Digital Commons Network^™

Immuno-Genomic Profiling Of Biopsy Specimens Predicts Neoadjuvant Chemotherapy Response In Esophageal Squamous Cell Carcinoma, Shota Sasagawa, Hiroaki Kato, Koji Nagaoka, Changbo Sun, Motohiro Imano, Takao Sato, Todd A Johnson, Masashi Fujita, Kazuhiro Maejima, Yuki Okawa, Kazuhiro Kakimi, Takushi Yasuda, Hidewaki Nakagawa

Faculty, Staff and Student Publications

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is primarily treated with platinum-based neoadjuvant chemotherapy (NAC). Some ESCCs respond well to NAC. However, biomarkers to predict NAC sensitivity and their response mechanism in ESCC remain unclear. We perform whole-genome sequencing and RNA sequencing analysis of 141 ESCC biopsy specimens before NAC treatment to generate a machine-learning-based diagnostic model to predict NAC reactivity in ESCC and analyzed the association between immunogenomic features and NAC response. Neutrophil infiltration may play an important role in ESCC response to NAC. We also demonstrate that specific copy-number alterations and copy-number …

Gray And White Matter Abnormality In Patients With T2dm-Related Cognitive Dysfunction: A Systemic Review And Meta-Analysis, Teng Ma, Ze-Yang Li, Ying Yu, Bo Hu, Yu Han, Min-Hua Ni, Yu-Xiang Huang, Hao-Han Chen, Wen Wang, Lin-Feng Yan, Guang-Bin Cui

Faculty, Staff and Student Publications

Aims/hypothesis

Brain structure abnormality in patients with type 2 diabetes mellitus (T2DM)-related cognitive dysfunction (T2DM-CD) has been reported for decades in magnetic resonance imaging (MRI) studies. However, the reliable results were still unclear. This study aimed to make a systemic review and meta-analysis to find the significant and consistent gray matter (GM) and white matter (WM) alterations in patients with T2DM-CD by comparing with the healthy controls (HCs).

Methods

Published studies were systemically searched from PubMed, MEDLINE, Cochrane Library and Web of Science databases updated to November 14, 2021. Studies reporting abnormal GM or WM between patients with T2DM-CD and …

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 …

Use Of Active Video Games With Or Without Videoconferencing On Health Outcomes In Adolescent And Young Adult Cancer Survivors: A Systematic Review, Ursela Christopherson, Stephanie J Wells, Nathan Parker, Elizabeth J Lyons, Michael D Swartz, Anna Blozinski, Karen Basen-Engquist, Susan Peterson, Maria C Swartz

Faculty, Staff and Student Publications

PURPOSE: Adolescent and young adult (AYA) cancer survivors experience greater functional deficits compared to non-cancer peers or older survivors with a similar diagnosis. Physical activity (PA) is a key strategy for mitigating functional decline, and motivation and peer support are critical PA facilitators in AYA cancer survivors. Active video games (AVGs) may be a "gateway" method to promote PA. Further, integrating AVGs into group videoconferencing, a medium used by AYAs to socialize, can capitalize on peer support needed for PA motivation. Thus, we examined the use of AVGs and/or videoconferencing in PA interventions that included AYA survivors and the effect …

A Cluster-Randomized Controlled Trial To Assess The Impact Of A Nutrition Intervention On Dietary Behaviors Among Early Care And Education Providers: The Create Healthy Futures Study, Dania Mofleh, Ru-Jye Chuang, Nalini Ranjit, Jill N Cox, Christine Anthony, Shreela V Sharma

Faculty, Staff and Student Publications

Create Healthy Futures is a self-paced, web-based intervention on improving healthy eating behaviors among Early Care and Education (ECE) providers. We examined the impact of web-based Create Healthy Futures on diet quality measured by the Alternative Healthy Eating Index (AHEI) 2010, dietary behaviors, and related psychosocial and environmental factors among ECE providers. A cluster randomized controlled trial (CRCT) was implemented with baseline surveys administered from October 2019-January 2020, intervention implementation from April-May 2020, and post-intervention from May 2020-August 2020. Centered-based ECE programs under the Pennsylvania Head Start Association (n = 12) were recruited and randomized to intervention (n = 5) …

Association Of Disease Outcomes With Physical Activity In Multiple Sclerosis: A Cross-Sectional Study, Trinh L T Huynh, Stephanie L Silveira, Brenda Jeng, Robert W Motl

Faculty, Staff and Student Publications

Purpose/Objective Research: This study examined combinations of disease outcomes (i.e., walking, cognition, and symptoms) as correlates of physical activity subgroups (insufficiently active vs. sufficiently active) in persons with multiple sclerosis (MS).

RESEARCH METHOD/DESIGN: This study included 213 participants who completed walking and cognitive function tests and self-report measures of symptoms and physical activity. Multivariate analysis of variance and discriminant function analysis identified combinations of MS outcomes associated with physical activity.

RESULTS: The sample had a mean age of 49.6 years (

CONCLUSION/IMPLICATIONS: The findings identified walking endurance and limitations, processing speed, depression, and fatigue as primary correlates of physical activity …

Expanding Acta2 Genotypes With Corresponding Phenotypes Overlapping With Smooth Muscle Dysfunction Syndrome, Anita Kaw, Kaveeta Kaw, Ellen M Hostetler, Ana Beleza-Meireles, Adam Smith-Collins, Catherine Armstrong, Ingrid Scurr, Timothy Cotts, Rajani Aatre, Michael J Bamshad, Dawn Earl, Abraham Groner, Katherine Agre, Yehuda Raveh, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

Pathogenic variants in ACTA2, encoding smooth muscle α-actin, predispose to thoracic aortic aneurysms and dissections. ACTA2 variants altering arginine 179 predispose to a more severe, multisystemic disease termed smooth muscle dysfunction syndrome (SMDS; OMIM 613834). Vascular complications of SMDS include patent ductus arteriosus (PDA) or aortopulmonary window, early-onset thoracic aortic disease (TAD), moyamoya-like cerebrovascular disease, and primary pulmonary hypertension. Patients also have dysfunction of other smooth muscle-dependent systems, including congenital mydriasis, hypotonic bladder, and gut hypoperistalsis. Here, we describe five patients with novel heterozygous ACTA2 missense variants, p.Arg179Gly, p.Met46Arg, p.Thr204Ile, p.Arg39Cys, and p.Ile66Asn, who have clinical complications that align or …

Ablation Of Long Noncoding Rna Malat1 Activates Antioxidant Pathway And Alleviates Sepsis In Mice, Jingshu Chen, Shu Tang, Sui Ke, James J Cai, Daniel Osorio, Andrei Golovko, Benjamin Morpurgo, Shaodong Guo, Yuxiang Sun, Melanie Winkle, George A Calin, Yanan Tian

Faculty, Staff and Student Publications

The metastasis-associated lung adenocarcinoma transcript1 (MALAT1) is a long noncoding RNA (lncRNA) and is known for its role in cancer development and prognosis. In this study, we report that MALAT1 plays an important role in regulating acute inflammatory responses in sepsis. In patient samples, MALAT1 expression was positively correlated with severity of sepsis. In cultured macrophages, LPS treatment significantly induced MALAT1 expression, while genetic ablation of MALAT1 greatly reduced proinflammatory cytokine levels. Furthermore, MALAT1-ablated mice had significantly increased survival rates in cecal ligation and puncture (CLP)-induced sepsis and LPS-induced endotoxemia. One novel and salient feature of MALAT1-ablated mice is greatly …

The Intricate Interplay Between Cancer Stem Cells And Cell-Of-Origin Of Cancer: Implications For Therapeutic Strategies, Luis Alberto Vega, Misu A Sanson, María Belén Cubria, Shrijana Regmi, Brittany J Shah, Samuel A Shelburne, Anthony R Flores

Faculty, Staff and Student Publications

Antimicrobial resistance-encoding mobile genetic elements (MGEs) may contribute to the disease potential of bacterial pathogens. We previously described the association of Group A Streptococcus (GAS) derived from invasive disease with increasingly frequent antimicrobial resistance (AMR). We hypothesized that a 65-kb AMR-encoding MGE (ICESpyM92), highly conserved among closely related emergent invasive emm92 GAS, contributes to GAS disease potential. Here, we provide evidence that a combination of ICESpyM92- and core genome-dependent differential gene expression (DGE) contributes to invasive disease phenotypes of emergent emm92 GAS. Using isogenic ICESpyM92 mutants generated in distinct emm92 genomic backgrounds, we determined the presence of ICESpyM92 enhances GAS …

Adipose Tissue-Specific Ablation Of Ces1d Causes Metabolic Dysregulation In Mice, Gang Li, Xin Li, Li Yang, Shuyue Wang, Yulin Dai, Baharan Fekry, Lucas Veillon, Lin Tan, Rebecca Berdeaux, Kristin Eckel-Mahan, Philip L Lorenzi, Zhongming Zhao, Richard Lehner, Kai Sun

Faculty, Staff and Student Publications

Carboxylesterase 1d (Ces1d) is a crucial enzyme with a wide range of activities in multiple tissues. It has been reported to localize predominantly in ER. Here, we found that Ces1d levels are significantly increased in obese patients with type 2 diabetes. Intriguingly, a high level of Ces1d translocates onto lipid droplets where it digests the lipids to produce a unique set of fatty acids. We further revealed that adipose tissue-specific Ces1d knock-out (FKO) mice gained more body weight with increased fat mass during a high fat-diet challenge. The FKO mice exhibited impaired glucose and lipid metabolism and developed exacerbated liver …

Preventing Cholesterol-Induced Perk (Protein Kinase Rna-Like Endoplasmic Reticulum Kinase) Signaling In Smooth Muscle Cells Blocks Atherosclerotic Plaque Formation, Abhijnan Chattopadhyay, Pujun Guan, Suravi Majumder, Kaveeta Kaw, Zhen Zhou, Chen Zhang, Siddharth K Prakash, Anita Kaw, L Maximillian Buja, Callie S Kwartler, Dianna M Milewicz

Faculty, Staff and Student Publications

BACKGROUND: Vascular smooth muscle cells (SMCs) undergo complex phenotypic modulation with atherosclerotic plaque formation in hyperlipidemic mice, which is characterized by de-differentiation and heterogeneous increases in the expression of macrophage, fibroblast, osteogenic, and stem cell markers. An increase of cellular cholesterol in SMCs triggers similar phenotypic changes in vitro with exposure to free cholesterol due to cholesterol entering the endoplasmic reticulum, triggering endoplasmic reticulum stress and activating Perk (protein kinase RNA-like endoplasmic reticulum kinase) signaling.

METHODS: We generated an SMC-specific

RESULTS: SMC-specific deletion of Perk reduces atherosclerotic plaque formation in male hyperlipidemic mice by 80%. Single-cell transcriptomic data identify 2 …

Unilateral Radiation Therapy For Tonsillar Cancer: Treatment Outcomes In The Era Of Human Papillomavirus, Positron-Emission Tomography, And Intensity Modulated Radiation Therapy, Nicolette Taku, Gregory Chronowski, G Brandon Gunn, William H Morrison, Neil D Gross, Amy C Moreno, Renata Ferrarotto, Steven J Frank, C David Fuller, Ryan P Goepfert, Jack Phan, Stephen Y Lai, Jay P Reddy, David I Rosenthal, Adam S Garden

Faculty, Staff and Student Publications

Purpose: The goal of this study was to evaluate disease, survival, and toxic effects after unilateral radiation therapy treatment for tonsillar cancer.

Methods and materials: A retrospective study was performed of patients treated at our institution within the period from 2000 to 2018. Summary statistics were used to assess the cohort by patient characteristics and treatments delivered. The Kaplan-Meier method was used to determine survival outcomes.

Results: The cohort comprised 403 patients, including 343 (85%) with clinical and/or radiographic evidence of ipsilateral cervical nodal disease and 181 (45%) with multiple involved nodes. Human papillomavirus was detected in 294 (73%) tumors. …

Insulin Resistance In Depression: A Large Meta-Analysis Of Metabolic Parameters And Variation, Brisa S Fernandes, Estela Salagre, Nitesh Enduru, Iria Grande, Eduard Vieta, Zhongming Zhao

Faculty, Staff and Student Publications

Increased insulin resistance is recognized in psychiatric disorders, such as schizophrenia and bipolar disorder, but its occurrence in depression is less clear. Our aims were to verify if insulin resistance is altered in depression, to test the metabolic subgroup hypothesis of depression and if there are changes with antidepressants. Inclusion criteria were studies including adult subjects with depression and either a control group or follow-up after treatment with antidepressants, and assessing fasting insulin or glucose levels or the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index. Seventy studies with 240,704 participants were included. Both insulin levels and the HOMA-IR index …

The Geriatric Nutritional Risk Index As A Predictor Of Complications In Geriatric Trauma Patients: Author Reply In Response To: “The Admission Serum Level Of Albumin Cannot Thoroughly Represent The Nutritional Status Of Trauma Patients”, Heather R Kregel, Patrick B Murphy, Mina Attia, David E Meyer, Rachel S Morris, Ezenwa C Onyema, Sasha D Adams, Charles E Wade, John A Harvin, Lillian S Kao, Thaddeus J Puzio

Faculty, Staff and Student Publications

BACKGROUND: Malnutrition is associated with increased morbidity and mortality after trauma. The Geriatric Nutritional Risk Index (GNRI) is a validated scoring system used to predict the risk of complications related to malnutrition in nontrauma patients. We hypothesized that GNRI is predictive of worse outcomes in geriatric trauma patients.

METHODS: This was a single-center retrospective study of trauma patients 65 years or older admitted in 2019. Geriatric Nutritional Risk Index was calculated based on admission albumin level and ratio of actual body weight to ideal body weight. Groups were defined as major risk (GNRI98). The primary outcome was mortality. Secondary outcomes …

Strategy For Generating Blinded Evidence For Single-Arm Trials With External Controls Using Expert Review Of Home Video, Bharti Manwani, Carson Finger, Lynda Lisabeth

Faculty, Staff and Student Publications

Stroke risk and prevalence increase with advanced age and women tend to be older than men at the time of their first stroke. Advanced age in women confers unique stroke risks that are beyond reproductive factors. Previous reviews and guidelines have largely focused on risk factors specific to women, with a predominant focus on reproductive factors and, therefore, younger to middle-aged women. This review aims to specifically describe stroke risk factors in elderly women, the population of women where the majority of strokes occur, with a focus on atrial fibrillation, hormone therapy, psychosocial risk factors, and cognitive impairment. Our review …

Clinical Outcomes Of Patients With Recurrent Microsatellite-Stable Endometrial Cancer In Early-Phase Immunotherapy Clinical Trials, Jeffrey A How, Amir A Jazaeri, Siqing Fu, Jordi Rodon Ahnert, Jing Gong, Bettzy Stephen, Hanna Ferreira Dalla Pria, Priya Bhosale, Amber Johnson, Ying Yuan, Funda Meric-Bernstam, Aung Naing

Faculty, Staff and Student Publications

Recurrent microsatellite stable (MSS) endometrial cancer has poor response to conventional therapy and limited efficacy with immune checkpoint monotherapy. We conducted a retrospective study of recurrent MSS endometrial cancer patients enrolled in immunotherapy-based clinical trials at MD Anderson Cancer Center between 1 January 2010 and 31 December 2019. Patients were evaluated for radiologic response using RECIST 1.1 criteria, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were treated with immune checkpoint inhibitors: 8 with monotherapy, 17 with immunotherapy (IO) in combination with another IO-only, and 10 with IO in combination with non-IO therapy. Among those treated with combination IO …

Maternal Iron Deficiency Programs Rat Offspring Hypertension In Relation To Renin-Angiotensin System And Oxidative Stress, Ya-Hui Chang, Wan-Hsuan Chen, Chung-Hao Su, Hong-Ren Yu, You-Lin Tain, Li-Tung Huang, Jiunn-Ming Sheen

Faculty, Staff and Student Publications

Hypertension is an important public health challenge, affecting up to 30-50% of adults worldwide. Several epidemiological studies indicate that high blood pressure originates in fetal life-the so-called programming effect or developmental origin of hypertension. Iron-deficiency anemia has become one of the most prevalent nutritional problems globally. Previous animal experiments have shown that prenatal iron-deficiency anemia adversely affects offspring hypertension. However, the underlying mechanism remains unclear. We used a maternal low-iron diet Sprague Dawley rat model to study changes in blood pressure, the renal renin-angiotensin system, oxidative stress, inflammation, and sodium transporters in adult male offspring. Our study revealed that 16-week-old …

Targeting De Novo Lipogenesis And The Lands Cycle Induces Ferroptosis In Kras-Mutant Lung Cancer, Caterina Bartolacci, Cristina Andreani, Gonçalo Vale, Stefano Berto, Margherita Melegari, Anna Colleen Crouch, Dodge L Baluya, George Kemble, Kurt Hodges, Jacqueline Starrett, Katerina Politi, Sandra L Starnes, Daniele Lorenzini, Maria Gabriela Raso, Luisa M Solis Soto, Carmen Behrens, Humam Kadara, Boning Gao, Ignacio I Wistuba, John D Minna, Jeffrey G Mcdonald, Pier Paolo Scaglioni

Faculty, Staff and Student Publications

Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, the role of FA in LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC). We demonstrate that FASN, the rate-limiting enzyme in FA synthesis, while being dispensable in EGFR-mutant or wild-type KRAS LC, is required for the viability of KMLC cells. Integrating lipidomic, transcriptomic and functional analyses, we demonstrate that FASN provides saturated and monounsaturated FA to the Lands cycle, the process remodeling oxidized phospholipids, such as PC. Accordingly, …

Clinical Factors Associated With Non-Obese Nonalcoholic Fatty Liver Disease Detected Among Us Adults In The Nhanes 2017-2018, Zayd Adnan Razouki, Xiaotao Zhang, Jessica P Hwang, Natalia I Heredia

Faculty, Staff and Student Publications

NAFLD can occur in non-obese individuals with BMI < 25 kg/m2. Our goal was to examine the prevalence and clinical factors associated with non-obese NAFLD using vibration-controlled transient elastography (VCTE) with controlled attenuation parameter which estimates steatosis and fibrosis among US adults. We aggregated data from the 2017−2018 cycle of NHANES and included adults (age ≥ 20 years) with BMI < 25 kg/m2 with complete data for the survey, medical examination, and VCTE along with controlled attenuation parameter (CAP). We excluded participants with risks of other liver diseases. We considered patients to have non-obese NAFLD if CAP was >285 dB/m, or non-obese NAFLD fibrosis if this CAP criteria was met and liver stiffness was >8.6 kPa. We calculated the adjusted OR and 95% CI for associations with non-obese NAFLD using multivariable logistic regression. The prevalence of non-obese NAFLD was 6.2% and Asian Americans (12.2%) had the highest non-obese NAFLD prevalence. Clinical factors associated with non-obese NAFLD were advanced age and metabolic syndrome (ORadjusted = 6.8, 95% CI 3.0−15.5). In a separate model, we found elevated glucose (ORadjusted = 4.1, 95% CI 2.1−7.9), triglycerides (ORadjusted = 3.8, 95% CI 1.7−8.5), and …

Sirpα Mediates Igf1 Receptor In Cardiomyopathy-Induced By Chronic Kidney Disease, Sandhya S Thomas, Jiao Wu, Giovanni Davogustto, Michael W Holliday, Kristin Eckel-Mahan, Daniela Verzola, Giacomo Garibotto, Zhaoyong Hu, William E Mitch, Heinrich Taegtmeyer

Faculty, Staff and Student Publications

BACKGROUND: Chronic kidney disease (CKD) is characterized by increased myocardial mass despite near-normal blood pressure, suggesting the presence of a separate trigger. A potential driver is SIRPα (signal regulatory protein alpha)-a mediator impairing insulin signaling. The objective of this study is to assess the role of circulating SIRPα in CKD-induced adverse cardiac remodeling.

METHODS: SIRPα expression was evaluated in mouse models and patients with CKD. Specifically, mutant, muscle-specific, or cardiac muscle-specific SIRPα KO (knockout) mice were examined after subtotal nephrectomy. Cardiac function was assessed by echocardiography. Metabolic responses were confirmed in cultured muscle cells or cardiomyocytes.

RESULTS: We demonstrate that …

Toward A Standard Formal Semantic Representation Of The Model Card Report, Muhammad Tuan Amith, Licong Cui, Degui Zhi, Kirk Roberts, Xiaoqian Jiang, Fang Li, Evan Yu, Cui Tao

Faculty, Staff and Student Publications

BACKGROUND: Model card reports aim to provide informative and transparent description of machine learning models to stakeholders. This report document is of interest to the National Institutes of Health's Bridge2AI initiative to address the FAIR challenges with artificial intelligence-based machine learning models for biomedical research. We present our early undertaking in developing an ontology for capturing the conceptual-level information embedded in model card reports.

RESULTS: Sourcing from existing ontologies and developing the core framework, we generated the Model Card Report Ontology. Our development efforts yielded an OWL2-based artifact that represents and formalizes model card report information. The current release of …

Toward A Standard Formal Semantic Representation Of The Model Card Report, Muhammad Tuan Amith, Licong Cui, Degui Zhi, Kirk Roberts, Xiaoqian Jiang, Fang Li, Evan Yu, Cui Tao

Faculty, Staff and Student Publications

BACKGROUND: Model card reports aim to provide informative and transparent description of machine learning models to stakeholders. This report document is of interest to the National Institutes of Health's Bridge2AI initiative to address the FAIR challenges with artificial intelligence-based machine learning models for biomedical research. We present our early undertaking in developing an ontology for capturing the conceptual-level information embedded in model card reports.

RESULTS: Sourcing from existing ontologies and developing the core framework, we generated the Model Card Report Ontology. Our development efforts yielded an OWL2-based artifact that represents and formalizes model card report information. The current release of …

Association Of Cardiovascular Health Through Young Adulthood With Genome-Wide Dna Methylation Patterns In Midlife: The Cardia Study, Yinan Zheng, Brian T Joyce, Shih-Jen Hwang, Jiantao Ma, Lei Liu, Norrina B Allen, Amy E Krefman, Jun Wang, Tao Gao, Drew R Nannini, Haixiang Zhang, David R Jacobs, Myron D Gross, Myriam Fornage, Cora E Lewis, Pamela J Schreiner, Stephen Sidney, Dongquan Chen, Philip Greenland, Daniel Levy, Lifang Hou, Donald M Lloyd-Jones

Faculty, Staff and Student Publications

Background: Cardiovascular health (CVH) from young adulthood is strongly associated with an individual's future risk of cardiovascular disease (CVD) and total mortality. Defining epigenomic biomarkers of lifelong CVH exposure and understanding their roles in CVD development may help develop preventive and therapeutic strategies for CVD.

Methods: In 1085 CARDIA study (Coronary Artery Risk Development in Young Adults) participants, we defined a clinical cumulative CVH score that combines body mass index, blood pressure, total cholesterol, and fasting glucose measured longitudinally from young adulthood through middle age over 20 years (mean age, 25-45). Blood DNA methylation at >840 000 methylation markers was …

Urinary Metabolites Of Polycyclic Aromatic Hydrocarbons In Firefighters: A Systematic Review And Meta-Analysis, Jooyeon Hwang, Chao Xu, Paul Grunsted, Robert J Agnew, Tara R Malone, Shari Clifton, Krista Thompson, Xin Xu

Faculty, Staff and Student Publications

Firefighters are intermittently exposed to complex, mixed pollutants in random settings. Of those pollutants, PAHs (polycyclic aromatic hydrocarbons) are the most commonly studied and best understood. PAH exposure can occur via multiple routes; therefore, the levels of hydroxylated metabolites of PAHs in urine have been used as a biomonitoring tool for risk assessment. We performed a systematic review and meta-analysis of the literature to estimate the levels of urinary hydroxylated PAH (OHPAH) among firefighters, determine risk attributions, and, finally, evaluate the scope of preventive efforts and their utility as diagnostic tools. The meta-regression confirmed increases in OHPAH concentrations after fire …

Vitamin E Enhances Cancer Immunotherapy By Reinvigorating Dendritic Cells Via Targeting Checkpoint Shp1, Xiangliang Yuan, Yimin Duan, Yi Xiao, Kai Sun, Yutao Qi, Yuan Zhang, Zamal Ahmed, Davide Moiani, Jun Yao, Hongzhong Li, Lin Zhang, Arseniy E Yuzhalin, Ping Li, Chenyu Zhang, Akosua Badu-Nkansah, Yohei Saito, Xianghua Liu, Wen-Ling Kuo, Haoqiang Ying, Shao-Cong Sun, Jenny C Chang, John A Tainer, Dihua Yu

Faculty, Staff and Student Publications

Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune-checkpoint therapy (ICT), are unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated patients with cancer who took vitamin E (VitE) had significantly improved survival. In mouse models, VitE increased ICT antitumor efficacy, which depended on dendritic cells (DC). VitE entered DCs via the SCARB1 receptor and restored tumor-associated DC functionality by directly binding to and inhibiting protein tyrosine phosphatase SHP1, a DC-intrinsic checkpoint. SHP1 inhibition, genetically or by VitE treatment, enhanced tumor antigen cross-presentation by DCs and …

The Use Of Second-Generation Antipsychotics And The Changes In Physical Growth In Children And Adolescents With Perinatally Acquired Hiv, Nan Xin, Jenni Durieux, Chunxia Yang, Suzanne Wolff, Hyun-Eui Kim, Andrew Dillin

Faculty, Staff and Student Publications

The mitochondrial unfolded protein response (UPRmt) is dedicated to promoting mitochondrial proteostasis and is linked to extreme longevity. The key regulator of this process is the transcription factor ATFS-1, which, upon UPRmt activation, is excluded from the mitochondria and enters the nucleus to regulate UPRmt genes. However, the repair proteins synthesized as a direct result of UPRmt activation must be transported into damaged mitochondria that had previously excluded ATFS-1 owing to reduced import efficiency. To address this conundrum, we analyzed the role of the import machinery when the UPRmt was induced. Using in vitro and in vivo analysis of mitochondrial …

Maternal Obesity, Pregnancy Weight Gain, And Birth Weight And Risk Of Colorectal Cancer, Caitlin C Murphy, Piera M Cirillo, Nickilou Y Krigbaum, Amit G Singal, Minjae Lee, Timothy Zaki, Ezra Burstein, Barbara A Cohn

Faculty, Staff and Student Publications

Objective: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Obesity is a well-established risk factor for CRC, and fetal or developmental origins of obesity may underlie its effect on cancer in adulthood. We examined associations of maternal obesity, pregnancy weight gain, and birth weight and CRC in adult offspring.

Design: The Child Health and Development Studies is a prospective cohort of women receiving prenatal care between 1959 and 1966 in Oakland, California (N=18 751 live births among 14 507 mothers). Clinical information was abstracted from mothers' medical records 6 months prior to pregnancy through delivery. Diagnoses of …

The 5th Edition Of The World Health Organization Classification Of Haematolymphoid Tumours: Lymphoid Neoplasms, Rita Alaggio, Catalina Amador, Ioannis Anagnostopoulos, Ayoma D Attygalle, Iguaracyra Barreto De Oliveira Araujo, Emilio Berti, Govind Bhagat, Anita Maria Borges, Daniel Boyer, Mariarita Calaminici, Amy Chadburn, John K C Chan, Wah Cheuk, Wee-Joo Chng, John K Choi, Shih-Sung Chuang, Sarah E Coupland, Magdalena Czader, Sandeep S Dave, Daphne De Jong, Ming-Qing Du, Kojo S Elenitoba-Johnson, Judith Ferry, Julia Geyer, Dita Gratzinger, Joan Guitart, Sumeet Gujral, Marian Harris, Christine J Harrison, Sylvia Hartmann, Andreas Hochhaus, Patty M Jansen, Kennosuke Karube, Werner Kempf, Joseph Khoury, Hiroshi Kimura, Wolfram Klapper, Alexandra E Kovach, Shaji Kumar, Alexander J Lazar, Stefano Lazzi, Lorenzo Leoncini, Nelson Leung, Vasiliki Leventaki, Xiao-Qiu Li, Megan S Lim, Wei-Ping Liu, Abner Louissaint, Andrea Marcogliese, L Jeffrey Medeiros, Michael Michal, Roberto N Miranda, Christina Mitteldorf, Santiago Montes-Moreno, William Morice, Valentina Nardi, Kikkeri N Naresh, Yasodha Natkunam, Siok-Bian Ng, Ilske Oschlies, German Ott, Marie Parrens, Melissa Pulitzer, S Vincent Rajkumar, Andrew C Rawstron, Karen Rech, Andreas Rosenwald, Jonathan Said, Clémentine Sarkozy, Shahin Sayed, Caner Saygin, Anna Schuh, William Sewell, Reiner Siebert, Aliyah R Sohani, Reuben Tooze, Alexandra Traverse-Glehen, Francisco Vega, Beatrice Vergier, Ashutosh D Wechalekar, Brent Wood, Luc Xerri, Wenbin Xiao

Faculty, Staff and Student Publications

We herein present an overview of the upcoming 5th edition of the World Health Organization Classification of Haematolymphoid Tumours focussing on lymphoid neoplasms. Myeloid and histiocytic neoplasms will be presented in a separate accompanying article. Besides listing the entities of the classification, we highlight and explain changes from the revised 4th edition. These include reorganization of entities by a hierarchical system as is adopted throughout the 5th edition of the WHO classification of tumours of all organ systems, modification of nomenclature for some entities, revision of diagnostic criteria or subtypes, deletion of certain entities, and introduction of new entities, as …

A Randomized, Double-Blind Trial Of Triheptanoin For Drug-Resistant Epilepsy In Glucose Transporter 1 Deficiency Syndrome, Pasquale Striano, Stéphane Auvin, Abigail Collins, Rita Horvath, Ingrid E Scheffer, Michal Tzadok, Ian Miller, Mary Kay Koenig, Adrian Lacy, Ronald Davis, Angela Garcia-Cazorla, Russell P Saneto, Melanie Brandabur, Susan Blair, Tony Koutsoukos, Darryl De Vivo

Faculty, Staff and Student Publications

Objective: This study was undertaken to evaluate efficacy and long-term safety of triheptanoin in patients >1 year old, not on a ketogenic diet, with drug-resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS).

Methods: UX007G-CL201 was a randomized, double-blind, placebo-controlled trial. Following a 6-week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo. Dosing was titrated to 35% of total daily calories over 2 weeks. After an 8-week placebo-controlled period, all patients received open-label triheptanoin through Week 52.

Results: The study included 36 patients (15 children, 13 adolescents, eight adults). A median 12.6% reduction in overall seizure …

Lymphatic Function And Anatomy In Early Stages Of Lipedema, John C Rasmussen, Melissa B Aldrich, Caroline E Fife, Karen L Herbst, Eva M Sevick-Muraca

Faculty, Staff and Student Publications

Objective: Lipedema is an inflammatory subcutaneous adipose tissue disease that develops in women and may progress to lipolymphedema, a condition similar to lymphedema, in which lymphatic dysfunction results in irresolvable edema. Because it has been shown that dilated lymphatic vessels, impaired pumping, and dermal backflow are associated with presymptomatic, cancer-acquired lymphedema, this study sought to understand whether these abnormal lymphatic characteristics also characterize early stages of lipedema prior to lipolymphedema development.

Methods: In a pilot study of 20 individuals with Stage I or II lipedema who had not progressed to lipolymphedema, lymphatic vessel anatomy and function in upper and lower …