Digital Commons Network^™

The Immune Response To Airway Mycosis, Wei Ruan, Xinxin Ma, In Hyuk Bang, Yafen Liang, Jochen Daniel Muehlschlegel, Kuang-Lei Tsai, Tingting W Mills, Xiaoyi Yuan, Holger K Eltzschig

Faculty, Staff and Student Publications

Despite increasing availability and more successful interventional approaches to restore coronary reperfusion, myocardial ischemia-reperfusion injury is a substantial cause of morbidity and mortality worldwide. During myocardial ischemia, the myocardium becomes profoundly hypoxic, thus causing stabilization of hypoxia-inducible transcription factors (HIF). Stabilization of HIF leads to a transcriptional program that promotes adaptation to hypoxia and cellular survival. Transcriptional consequences of HIF stabilization include increases in extracellular production and signaling effects of adenosine. Extracellular adenosine functions as a signaling molecule via the activation of adenosine receptors. Several studies implicated adenosine signaling in cardioprotection, particularly through the activation of the Adora2a and Adora2b …

Oncogenic Collagen I Homotrimers From Cancer Cells Bind To Α3Β1 Integrin And Impact Tumor Microbiome And Immunity To Promote Pancreatic Cancer, Yang Chen, Sujuan Yang, Jena Tavormina, Desiree Tampe, Michael Zeisberg, Huamin Wang, Krishnan K Mahadevan, Chang-Jiun Wu, Hikaru Sugimoto, Chia-Chi Chang, Robert R Jenq, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3β1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics. Deletion of Col1 homotrimers enhances …

Miracle Of Microrna-Driven Cancer Nanotherapeutics, Goknur Kara, Banu Arun, George A Calin, Bulent Ozpolat

Faculty, Staff and Student Publications

MicroRNAs (miRNAs) are non-protein-coding RNA molecules 20-25 nucleotides in length that can suppress the expression of genes involved in numerous physiological processes in cells. Accumulating evidence has shown that dysregulation of miRNA expression is related to the pathogenesis of various human diseases and cancers. Thus, stragegies involving either restoring the expression of tumor suppressor miRNAs or inhibiting overexpressed oncogenic miRNAs hold potential for targeted cancer therapies. However, delivery of miRNAs to tumor tissues is a challenging task. Recent advances in nanotechnology have enabled successful tumor-targeted delivery of miRNA therapeutics through newly designed nanoparticle-based carrier systems. As a result, miRNA therapeutics …

Adaptation And Dosimetric Commissioning Of A Synchrotron-Based Proton Beamline For Flash Experiments, Ming Yang, Xiaochun Wang, Fada Guan, Uwe Titt, Kiminori Iga, Dadi Jiang, Takeshi Takaoka, Satoshi Tootake, Tadashi Katayose, Masumi Umezawa, Emil Schüler, Steven Frank, Steven H Lin, Narayan Sahoo, Albert C Koong, Radhe Mohan, X Ronald Zhu

Faculty, Staff and Student Publications

Objective. Irradiation with ultra-high dose rates (>40 Gy s^-1), also known as FLASH irradiation, has the potential to shift the paradigm of radiation therapy because of its reduced toxicity to normal tissues compared to that of conventional irradiations. The goal of this study was to (1) achieve FLASH irradiation conditions suitable for pre-clinicalin vitroandin vivobiology experiments using our synchrotron-based proton beamline and (2) commission the FLASH irradiation conditions achieved.

Approach. To achieve these suitable FLASH conditions, we made a series of adaptations to our proton beamline, including modifying the spill length …

Asymmetric Synthesis Of Nortropanes Via Rh-Catalyzed Allylic Arylation, Yan Zhang, F Wieland Goetzke, Kirsten E Christensen, Stephen P Fletcher

Faculty, Staff and Student Publications

Tropane derivatives are extensively used in medicine, but catalytic asymmetric methods for their synthesis are underexplored. Here, we report Rh-catalyzed asymmetric Suzuki–Miyaura-type cross-coupling reactions between a racemic N-Boc-nortropane-derived allylic chloride and (hetero)aryl boronic esters. The reaction proceeds via an unexpected kinetic resolution, and the resolved enantiopure allyl chloride can undergo highly enantiospecific reactions with N-, O-, and S-containing nucleophiles. The method was applied in a highly stereoselective formal synthesis of YZJ-1139(1), a potential insomnia treatment that recently completed Phase II clinical trials. Our report represents an asymmetric catalytic method for the synthesis of YZJ-1139(1) and related compounds.

The Value Of In Vivo Reflectance Confocal Microscopy As An Assessment Tool In Chemotherapy-Induced Peripheral Neuropathy: A Pilot Study, Sabrina R Ramnarine, Patrick M Dougherty, Roman Rolke, Linda J Williams, Christi Alessi-Fox, Andrew J Coleman, Caterina Longo, Lesley A Colvin, Marie T Fallon

Faculty, Staff and Student Publications

Background: There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner's corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN.

Patients and methods: Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical …

A Multi-Layer Functional Genomic Analysis To Understand Noncoding Genetic Variation In Lipids, Shweta Ramdas, Jonathan Judd, Sarah E Graham, Stavroula Kanoni, Yuxuan Wang, Ida Surakka, Brandon Wenz, Shoa L Clarke, Alessandra Chesi, Andrew Wells, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W Winkler, Adam E Locke, Eirini Marouli, Greg J M Zajac, Kuan-Han H Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M Brumpton, Humaira Rasheed, Aki S Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A Rosenthal, Todd Lingren, Qiping Feng, Iftikhar J Kullo, Akira Narita, Jun Takayama, Hilary C Martin, Karen A Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E Miller, Archie Campbell, Kuang Lin, Iona Y Millwood, Asif Rasheed, George Hindy, Jessica D Faul, Wei Zhao, David R Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R Brown, Weihua Zhang, Ketian Yu, Ellen M Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian'an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R Wood, Yingji Ji, Zishan Gao, Simon Haworth, Ruth E Mitchell, Jin Fang Chai, Mette Aadahl, Anne A Bjerregaard, Jie Yao, Ani Manichaikul, Wen-Jane Lee, Chao Agnes Hsiung, Helen R Warren, Julia Ramirez, Jette Bork-Jensen, Line L Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F Mcdaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Sebastian Schönherr, Lukas Forer, Markus Scholz, Tessel E Galesloot, Jonathan P Bradfield, Sanni E Ruotsalainen, E Warwick Daw, Joseph M Zmuda, Jonathan S Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A Brody, Phuong Le, Mary F Feitosa, Mary K Wojczynski, Daiane Hemerich, Michael Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W Benjamins, Jorgen Engmann, Tsao L Noah, Anurag Verma, Roderick C Slieker, Ken Sin Lo, Nuno R Zilhao, Marcus E Kleber, Graciela E Delgado, Shaofeng Huo, Daisuke D Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L Leonard, Jonathan Marten, Carina Emmel, Börge Schmidt, Laura J Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S Nongmaithem, Alagu Sankareswaran, Marguerite R Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R H J Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C Warner, Ya Xing Wang, Wen B Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A Kentistou, Bernhard Banas, Anna Morgan, Karina Meidtner, Lawrence F Bielak, Jennifer A Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J Van Der Most, Niina Pitkänen, Brian E Cade, Sander W Van Der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R Bentley, Ayo P Doumatey, Adebowale A Adeyemo, Jong Young Lee, Eva R B Petersen, Aneta A Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W Rayner, Carol A Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O Obura, Jessica Van Setten, Karen Y He, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D Jackson, Alexander P Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C Bis, Lenore J Launer, Huaixing Li, Mike A Nalls, Olli T Raitakari, Sahoko Ichihara, Sarah H Wild, Christopher P Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique De Kleijn, Gert J De Borst, Eung Kweon Kim, Hieab H H Adams, M Arfan Ikram, Xiaofeng Zhu, Folkert W Asselbergs, Adriaan O Kraaijeveld, Joline W J Beulens, Xiao-Ou Shu, Loukianos S Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E Pennell, Trevor A Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M Heid, Klaus J Stark, Martina E Zimmermann, Henry Völzke, Georg Homuth, Michele K Evans, Alan B Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E Hoefer, Susan Redline, Katja Pahkala, Albertine J Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Patricia A Peyser, Norihiro Kato, Matthias B Schulze, Giorgia Girotto, Carsten A Böger, Bettina Jung, Peter K Joshi, David A Bennett, Philip L De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J Caulfield, Patricia B Munroe, Xiuqing Guo, Marina Ciullo, Jost B Jonas, Nilesh J Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Linda S Adair, Sonny Augustin Bechayda, H Janaka De Silva, Ananda R Wickremasinghe, Ronald M Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke I Den Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G Wilson, Lars Lind, Chew-Kiat Heng, Amanda E Nelson, Yvonne M Golightly, James F Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J Scott, D C Rao, Donna K Arnett, Mark Walker, Laura J Scott, Heikki A Koistinen, Giriraj R Chandak, Josep M Mercader, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, E Shyong Tai, Rob M Van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F Reilly, Amy Jayne Mcknight, Frank Kee, Karl-Heinz Jöckel, Mark I Mccarthy, Colin N A Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M Van Duijn, Zi-Bing Jin, Fan Lu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M T Hart, Petra J M Elders, Daniel J Rader, Scott M Damrauer, Meena Kumari, Mika Kivimaki, Pim Van Der Harst, Tim D Spector, Ruth J F Loos, Michael A Province, Esteban J Parra, Miguel Cruz, Bruce M Psaty, Ivan Brandslund, Peter P Pramstaller, Charles N Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F A Grant, Lambertus Kiemeney, Jacqueline De Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W Franks, Allan Linneberg, J Wouter Jukema, Amit V Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O Mook-Kanamori, Ko Willems Van Dijk, Hugh Watkins, David P Strachan, Niels Grarup, Peter Sever, Neil Poulter, Wayne Huey-Herng Sheu, Jerome I Rotter, Thomas M Dantoft, Fredrik Karpe, Matt J Neville, Nicholas J Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T Hattersley, Nancy L Pedersen, Patrik K E Magnusson, Dorret I Boomsma, Eco J C De Geus, L Adrienne Cupples, Joyce B J Van Meurs, Arfan Ikram, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J Wareham, Claudia Langenberg, Eleftheria Zeggini, Jaakko Tuomilehto, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C Chambers, Jaspal S Kooner, Paul S De Vries, Alanna C Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E North, Martha Daviglus, Peter Kraft, Nicholas G Martin, John B Whitfield, Shahid Abbas, Danish Saleheen, Robin G Walters, Michael V Holmes, Corri Black, Blair H Smith, Aris Baras, Anne E Justice, Julie E Buring, Paul M Ridker, Daniel I Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A Van Heel, Richard C Trembath, Wei-Qi Wei, Gail P Jarvik, Bahram Namjou, M Geoffrey Hayes, Marylyn D Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, Y Eugene Chen, Yuk-Lam Ho, Julie A Lynch, Philip S Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, John M Gaziano, Peter Wilson, Karen L Mohlke, Timothy M Frayling, Joel N Hirschhorn, Sekar Kathiresan, Michael Boehnke, Million Veterans Program, Global Lipids Genetics Consortium, Struan Grant, Pradeep Natarajan, Yan V Sun, Andrew P Morris, Panos Deloukas, Gina Peloso, Themistocles L Assimes, Cristen J Willer, Xiang Zhu, Christopher D Brown

Faculty, Staff and Student Publications

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective …

Bioengineering Tools Applied To Dentistry: Validation Methods For In Vitro And In Silico Analysis, Jefferson David Melo De Matos, Daher Antonio Queiroz, Leonardo Jiro Nomura Nakano, Valdir Cabral Andrade, Nathália De Carvalho Ramos Ribeiro, Alexandre Luiz Souto Borges, Marco Antonio Bottino, Guilherme Da Rocha Scalzer Lopes

Faculty, Staff and Student Publications

This study aimed to evaluate the use of bioengineering tools, finite element analysis, strain gauge analysis, photoelastic analysis, and digital image correlation, in computational studies with greater validity and reproducibility. A bibliographic search was performed in the main health databases PUBMED and Scholar Google, in which different studies, among them, laboratory studies, case reports, systematic reviews, and literature reviews, which were developed in living individuals, were included. Therefore, articles that did not deal with the use of finite element analysis, strain gauge analysis, photoelastic analysis, and digital image correlation were excluded, as well as their use in computational studies with …

Risk Assessment With Low-Pass Whole-Genome Sequencing Of Cell-Free Dna Before Cd19 Car T-Cell Therapy For Large B-Cell Lymphoma, Hua-Jay J Cherng, Ryan Sun, Bryant Sugg, Russell Irwin, Haopeng Yang, Cao Cuong Le, Qing Deng, Luis Fayad, Nathan H Fowler, Simrit Parmar, Raphael Steiner, Fredrick Hagemeister, Ranjit Nair, Hun Ju Lee, Maria Rodriguez, Felipe Samaniego, Swaminathan P Iyer, Christopher R Flowers, Linghua Wang, Loretta J Nastoupil, Sattva S Neelapu, Sairah Ahmed, Paolo Strati, Michael R Green, Jason Westin

Faculty, Staff and Student Publications

Patients with relapsed or refractory large B-cell lymphomas (rrLBCL) can achieve long-term remission after CD19 chimeric antigen receptor T-cell therapy (CART19). However, more than half of recipients will experience treatment failure. Thus, approaches are needed to identify high-risk patients who may benefit from alternative or consolidative therapy. We evaluated low-pass whole-genome sequencing (lpWGS) of cell-free DNA (cfDNA) before CART19 as a new approach for risk stratification. We performed lpWGS on pretreatment plasma samples from 122 patients at time of leukapheresis who received standard-of-care CART19 for rrLBCL to define DNA copy number alterations (CNAs). In multivariable selection, high focal CNA score …

Primary Cutaneous Lymphoma: Recommendations For Clinical Trial Design And Staging Update From The Iscl, Usclc, And Eortc, Elise A Olsen, Sean Whittaker, Rein Willemze, Lauren Pinter-Brown, Francine Foss, Larisa Geskin, Lawrence Schwartz, Steven Horwitz, Joan Guitart, John Zic, Youn H Kim, Gary S Wood, Madeleine Duvic, Wei Ai, Michael Girardi, Alejandro Gru, Emmanuella Guenova, Emmilia Hodak, Richard Hoppe, Werner Kempf, Ellen Kim, Mary Jo Lechowicz, Pablo Ortiz-Romero, Evangelia Papadavid, Pietro Quaglino, Mark Pittelkow, H Miles Prince, Jose Antonio Sanches, Makoto Sugaya, Maarten Vermeer, Jasmine Zain, Robert Knobler, Rudolf Stadler, Martine Bagot, Julia Scarisbrick

Faculty, Staff and Student Publications

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), …

Tale Of Two Cities: Narrative Review Of Oxygen, Sung-Ho Ahn, Angela Burkett, Atzhiry Paz, Jude P Savarraj, Sarah Hinds, Georgene Hergenroeder, Aaron M Gusdon, Xuefeng Ren, Jeong-Ho Hong, Huimahn A Choi

Faculty, Staff and Student Publications

BACKGROUND: Cerebral edema (CE) at admission is a surrogate marker of 'early brain injury' (EBI) after subarachnoid hemorrhage (SAH). Only recently has the focus on the changes in CE after SAH such as delayed resolution or newly developed CE been examined. Among several factors, an early systemic inflammatory response has been shown to be associated with CE. We investigate inflammatory markers in subjects with early CE which does not resolve, i.e., persistent CE after SAH.

METHODS: Computed tomography scans of SAH patients were graded at admission and at 7 days after SAH for CE using the 0-4 'subarachnoid hemorrhage early …

Implant-Abutment Misfit After Cyclic Loading: An In Vitro Experimental Study, John Eversong Lucena De Vasconcelos, Jefferson David Melo De Matos, Daher Antonio Queiroz, Guilherme Da Rocha Scalzer Lopes, Bruna Caroline Gonçalves Vasconcelos De Lacerda, Marco Antonio Bottino, Cecilia Pedroso Turssi, Roberta Tarkany Basting, Flávia Lucisano Botelho Do Amaral, Fabiana Mantovani Gomes França

Faculty, Staff and Student Publications

This study aimed to evaluate the influence of thermomechanical cycling (TMC) and type of abutment on the misfit and compressive strength of the implant−abutment interface. Forty 3.75-mm external hexagon implants with 25° angled abutments were divided into four groups (N = 10). Group A: overcast plus TMC; Group B: overcast without TMC; Group C: completely cast plus TMC; Group D: completely cast without TMC. Abutments were fixed to the implants with 32-Ncm torque, and groups A and C specimens were cyclically loaded at 80 N with 2 Hz for 1 million cycles. The misfit on the implant−abutment interface was evaluated …

Microenvironmental Landscape Of Human Melanoma Brain Metastases In Response To Immune Checkpoint Inhibition, Christopher Alvarez-Breckenridge, Samuel C Markson, Jackson H Stocking, Naema Nayyar, Matt Lastrapes, Matthew R Strickland, Albert E Kim, Magali De Sauvage, Ashish Dahal, Juliana M Larson, Joana L Mora, Andrew W Navia, Robert H Klein, Benjamin M Kuter, Corey M Gill, Mia Bertalan, Brian Shaw, Alexander Kaplan, Megha Subramanian, Aarushi Jain, Swaminathan Kumar, Husain Danish, Michael White, Osmaan Shahid, Kristen E Pauken, Brian C Miller, Dennie T Frederick, Christine Hebert, Mckenzie Shaw, Maria Martinez-Lage, Matthew Frosch, Nancy Wang, Elizabeth Gerstner, Brian V Nahed, William T Curry, Bob Carter, Daniel P Cahill, Genevieve Marie Boland, Benjamin Izar, Michael A Davies, Arlene H Sharpe, Mario L Suvà, Ryan J Sullivan, Priscilla K Brastianos, Scott L Carter

Faculty, Staff and Student Publications

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM …

Robust And Efficient Assessment Of Potency (Reap) As A Quantitative Tool For Dose-Response Curve Estimation, Shouhao Zhou, Xinyi Liu, Xinying Fang, Vernon M Chinchilli, Michael Wang, Hong-Gang Wang, Nikolay V Dokholyan, Chan Shen, J Jack Lee

Faculty, Staff and Student Publications

The median-effect equation has been widely used to describe the dose-response relationship and identify compounds that activate or inhibit specific disease targets in contemporary drug discovery. However, the experimental data often contain extreme responses, which may significantly impair the estimation accuracy and impede valid quantitative assessment in the standard estimation procedure. To improve the quantitative estimation of the dose-response relationship, we introduce a novel approach based on robust beta regression. Substantive simulation studies under various scenarios demonstrate solid evidence that the proposed approach consistently provides robust estimation for the median-effect equation, particularly when there are extreme outcome observations. Moreover, simulation …

Dual Leucine Zipper Kinase Regulates Dscam Expression Through A Noncanonical Function Of The Cytoplasmic Poly(A)-Binding Protein, Monika Singh, Bing Ye, Jung Hwan Kim

Faculty, Staff and Student Publications

Dual leucine zipper kinase (DLK) plays a pivotal role in the development, degeneration, and regeneration of neurons. DLK can regulate gene expression post-transcriptionally, but the underlying mechanism remains poorly understood. The Drosophila DLK, Wallenda (Wnd), regulates the expression of Down syndrome cell adhesion molecule (Dscam) to control presynaptic arbor growth. This regulation is mediated by the 3′ untranslated region (3′UTR) of Dscam mRNA, which suggests that RNA binding proteins (RBPs) mediate DLK function. We performed a genome-wide cell-based RNAi screen of RBPs and identified the cytoplasmic poly(A)-binding protein, pAbp, as an RBP that mediates Wnd-induced increase in Dscam expression. Genetic …

Polygenic Risk, Midlife Life's Simple 7, And Lifetime Risk Of Stroke, Emy A Thomas, Nitesh Enduru, Adrienne Tin, Eric Boerwinkle, Michael E Griswold, Thomas H Mosley, Rebecca F Gottesman, Myriam Fornage

Faculty, Staff and Student Publications

Background

Recent genetic discoveries in stroke have unleashed the potential of using genetic information for risk prediction and health interventions aimed at disease prevention. We sought to estimate the lifetime risk of stroke (LTRS) by levels of genetic risk and to investigate whether optimal cardiovascular health can offset the negative impact of high genetic risk on lifetime risk of stroke.

Methods and Results

Study participants were 11 568 middle‐aged adults (56% women, 23% Black adults), who were free of stroke at baseline and were followed up for a median of 28 years. The remaining LTRS was estimated according to levels …

Adenosine Metabolized From Extracellular Atp Promotes Type 2 Immunity Through Triggering A2bar Signaling In Intestinal Epithelial Cells, Darine W El-Naccache, Fei Chen, Mark J Palma, Alexander Lemenze, Matthew A Fischer, Wenhui Wu, Pankaj K Mishra, Holger K Eltzschig, Simon C Robson, Francesco Di Virgilio, George S Yap, Karen L Edelblum, György Haskó, William C Gause

Faculty, Staff and Student Publications

Intestinal nematode parasites can cross the epithelial barrier, causing tissue damage and release of danger-associated molecular patterns (DAMPs) that may promote host protective type 2 immunity. We investigate whether adenosine binding to the A2B adenosine receptor (A2BAR) on intestinal epithelial cells (IECs) plays an important role. Specific blockade of IEC A2BAR inhibits the host protective memory response to the enteric helminth, Heligmosomoides polygyrus bakeri (Hpb), including disruption of granuloma development at the host-parasite interface. Memory T cell development is blocked during the primary response, and transcriptional analyses reveal profound impairment of IEC activation. Extracellular ATP is visualized 24 h after …

Adenosine Metabolized From Extracellular Atp Promotes Type 2 Immunity Through Triggering A2bar Signaling In Intestinal Epithelial Cells, Darine W El-Naccache, Fei Chen, Mark J Palma, Alexander Lemenze, Matthew A Fischer, Wenhui Wu, Pankaj K Mishra, Holger K Eltzschig, Simon C Robson, Francesco Di Virgilio, George S Yap, Karen L Edelblum, György Haskó, William C Gause

Faculty, Staff and Student Publications

Intestinal nematode parasites can cross the epithelial barrier, causing tissue damage and release of danger-associated molecular patterns (DAMPs) that may promote host protective type 2 immunity. We investigate whether adenosine binding to the A

Muscle And Adipose Tissue Segmentations At The Third Cervical Vertebral Level In Patients With Head And Neck Cancer, Kareem A Wahid, Brennan Olson, Rishab Jain, Aaron J Grossberg, Dina El-Habashy, Cem Dede, Vivian Salama, Moamen Abobakr, Abdallah S R Mohamed, Renjie He, Joel Jaskari, Jaakko Sahlsten, Kimmo Kaski, Clifton D Fuller, Mohamed A Naser

Faculty, Staff and Student Publications

The accurate determination of sarcopenia is critical for disease management in patients with head and neck cancer (HNC). Quantitative determination of sarcopenia is currently dependent on manually-generated segmentations of skeletal muscle derived from computed tomography (CT) cross-sectional imaging. This has prompted the increasing utilization of machine learning models for automated sarcopenia determination. However, extant datasets currently do not provide the necessary manually-generated skeletal muscle segmentations at the C3 vertebral level needed for building these models. In this data descriptor, a set of 394 HNC patients were selected from The Cancer Imaging Archive, and their skeletal muscle and adipose tissue was …

Risk Of Alzheimer’S Disease Following Influenza Vaccination: A Claims-Based Cohort Study Using Propensity Score Matching, Avram S Bukhbinder, Yaobin Ling, Omar Hasan, Xiaoqian Jiang, Yejin Kim, Kamal N Phelps, Rosemarie E Schmandt, Albert Amran, Ryan Coburn, Srivathsan Ramesh, Qian Xiao, Paul E Schulz

Faculty, Staff and Student Publications

BACKGROUND: Prior studies have found a reduced risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions. However, the effect of influenza vaccination on Alzheimer's disease (AD) risk in a general cohort of older US adults has not been characterized.

OBJECTIVE: To compare the risk of incident AD between patients with and without prior influenza vaccination in a large US claims database.

METHODS: Deidentified claims data spanning September 1, 2009 through August 31, 2019 were used. Eligible patients were free of dementia during the 6-year look-back period and≥65 years …

Structural Plasticity Can Produce Metaplasticity, Wenli Zhao, Shuo Han, Na Qiu, Wenbo Feng, Mengjie Lu, Wenru Zhang, Mu Wang, Qingtong Zhou, Shutian Chen, Wei Xu, Juan Du, Xiaojing Chu, Cuiying Yi, Antao Dai, Liaoyuan Hu, Michelle Y Shen, Yaping Sun, Qing Zhang, Yingli Ma, Wenge Zhong, Dehua Yang, Ming-Wei Wang, Beili Wu, Qiang Zhao

Faculty, Staff and Student Publications

Somatostatin receptors (SSTRs) play versatile roles in inhibiting the secretion of multiple hormones such as growth hormone and thyroid-stimulating hormone, and thus are considered as targets for treating multiple tumors. Despite great progress made in therapeutic development against this diverse receptor family, drugs that target SSTRs still show limited efficacy with preferential binding affinity and conspicuous side-effects. Here, we report five structures of SSTR2 and SSTR4 in different states, including two crystal structures of SSTR2 in complex with a selective peptide antagonist and a non-peptide agonist, respectively, a cryo-electron microscopy (cryo-EM) structure of Gi1-bound SSTR2 in the presence of the …

Updated Estimates Of Sepsis Hospitalizations At United States Academic Medical Centers, Hei Kit Chan, Swapnil Khose, Summer Chavez, Bela Patel, Henry E Wang

Faculty, Staff and Student Publications

Objective: Sepsis is a major public health problem. Understanding the epidemiology of sepsis subtypes is important to quantify the magnitude of the problem and identify targets for system wide treatment strategies. We sought to describe the current national epidemiology of community-acquired (CAS), hospital-acquired (HAS) and healthcare-associated sepsis (HCAS) hospitalizations among academic medical centers in the United States using current discharge diagnosis taxonomies.

Methods: Retrospective analysis of patient discharge data from the Vizient Clinical Data Base/Resource Manager. We identified sepsis hospitalizations using four ICD-10 coding strategies: (1) "Martin" sepsis codes (21 ICD-10 codes), (2) "Angus" sepsis codes (ICD-10 infection + ICD-10 …

Integrated Regulation Of Pka By Fast And Slow Neurotransmission In The Nucleus Accumbens Controls Plasticity And Stress Responses, Rachel Thomas, Adan Hernandez, David R Benavides, Wei Li, Chunfeng Tan, Alan Umfress, Florian Plattner, Ayanabha Chakraborti, Lucas Pozzo-Miller, Susan S Taylor, James A Bibb

Faculty, Staff and Student Publications

Cortical glutamate and midbrain dopamine neurotransmission converge to mediate striatum-dependent behaviors, while maladaptations in striatal circuitry contribute to mental disorders. However, the crosstalk between glutamate and dopamine signaling has not been entirely elucidated. Here we uncover a molecular mechanism by which glutamatergic and dopaminergic signaling integrate to regulate cAMP-dependent protein kinase (PKA) via phosphorylation of the PKA regulatory subunit, RIIβ. Using a combination of biochemical, pharmacological, neurophysiological, and behavioral approaches, we find that glutamate-dependent reduction in cyclin-dependent kinase 5 (Cdk5)-dependent RIIβ phosphorylation alters the PKA holoenzyme autoinhibitory state to increase PKA signaling in response to dopamine. Furthermore, we show that …

Building Consensus For A Shared Definition Of Adverse Events: A Case Study In The Profession Of Dentistry, Amy Franklin, Elsbeth Kalenderian, Nutan Hebballi, Veronique Delattre, Jini Etoule, Joel White, Ram Vaderhobli, Denice Stewart, Karla Kent, Alfa Yansane, Muhammad Walji

Faculty, Staff and Student Publications

BACKGROUND: To achieve high-quality health care, adverse events (AEs) must be proactively recognized and mitigated. However, there is often ambiguity in applying guidelines and definitions. We describe the iterative calibration process needed to achieve a shared definition of AEs in dentistry. Our alignment process includes both independent and consensus building approaches.

OBJECTIVE: We explore the process of defining dental AEs and the steps necessary to achieve alignment across different care providers.

METHODS: Teams from 4 dental institutions across the United States iteratively reviewed patient records after identification of charts using an automated trigger tool. Calibration across teams was supported through …

Knowledge Representation And Management: Notable Contributions In 2021, Licong Cui, Ferdinand Dhombres, Jean Charlet

Faculty, Staff and Student Publications

OBJECTIVES: To select, present, and summarize the best papers in the field of Knowledge Representation and Management (KRM) published in 2021.

METHODS: Following the International Medical Informatics Association (IMIA) Yearbook guidelines, a comprehensive and standardized review of the biomedical informatics literature was performed to select the best KRM papers published in 2021, based on PubMed queries.

RESULTS: A total of 1,231 publications were retrieved from PubMed. We nominated 15 candidate best papers, and four of them were finally selected as the best papers in the KRM section. The topics covered by these papers include knowledge graph, ontology development, ontology alignment, …

Charting The Proteome Landscape In Major Psychiatric Disorders: From Biomarkers To Biological Pathways Towards Drug Discovery, Brisa S Fernandes, Yulin Dai, Peilin Jia, Zhongming Zhao

Faculty, Staff and Student Publications

Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are major mental disorders that affect a significant proportion of the global population. Advancing our knowledge of the pathophysiology of these disorders and identifying biomarkers are urgent needs for developing objective diagnostic tests and new therapeutics. In this study, we performed a systematic review and then extracted, curated, and analyzed proteomics data from published studies, aiming to assess the proteome in peripheral blood of individuals with SZ, BD, or MDD. Then, we performed pathway and network analyses to illuminate the biological themes concatenated by the differentially expressed proteins by systematically …

Genome-Wide Bidirectional Crispr Screens Identify Mucins As Host Factors Modulating Sars-Cov-2 Infection, Scott B Biering, Sylvia A Sarnik, Eleanor Wang, James R Zengel, Sarah R Leist, Alexandra Schäfer, Varun Sathyan, Padraig Hawkins, Kenichi Okuda, Cyrus Tau, Aditya R Jangid, Connor V Duffy, Jin Wei, Rodney C Gilmore, Mia Madel Alfajaro, Madison S Strine, Xammy Nguyenla, Erik Van Dis, Carmelle Catamura, Livia H Yamashiro, Julia A Belk, Adam Begeman, Jessica C Stark, D Judy Shon, Douglas M Fox, Shahrzad Ezzatpour, Emily Huang, Nico Olegario, Arjun Rustagi, Allison S Volmer, Alessandra Livraghi-Butrico, Eddie Wehri, Richard R Behringer, Dong-Joo Cheon, Julia Schaletzky, Hector C Aguilar, Andreas S Puschnik, Brian Button, Benjamin A Pinsky, Catherine A Blish, Ralph S Baric, Wanda K O'Neal, Carolyn R Bertozzi, Craig B Wilen, Richard C Boucher, Jan E Carette, Sarah A Stanley, Eva Harris, Silvana Konermann, Patrick D Hsu

Faculty, Staff and Student Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a …

Real-World Matching Performance Of Deidentified Record-Linking Tokens, Elmer V Bernstam, Reuben Joseph Applegate, Alvin Yu, Deepa Chaudhari, Tian Liu, Alex Coda, Jonah Leshin

Faculty, Staff and Student Publications

OBJECTIVE: Our objective was to evaluate tokens commonly used by clinical research consortia to aggregate clinical data across institutions.

METHODS: This study compares tokens alone and token-based matching algorithms against manual annotation for 20,002 record pairs extracted from the University of Texas Houston's clinical data warehouse (CDW) in terms of entity resolution.

RESULTS: The highest precision achieved was 99.9% with a token derived from the first name, last name, gender, and date-of-birth. The highest recall achieved was 95.5% with an algorithm involving tokens that reflected combinations of first name, last name, gender, date-of-birth, and social security number.

DISCUSSION: To protect …

Development Of A Quality Improvement Dental Chart Review Training Program, Elsbeth Kalenderian, Nutan B Hebballi, Amy Franklin, Alfa Yansane, Ana M Ibarra Noriega, Joel White, Muhammad F Walji

Faculty, Staff and Student Publications

INTRODUCTION: Chart review is central to understanding adverse events (AEs) in medicine. In this article, we describe the process and results of educating chart reviewers assigned to evaluate dental AEs.

METHODS: We developed a Web-based training program, "Dental Patient Safety Training," which uses both independent and consensus-based curricula, for identifying AEs recorded in electronic health records in the dental setting. Training included (1) didactic education, (2) skills training using videos and guided walkthroughs, (3) quizzes with feedback, and (4) hands-on learning exercises. In addition, novice reviewers were coached weekly during consensus review discussions. TeamExpert was composed of 2 experienced reviewers, …

Twist1 Interacts With Β/Δ-Catenins During Neural Tube Development And Regulates Fate Transition In Cranial Neural Crest Cells, Jessica W Bertol, Shelby Johnston, Rabia Ahmed, Victoria K Xie, Kelsea M Hubka, Lissette Cruz, Larissa Nitschke, Marta Stetsiv, Jeremy P Goering, Paul Nistor, Sally Lowell, Hanne Hoskens, Peter Claes, Seth M Weinberg, Irfan Saadi, Mary C Farach-Carson, Walid D Fakhouri

Faculty, Staff and Student Publications

Cell fate determination is a necessary and tightly regulated process for producing different cell types and structures during development. Cranial neural crest cells (CNCCs) are unique to vertebrate embryos and emerge from the neural plate borders into multiple cell lineages that differentiate into bone, cartilage, neurons and glial cells. We have previously reported that Irf6 genetically interacts with Twist1 during CNCC-derived tissue formation. Here, we have investigated the mechanistic role of Twist1 and Irf6 at early stages of craniofacial development. Our data indicate that TWIST1 is expressed in endocytic vesicles at the apical surface and interacts with β/δ-catenins during neural …