-task (DMT) model for joint tumor enlargement prediction (TEP) and automatic tumor segmentation (TS) for vestibular schwannoma (VS) patients using their initial diagnostic contrast-enhanced T1-weighted (ceT1) magnetic resonance images (MRIs).

Methods: Initial ceT1 MRIs for VS patients meeting the inclusion/exclusion criteria of this study were retrospectively collected. VSs on the initial MRIs and their first follow-up scans were manually contoured. Tumor volume and enlargement ratio were measured based on expert contours. A DMT model was constructed for jointly TS and TEP. The manually segmented VS volume on the initial scan and the tumor enlargement label …

Advances In Vaccine Development For Cancer Prevention And Treatment In Lynch Syndrome, Ana M Bolivar, Fahriye Duzagac, Krishna M Sinha, Eduardo Vilar

Faculty, Staff and Student Publications

Lynch Syndrome (LS) is one of the most common hereditary cancer syndromes, and is caused by mutations in one of the four DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6 and PMS2. Tumors developed by LS carriers display high levels of microsatellite instability, which leads to the accumulation of large numbers of mutations, among which frameshift insertion/deletions (indels) within microsatellite (MS) loci are the most common. As a result, MMR-deficient (MMRd) cells generate increased rates of tumor-specific neoantigens (neoAgs) that can be recognized by the immune system to activate cancer cell killing. In this context, LS is an ideal …

Cancer Germline Predisposing Variants And Late Mortality From Subsequent Malignant Neoplasms Among Long-Term Childhood Cancer Survivors: A Report From The St Jude Lifetime Cohort And The Childhood Cancer Survivor Study, Cheng Chen, Na Qin, Mingjuan Wang, Qian Dong, Saima Sultana Tithi, Yawei Hui, Wenan Chen, Gang Wu, Dennis Kennetz, Michael N Edmonson, Michael C Rusch, Andrew Thrasher, John Easton, Heather L Mulder, Nan Song, Noel-Marie Plonski, Kyla Shelton, Cindy Im, Matthew J Ehrhardt, Kim E Nichols, Wendy M Leisenring, Kayla L Stratton, Rebecca Howell, Yutaka Yasui, Smita Bhatia, Gregory T Armstrong, Kirsten K Ness, Melissa M Hudson, Jinghui Zhang, Hui Wang, Deo Kumar Srivastava, Leslie L Robison, Zhaoming Wang

Faculty, Staff and Student Publications

Background: Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis).

Methods: In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or …

The Microtubule Quartet Protein Snap1 In Trypanosoma Brucei Facilitates Flagellum And Cell Division Plane Positioning By Promoting Basal Body Segregation, Martin Carbo-Tano, Mathilde Lapoix, Xinyu Jia, Olivier Thouvenin, Marco Pascucci, François Auclair, Feng B Quan, Shahad Albadri, Vernie Aguda, Younes Farouj, Elizabeth M C Hillman, Ruben Portugues, Filippo Del Bene, Tod R Thiele, Réjean Dubuc, Claire Wyart

Faculty, Staff and Student Publications

The mesencephalic locomotor region (MLR) is a brain stem area whose stimulation triggers graded forward locomotion. How MLR neurons recruit downstream vsx2+ (V2a) reticulospinal neurons (RSNs) is poorly understood. Here, to overcome this challenge, we uncovered the locus of MLR in transparent larval zebrafish and show that the MLR locus is distinct from the nucleus of the medial longitudinal fasciculus. MLR stimulations reliably elicit forward locomotion of controlled duration and frequency. MLR neurons recruit V2a RSNs via projections onto somata in pontine and retropontine areas, and onto dendrites in the medulla. High-speed volumetric imaging of neuronal activity reveals that …

Kras G12c In Advanced Nsclc: Prevalence, Co-Mutations, And Testing, Tony Kiat Hon Lim, Ferdinandos Skoulidis, Keith M Kerr, Myung-Ju Ahn, Joshua R Kapp, Fernando A Soares, Yasushi Yatabe

Faculty, Staff and Student Publications

KRAS is the most commonly mutated oncogene in advanced, non-squamous, non-small cell lung cancer (NSCLC) in Western countries. Of the various KRAS mutants, KRAS G12C is the most common variant (~40%), representing 10-13% of advanced non-squamous NSCLC. Recent regulatory approvals of the KRASG12C-selective inhibitors sotorasib and adagrasib for patients with advanced or metastatic NSCLC harboring KRASG12C have transformed KRAS into a druggable target. In this review, we explore the evolving role of KRAS from a prognostic to a predictive biomarker in advanced NSCLC, discussing KRAS G12C biology, real-world prevalence, clinical relevance of co-mutations, and approaches to molecular testing. Real-world evidence …

X, But Not Y, Chromosomal Complement Contributes To Stroke Sensitivity In Aged Animals, Shaohua Qi, Conelius Ngwa, Abdullah Al Mamun, Sharmeen Romana, Ting Wu, Sean P Marrelli, Arthur P Arnold, Louise D Mccullough, Fudong Liu

Faculty, Staff and Student Publications

Post-menopausal women become vulnerable to stroke and have poorer outcomes and higher mortality than age-matched men, and previous studies suggested that sex chromosomes play a vital role in mediating stroke sensitivity in the aged. It is unknown if this is due to effects of the X or Y chromosome. The present study used the XY* mouse model (with four genotypes: XX and XO gonadal females and XY and XXY gonadal males) to compare the effect of the X vs. Y chromosome compliment in stroke. Aged (18-20 months) and gonadectomized young (8-12 weeks) mice were subjected to a 60-min middle cerebral …

International Association For The Study Of Lung Cancer Study Of Reproducibility In Assessment Of Pathologic Response In Resected Lung Cancers After Neoadjuvant Therapy, Sanja Dacic, William Travis, Mary Redman, Anjali Saqi, Wendy A Cooper, Alain Borczuk, Jin-Haeng Chung, Carolyn Glass, Javier Martin Lopez, Anja C Roden, Lynette Sholl, Annikka Weissferdt, Juan Posadas, Angela Walker, Hu Zhu, Manuja T Wijeratne, Casey Connolly, Murry Wynes, Neus Bota-Rabassedas, Beatriz Sanchez-Espiridion, J Jack Lee, Sabina Berezowska, Teh-Ying Chou, Keith Kerr, Andrew Nicholson, Claudia Poleri, Kurt A Schalper, Ming-Sound Tsao, David P Carbone, Neal Ready, Tina Cascone, John Heymach, Boris Sepesi, Catherine Shu, Naiyer Rizvi, Josuha Sonett, Nasser Altorki, Mariano Provencio, Paul A Bunn, Mark G Kris, Chandra P Belani, Karen Kelly, Ignacio Wistuba

Faculty, Staff and Student Publications

Introduction: Pathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria.

Methods: An international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin-stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable …

Renal Cell Carcinoma Of Variant Histology: Biology And Therapies, Pavlos Msaouel, Giannicola Genovese, Nizar M Tannir

Faculty, Staff and Student Publications

The term variant histology renal cell carcinomas (vhRCCs), also known as non-clear cell RCCs, refers to a diverse group of malignancies with distinct biologic and therapeutic considerations. The management of vhRCC subtypes is often based on extrapolating results from the more common clear cell RCC studies or basket trials that are not specific to each histology. The unique management of each vhRCC subtype necessitates accurate pathologic diagnosis and dedicated research efforts. Herein, we discuss tailored recommendations for each vhRCC histology informed by ongoing research and clinical experience.

Bayesian Approach For Design And Analysis Of Medical Device Trials In The Era Of Modern Clinical Studies, Han Cao, Chen Yao, Ying Yuan

Faculty, Staff and Student Publications

Medical device technology develops rapidly, and the life cycle of a medical device is much shorter than drugs. It is necessary to evaluate the safety and effectiveness of a medical device in a timely manner to keep up with technology flux. Bayesian methods provides an efficient approach to addressing this challenge. In this article, we review the characteristics of the Bayesian approach and some Bayesian designs that were commonly used in medical device regulatory setting, including Bayesian adaptive design, Bayesian diagnostic design, Bayesian multiregional design, and Bayesian label expansion study. We illustrate these designs with medical devices approved by the …

Dynamics Of The Dynll1-Mre11 Complex Regulate Dna End Resection And Recruitment Of Shieldin To Dsbs, Michelle L Swift, Rui Zhou, Aleem Syed, Lisa A Moreau, Bartłomiej Tomasik, John A Tainer, Panagiotis A Konstantinopoulos, Alan D D'Andrea, Yizhou Joseph He, Dipanjan Chowdhury

Faculty, Staff and Student Publications

The extent and efficacy of DNA end resection at DNA double-strand breaks (DSB) determine the repair pathway choice. Here we describe how the 53BP1-associated protein DYNLL1 works in tandem with the Shieldin complex to protect DNA ends. DYNLL1 is recruited to DSBs by 53BP1, where it limits end resection by binding and disrupting the MRE11 dimer. The Shieldin complex is recruited to a fraction of 53BP1-positive DSBs hours after DYNLL1, predominantly in G1 cells. Shieldin localization to DSBs depends on MRE11 activity and is regulated by the interaction of DYNLL1 with MRE11. BRCA1-deficient cells rendered resistant to PARP inhibitors by …

Cytosolic Dna Accumulation Promotes Breast Cancer Immunogenicity Via A Sting-Independent Pathway, Jing Zhang, Hui Dai, Lei Huo, Jared K Burks, Daniel J Mcgrail, Shiaw-Yih Lin

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint blockade (ICB) has revolutionized cancer treatment. However, ICB alone has demonstrated only benefit in a small subset of patients with breast cancer. Recent studies have shown that agents targeting DNA damage response improve the efficacy of ICB and promote cytosolic DNA accumulation. However, recent clinical trials have shown that these agents are associated with hematological toxicities. More effective therapeutic strategies are urgently needed.

METHODS: Primary triple negative breast cancer tumors were stained for cytosolic single-stranded DNA (ssDNA) using multiplex immunohistochemical staining. To increase cytosolic ssDNA, we genetically silenced TREX1. The role of tumor cytosolic ssDNA in promoting …

Anchors: A Way For Ftsz Filaments To Stay Membrane Bound, Arindam Naha, Daniel P Haeusser, William Margolin

Faculty, Staff and Student Publications

Most bacteria use the tubulin homolog FtsZ to organize their cell division. FtsZ polymers initially assemble into mobile complexes that circle around a ring-like structure at the cell midpoint, followed by the recruitment of other proteins that will constrict the cytoplasmic membrane and synthesize septal peptidoglycan to divide the cell. Despite the need for FtsZ polymers to associate with the membrane, FtsZ lacks intrinsic membrane binding ability. Consequently, FtsZ polymers have evolved to interact with the membrane through adaptor proteins that both bind FtsZ and the membrane. Here, we discuss recent progress in understanding the functions of these FtsZ membrane …

Basic: A Bayesian Adaptive Synthetic-Control Design For Phase Ii Clinical Trials, Liyun Jiang, Peter F Thall, Fangrong Yan, Scott Kopetz, Ying Yuan

Faculty, Staff and Student Publications

Background: Randomized controlled trials are considered the gold standard for evaluating experimental treatments but often require large sample sizes. Single-arm trials require smaller sample sizes but are subject to bias when using historical control data for comparative inferences. This article presents a Bayesian adaptive synthetic-control design that exploits historical control data to create a hybrid of a single-arm trial and a randomized controlled trial.

Methods: The Bayesian adaptive synthetic control design has two stages. In stage 1, a prespecified number of patients are enrolled in a single arm given the experimental treatment. Based on the stage 1 data, applying propensity …

A Translational Blueprint For Developing Intraoperative Imaging Agents Via Radiopharmaceutical-Guided Drug Design, Teresa E Sullivan, Servando Hernandez Vargas, Sukhen C Ghosh, Solmaz Aghaamiri, Naruhiko Ikoma, Ali Azhdarinia

Faculty, Staff and Student Publications

Cancer imaging is a rapidly evolving field due to the discovery of novel molecular targets and the availability of corresponding techniques to detect them with high precision, accuracy, and sensitivity. Nuclear medicine is the most widely used molecular imaging modality and has a growing toolkit of clinically used radiopharmaceuticals that enable whole-body tumor visualization, staging, and treatment monitoring for a variety of tumors in a non-invasive manner. The need for similar imaging capabilities in the operating room has led to the emergence of fluorescence-guided surgery (FGS) as a powerful technique that gives surgeons unprecedented ability to distinguish tumors from healthy …

Pd-1 Blockade In Combination With Dasatinib Potentiates Induction Of Anti-Acute Lymphocytic Leukemia Immunity, Paul Koller, Natalia Baran, Karine Harutyunyan, Antonio Cavazos, Saradhi Mallampati, Renee L Chin, Zhou Jiang, Xian Sun, Heng-Huan Lee, Jennifer L Hsu, Patrick Williams, Xuelin Huang, Michael A Curran, Mien-Chie Hung, Marina Konopleva

Faculty, Staff and Student Publications

Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism …