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Dna Methylation Analysis Is Used To Identify Novel Genetic Loci Associated With Circulating Fibrinogen Levels In Blood, Julie Hahn, Jan Bressler, Arce Domingo-Relloso, Ming-Huei Chen, Daniel L Mccartney, Alexander Teumer, Jenny Van Dongen, Marcus E Kleber, Dylan Aïssi, Brenton R Swenson, Jie Yao, Wei Zhao, Jian Huang, Yujing Xia, Michael R Brown, Ricardo Costeira, Eco J C De Geus, Graciela E Delgado, Dre'von A Dobson, Paul Elliott, Hans J Grabe, Xiuqing Guo, Sarah E Harris, Jennifer E Huffman, Sharon L R Kardia, Yongmei Liu, Stefan Lorkowski, Riccardo E Marioni, Matthias Nauck, Scott M Ratliff, Maria Sabater-Lleal, Tim D Spector, Pierre Suchon, Kent D Taylor, Florian Thibord, David-Alexandre Trégouët, Kerri L Wiggins, Gonneke Willemsen, Jordana T Bell, Dorret I Boomsma, Shelley A Cole, Simon R Cox, Abbas Dehghan, Andreas Greinacher, Karin Haack, Winfried März, Pierre-Emmanuel Morange, Jerome I Rotter, Nona Sotoodehnia, Maria Tellez-Plaza, Ana Navas-Acien, Jennifer A Smith, Andrew D Johnson, Myriam Fornage, Nicholas L Smith, Alisa S Wolberg, Alanna C Morrison, Paul S De Vries

Faculty, Staff and Student Publications

Background:

Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa.

Methods:

We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American Indian, and Hispanic participants representing 14 studies from the CHARGE consortium. Circulating leukocyte DNA methylation was measured in 12,904 participants using the Illumina 450K array, and in 5,133 participants using the EPIC array. Each study performed an EWAS of fibrinogen using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific …

One Immune System Plays Many Parts: The Dynamic Role Of The Immune System In Chronic Pain And Opioid Pharmacology, Sanam Mustafa, Juliana E Bajic, Benjamin Barry, Samuel Evans, Kariel R Siemens, Mark R Hutchinson, Peter M Grace

Faculty, Staff and Student Publications

The transition from acute to chronic pain is an ongoing major problem for individuals, society and healthcare systems around the world. It is clear chronic pain is a complex multidimensional biological challenge plagued with difficulties in pain management, specifically opioid use. In recent years the role of the immune system in chronic pain and opioid pharmacology has come to the forefront. As a highly dynamic and versatile network of cells, tissues and organs, the immune system is perfectly positioned at the microscale level to alter nociception and drive structural adaptations that underpin chronic pain and opioid use. In this review, …

Higher Hippocampal Diffusivity Values In Welders Are Associated With Greater R2* In The Red Nucleus And Lower Psychomotor Performance, Eun-Young Lee, Juhee Kim, Janina Manzieri Prado-Rico, Guangwei Du, Mechelle M Lewis, Lan Kong, Byoung-Gwon Kim, Young-Seoub Hong, Jeff D Yanosky, Richard B Mailman, Xuemei Huang

Faculty, Staff and Student Publications

INTRODUCTION: Chronic excessive welding exposure may be related to higher metal accumulation and structural differences in different subcortical structures. We examined how welding affected brain structures and their associations with metal exposure and neurobehavioral consequences.

METHODS: Study includes 42 welders and 31 controls without a welding history. Welding-related structural differences were assessed by volume and diffusion tensor imaging (DTI) metrics in basal ganglia, red nucleus (RN), and hippocampus. Metal exposure was estimated by both exposure questionnaires and whole blood metal levels. Brain metal accumulations were estimated by R1 (for Mn) and R2* (for Fe). Neurobehavioral status was assessed by standard …

Long Noncoding Rna 01534 Maintains Cancer Stemness By Downregulating Endoplasmic Reticulum Stress Response In Colorectal Cancer, Momoko Ichihara, Hidekazu Takahashi, Naohiro Nishida, Cristina Ivan, Daisuke Okuzaki, Yuhki Yokoyama, Masahisa Ohtsuka, Norikatsu Miyoshi, Mamoru Uemura, Shinji Tanaka, George Adrian Calin, Masaki Mori, Yuichiro Doki, Hidetoshi Eguchi, Hirofumi Yamamoto

Faculty, Staff and Student Publications

Background: Studies have shown that cancer stemness and the endoplasmic reticulum (ER) stress response are inversely regulated in colorectal cancer (CRC), but the mechanism has not been fully clarified. Long noncoding RNAs (lncRNAs) play key roles in cancer progression and metastasis. In this study we investigated lncRNA 01534 (LINC01534) as a possible modulator between cancer stemness and ER stress response.

Methods: In vitro experiments using CRC cell lines were performed to explore a possible role of LINC01534. The expression of LINC01534 in clinical CRC samples was assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and in situ hybridization.

Results: Silencing …

Disclosing Quantitative Rt-Pcr Raw Data During Manuscript Submission: A Call For Action, Andreas Untergasser, Jan Hellemans, Michael W Pfaffl, Jan M Ruijter, Maurice J B Van Den Hoff, Mihnea P Dragomir, Douglas Adamoski, Sandra Martha Gomes Dias, Rui Manuel Reis, Manuela Ferracin, Emmanuel Dias-Neto, Ian Marsh, Mikael Kubista, Muller Fabbri, Ajay Goel, Ondřej Slabý, Erik Knutsen, Baoqing Chen, Massimo Negrini, Koshi Mimori, Martin Pichler, Maria Papatriantafyllou, Simone Anfossi, Thomas D Schmittgen, Jim Huggett, Stephen Bustin, Jo Vandesompele, George A Calin, Heroic (The Initiative Group On Qrt Disclosure) Consortium

Faculty, Staff and Student Publications

Accuracy and transparency of scientific data are becoming more and more relevant with the increasing concern regarding the evaluation of data reproducibility in many research areas. This concern is also true for quantifying coding and noncoding RNAs, with the remarkable increase in publications reporting RNA profiling and sequencing studies. To address the problem, we propose the following recommendations: (a) accurate documentation of experimental procedures in Materials and methods (and not only in the supplementary information, as many journals have a strict mandate for making Materials and methods as visible as possible in the main text); (b) submission of RT‐qPCR raw …

Publisher Correction: Comprehensive Molecular Characterization Of Mitochondrial Genomes In Human Cancers, Yuan Yuan, Young Seok Ju, Youngwook Kim, Jun Li, Yumeng Wang, Christopher J Yoon, Yang Yang, Inigo Martincorena, Chad J Creighton, John N Weinstein, Yanxun Xu, Leng Han, Hyung-Lae Kim, Hidewaki Nakagawa, Keunchil Park, Peter J Campbell, Han Liang, Pcawg Consortium

Faculty, Staff and Student Publications

No abstract provided.

Genomic And Transcriptomic Analysis Of Checkpoint Blockade Response In Advanced Non-Small Cell Lung Cancer, Arvind Ravi, Matthew D Hellmann, Monica B Arniella, Mark Holton, Samuel S Freeman, Vivek Naranbhai, Chip Stewart, Ignaty Leshchiner, Jaegil Kim, Yo Akiyama, Aaron T Griffin, Natalie I Vokes, Mustafa Sakhi, Vashine Kamesan, Hira Rizvi, Biagio Ricciuti, Patrick M Forde, Valsamo Anagnostou, Jonathan W Riess, Don L Gibbons, Nathan A Pennell, Vamsidhar Velcheti, Subba R Digumarthy, Mari Mino-Kenudson, Andrea Califano, John V Heymach, Roy S Herbst, Julie R Brahmer, Kurt A Schalper, Victor E Velculescu, Brian S Henick, Naiyer Rizvi, Pasi A Jänne, Mark M Awad, Andrew Chow, Benjamin D Greenbaum, Marta Luksza, Alice T Shaw, Jedd Wolchok, Nir Hacohen, Gad Getz, Justin F Gainor

Faculty, Staff and Student Publications

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of …

Monte Carlo-Derived 99m Tc Uptake Quantification With Commercial Planar Mbi: Absolute Tumor Activity, Benjamin P Lopez, Srinivas Cheenu Kappadath

Faculty, Staff and Student Publications

BACKGROUND: Molecular breast imaging (MBI) of 99mTc-sestamibi is an emerging adjunct qualitative tool in the detection and diagnosis of breast cancer.

PURPOSE: This work outlines the development and performance evaluation of a methodology to absolutely quantify tumor 99mTc activity uptake using a commercially available dual-headed MBI system by implementing corrections for background, scatter, attenuation, and detector characteristics.

METHODS: A validated Monte Carlo application of a commercial MBI system was used to simulate over 7000 unique acquisitions of spherical and ellipsoidal tumors in breast tissue. Tumor absolute activity was calculated following background, scatter, and attenuation corrections of tumor region of interest …

Gwas And Meta-Analysis Identifies 49 Genetic Variants Underlying Critical Covid-19, Erola Pairo-Castineira, Konrad Rawlik, Andrew D Bretherick, Ting Qi, Yang Wu, Isar Nassiri, Glenn A Mcconkey, Marie Zechner, Lucija Klaric, Fiona Griffiths, Wilna Oosthuyzen, Athanasios Kousathanas, Anne Richmond, Jonathan Millar, Clark D Russell, Tomas Malinauskas, Ryan Thwaites, Kirstie Morrice, Sean Keating, David Maslove, Alistair Nichol, Malcolm G Semple, Julian Knight, Manu Shankar-Hari, Charlotte Summers, Charles Hinds, Peter Horby, Lowell Ling, Danny Mcauley, Hugh Montgomery, Peter J M Openshaw, Colin Begg, Timothy Walsh, Albert Tenesa, Carlos Flores, José A Riancho, Augusto Rojas-Martinez, Pablo Lapunzina, Genomicc Investigators, Scourge Consortium, Isaricc Investigators, 23andme Covid-19 Team, Jian Yang, Chris P Ponting, James F Wilson, Veronique Vitart, Malak Abedalthagafi, Andre D Luchessi, Esteban J Parra, Raquel Cruz, Angel Carracedo, Angie Fawkes, Lee Murphy, Kathy Rowan, Alexandre C Pereira, Andy Law, Benjamin Fairfax, Sara Clohisey Hendry, J Kenneth Baillie

Faculty, Staff and Student Publications

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a …

Applicability And Usage Of Dose Mapping/Accumulation In Radiotherapy, Martina Murr, Kristy K Brock, Marco Fusella, Nicholas Hardcastle, Mohammad Hussein, Michael G Jameson, Isak Wahlstedt, Johnson Yuen, Jamie R Mcclelland, Eliana Vasquez Osorio

Faculty, Staff and Student Publications

Dose mapping/accumulation (DMA) is a topic in radiotherapy (RT) for years, but has not yet found its widespread way into clinical RT routine. During the ESTRO Physics workshop 2021 on "commissioning and quality assurance of deformable image registration (DIR) for current and future RT applications", we built a working group on DMA from which we present the results of our discussions in this article. Our aim in this manuscript is to shed light on the current situation of DMA in RT and to highlight the issues that hinder consciously integrating it into clinical RT routine. As a first outcome of …

Heterogeneity Of Treatment Effects Of Hydrocortisone By Risk Of Bronchopulmonary Dysplasia Or Death Among Extremely Preterm Infants In The National Institute Of Child Health And Human Development Neonatal Research Network Trial: A Secondary Analysis Of A Randomized Clinical Trial, Samuel J Gentle, Matthew A Rysavy, Lei Li, Matthew M Laughon, Ravi M Patel, Erik A Jensen, Susan Hintz, Namasivayam Ambalavanan, Waldemar A Carlo, Kristi Watterberg, National Institute Of Child Health And Human Development Neonatal Research Network

Faculty, Staff and Student Publications

IMPORTANCE: Extremely preterm infants who develop bronchopulmonary dysplasia (BPD) are at a higher risk for adverse pulmonary and neurodevelopmental outcomes. In the National Institute of Child Health and Human Development Neonatal Research Network (NICHD NRN) Hydrocortisone Trial, hydrocortisone neither reduced rates of BPD or death nor increased rates of neurodevelopmental impairment (NDI) or death.

OBJECTIVE: To determine whether estimated risk for grades 2 to 3 BPD or death is associated with the effect of hydrocortisone on the composite outcomes of (1) grades 2 to 3 BPD or death and (2) moderate or severe NDI or death.

DESIGN, SETTING, AND PARTICIPANTS: …

Brain Engagement During A Cognitive Flexibility Task Relates To Academic Performance In English Learners, Tehila Nugiel, Mackenzie E Mitchell, Damion V Demeter, Annacarolina Garza, Paul T Cirino, Arturo E Hernandez, Jenifer Juranek, Jessica A Church

Faculty, Staff and Student Publications

English Learners (ELs), students from non-English-speaking backgrounds, are a fast-growing, understudied, group of students in the U.S. with unique learning challenges. Cognitive flexibility—the ability to switch between task demands with ease—may be an important factor in learning for ELs as they have to manage learning in their non-dominant language and access knowledge in multiple languages. We used functional MRI to measure cognitive flexibility brain activity in a group of Hispanic middle school ELs (N = 63) and related it to their academic skills. We found that brain engagement during the cognitive flexibility task was related to both out-of-scanner reading …

Accuracy Of Administrative Claim Data For Gastric Adenoma After Endoscopic Resection, Ga-Yeong Shin, Hyun Ho Choi, Jae Myung Park, Sang Yoon Kim, Jun Young Park, Donghoon Kang, Yu Kyung Cho, Sung Soo Kim, Myung-Gyu Choi

Faculty, Staff and Student Publications

BACKGROUND/AIMS: Administrative databases provide valuable information for large-cohort studies. This study aimed to evaluate the diagnostic accuracy of an administrative database for resected gastric adenomas.

METHODS: Data of patients who underwent endoscopic resection for benign gastric lesions were collected from three hospitals. Gastric adenoma cases were identified in the hospital database using International Classification of Diseases (ICD) 10-codes. The non-adenoma group included patients without gastric adenoma codes. The diagnostic accuracy for gastric adenoma was analyzed based on the pathological reports of the resected specimen.

RESULTS: Among 5,095 endoscopic resections with codes for benign gastric lesions, 3,909 patients were included in …

Depression, Stress And Regional Cerebral Blood Flow, Joshua Chiappelli, Bhim M Adhikari, Mark D Kvarta, Heather A Bruce, Eric L Goldwaser, Yizhou Ma, Shuo Chen, Seth Ament, Alan R Shuldiner, Braxton D Mitchell, Peter Kochunov, Danny Jj Wang, L Elliot Hong

Faculty, Staff and Student Publications

Decreased cerebral blood flow (CBF) may be an important mechanism associated with depression. In this study we aimed to determine if the association of CBF and depression is dependent on current level of depression or the tendency to experience depression over time (trait depression), and if CBF is influenced by depression-related factors such as stressful life experiences and antidepressant medication use. CBF was measured in 254 participants from the Amish Connectome Project (age 18-76, 99 men and 154 women) using arterial spin labeling. All participants underwent assessment of symptoms of depression measured with the Beck Depression Inventory and Maryland Trait …

Age-Related Changes In Left Ventricular Vortex And Energy Loss Patterns: From Newborns To Adults, Kristian C Becker, Jennifer Cohen, Jon D Nyce, Jen Lie Yau, Santosh C Uppu, Partho P Sengupta, Shubhika Srivastava

Faculty, Staff and Student Publications

Left ventricular vortex formation optimizes the effective transport of blood volume while minimizing energy loss (EL). Vector flow mapping (VFM)-derived EL patterns have not been described in children, especially in those less than 1 yr of age. A prospective cohort of 66 (0 days-22 yr, 14 patients ≤ 2 mo) cardiovascularly normal children was used to determine left ventricular (LV) vortex number, size (mm2), strength (m2/s), and energy loss (mW/m/m2) in systole and diastole and compared across age groups. One early diastolic (ED) vortex at the anterior mitral leaflet and one late diastolic (LD) vortex at the LV outflow tract …

Association Between The Epigenetic Lifespan Predictor Grimage And History Of Suicide Attempt In Bipolar Disorder, Camila N C Lima, Emese H C Kovács, Salahudeen Mirza, Alexandra Del Favero-Campbell, Alexandre Paim Diaz, Joao Quevedo, Benney M R Argue, Jenny Gringer Richards, Aislinn Williams, John A Wemmie, Vincent A Magnotta, Jess G Fiedorowicz, Jair C Soares, Marie E Gaine, Gabriel R Fries

Faculty, Staff and Student Publications

Bipolar disorder (BD) has been previously associated with premature mortality and aging, including acceleration of epigenetic aging. Suicide attempts (SA) are greatly elevated in BD and are associated with decreased lifespan, biological aging, and poorer clinical outcomes. We investigated the relationship between GrimAge, an epigenetic clock trained on time-to-death and associated with mortality and lifespan, and SA in two independent cohorts of BD individuals (discovery cohort - controls (n = 50), BD individuals with (n = 77, BD/SA) and without (n = 67, BD/non-SA) lifetime history of SA; replication cohort - BD/SA (n = 48) and BD/non-SA (n = 47)). …

Assessment Of Corticosteroid Therapy And Death Or Disability According To Pretreatment Risk Of Death Or Bronchopulmonary Dysplasia In Extremely Preterm Infants, Erik A Jensen, Laura Elizabeth Wiener, Matthew A Rysavy, Kevin C Dysart, Marie G Gantz, Eric C Eichenwald, Rachel G Greenberg, Heidi M Harmon, Matthew M Laughon, Kristi L Watterberg, Michele C Walsh, Bradley A Yoder, Scott A Lorch, Sara B Demauro

Faculty, Staff and Student Publications

IMPORTANCE: Meta-analyses suggest that corticosteroids may be associated with increased survival without cerebral palsy in infants at high risk of bronchopulmonary dysplasia (BPD) but are associated with adverse neurologic outcomes in low-risk infants. Whether this association exists in contemporary practice is uncertain because most randomized clinical trials administered corticosteroids earlier and at higher doses than currently recommended.

OBJECTIVE: To evaluate whether the pretreatment risk of death or grade 2 or 3 BPD at 36 weeks' postmenstrual age modified the association between postnatal corticosteroid therapy and death or disability at 2 years' corrected age in extremely preterm infants.

DESIGN, SETTING, AND …

Mastro I: Meta-Analysis And Systematic Review Of Thrombectomy Stent Retriever Outcomes: Comparing Functional, Safety And Recanalization Outcomes Between Embotrap, Solitaire And Trevo In Acute Ischemic Stroke, Osama O Zaidat, Shelly Ikeme, Sunil A Sheth, Shinichi Yoshimura, Xin-Guang Yang, Waleed Brinjikji, David F Kallmes, Patrick Brouwer, John Pederson, Ranita Tarchand, Annie Steffenson, Kevin M Kallmes, Jillienne Touchette, Tommy Andersson

Faculty, Staff and Student Publications

Aims:

Stent-retriever (SR) thrombectomy has demonstrated superior outcomes in patients with acute ischemic stroke compared with medical management alone, but differences among SRs remain unexplored. We conducted a Systematic Review/Meta-Analysis to compare outcomes between three SRs: EmboTrap^®, Solitaire™, and Trevo^®.

Methods:

We conducted a PRISMA-compliant Systematic Review among English-language studies published after 2014 in PubMed/MEDLINE that reported SRs in ≥25 patients. Functional and safety outcomes included 90-day modified Rankin scale (mRS 0-2), mortality, symptomatic intracranial hemorrhage (sICH), and embolization to new territory (ENT). Recanalization outcomes included modified thrombolysis in cerebral infarction (mTICI) and first-pass recanalization (FPR). …

Assessment Of Heterogeneity Amongaassessment Of Heterogeneity Among Participants In The Parkinson’S Progression Markers Initiative Cohort Using Α-Synuclein Seed Amplification: A Cross-Sectional Study Participants In The Parkinson's Progression Markers Initiative Cohort Using Α-Synuclein Seed Amplification: A Cross-Sectional Study, Andrew Siderowf, Luis Concha-Marambio, David-Erick Lafontant, Carly M Farris, Yihua Ma, Paula A Urenia, Hieu Nguyen, Roy N Alcalay, Lana M Chahine, Tatiana Foroud, Douglas Galasko, Karl Kieburtz, Kalpana Merchant, Brit Mollenhauer, Kathleen L Poston, John Seibyl, Tanya Simuni, Caroline M Tanner, Daniel Weintraub, Aleksandar Videnovic, Seung Ho Choi, Ryan Kurth, Chelsea Caspell-Garcia, Christopher S Coffey, Mark Frasier, Luis M A Oliveira, Samantha J Hutten, Todd Sherer, Kenneth Marek, Claudio Soto

Faculty, Staff and Student Publications

BACKGROUND: Emerging evidence shows that α-synuclein seed amplification assays (SAAs) have the potential to differentiate people with Parkinson's disease from healthy controls. We used the well characterised, multicentre Parkinson's Progression Markers Initiative (PPMI) cohort to further assess the diagnostic performance of the α-synuclein SAA and to examine whether the assay identifies heterogeneity among patients and enables the early identification of at-risk groups.

METHODS: This cross-sectional analysis is based on assessments done at enrolment for PPMI participants (including people with sporadic Parkinson's disease from LRRK2 and GBA variants, healthy controls, prodromal individuals with either rapid eye movement sleep behaviour disorder (RBD) …

Tert Promotor Status Does Not Add Prognostic Information In Idh-Wildtype Glioblastomas Fulfilling Other Diagnostic Who Criteria: A Report Of The Rano Resect Group, Antonio Dono, Ali M Moosvi, Puneetha S Goli, Allison C Bellman, Phyu P Aung, Yoshua Esquenazi, Leomar Y Ballester

Faculty, Staff and Student Publications

Genomic alterations are critical for the diagnosis, prognostication, and treatment of patients with infiltrating gliomas. Telomerase reverse transcriptase promoter ( TERT p) mutations are among such crucial alterations. Although DNA sequencing is the preferred method for identifying TERT p mutations, it has limitations related to cost and accessibility. We tested telomerase reverse transcriptase (TERT) immunohistochemistry (IHC) as a surrogate for TERT p mutations in infiltrating gliomas. Thirty-one infiltrating gliomas were assessed by IHC using an anti-TERT Y182 antibody. IHC results were analyzed by a board-certified neuropathologist. Tumors were analyzed by targeted next-generation sequencing. A literature review of the use of …

Microbial Colonization Of Capsular Traction Sutures In Hip Arthroscopic Surgery, Ian S Patten, Yuhang Sun, David R Maldonado, Michael S Lee, Michael B Banffy

Faculty, Staff and Student Publications

BACKGROUND: A common practice in hip arthroscopic surgery is the utilization of capsular traction sutures that can be incorporated into the capsular repair site at the end of the procedure, potentially seeding the hip joint with colonized suture material.

PURPOSE: To investigate the rate of the microbial colonization of capsular traction sutures used during hip arthroscopic surgery and to identify patient-associated risk factors for this microbial colonization.

STUDY DESIGN: Cross-sectional study; Level of evidence, 3.

METHODS: A total of 50 consecutive patients who underwent hip arthroscopic surgery with a single surgeon were enrolled. There were 4 braided nonabsorbable sutures utilized …

Interleukin-33 Facilitates Liver Regeneration Through Serotonin-Involved Gut-Liver Axis, Yankai Wen, Christoph Emontzpohl, Long Xu, Constance L Atkins, Jong-Min Jeong, Yang Yang, Kangho Kim, Chuan Wu, Shizuo Akira, Cynthia Ju

Faculty, Staff and Student Publications

BACKGROUND AND AIMS: Insufficient liver regeneration causes post-hepatectomy liver failure and small-for-size syndrome. Identifying therapeutic targets to enhance hepatic regenerative capacity remains urgent. Recently, increased IL-33 was observed in patients undergoing liver resection and in mice after partial hepatectomy (PHx). The present study aims to investigate the role of IL-33 in liver regeneration after PHx and to elucidate its underlying mechanisms.

APPROACH AND RESULTS: We performed PHx in IL-33 -/- , suppression of tumorigenicity 2 (ST2) -/- , and wild-type control mice, and found deficiency of IL-33 or its receptor ST2 delayed liver regeneration. The insufficient liver regeneration could be …

One Immune System Plays Many Parts: The Dynamic Role Of The Immune System In Chronic Pain And Opioid Pharmacology, Sanam Mustafa, Juliana E Bajic, Benjamin Barry, Samuel Evans, Kariel R Siemens, Mark R Hutchinson, Peter M Grace

Faculty, Staff and Student Publications

The transition from acute to chronic pain is an ongoing major problem for individuals, society and healthcare systems around the world. It is clear chronic pain is a complex multidimensional biological challenge plagued with difficulties in pain management, specifically opioid use. In recent years the role of the immune system in chronic pain and opioid pharmacology has come to the forefront. As a highly dynamic and versatile network of cells, tissues and organs, the immune system is perfectly positioned at the microscale level to alter nociception and drive structural adaptations that underpin chronic pain and opioid use. In this review, …

Molecular Identity Changes Of Tumor-Associated Macrophages And Microglia After Magnetic Resonance Imaging-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening In A Mouse Glioblastoma Model, Yanrong Zhang, Jing Wang, Sara Natasha Ghobadi, Haiyan Zhou, Ai Huang, Marco Gerosa, Qingyi Hou, Olivier Keunen, Anna Golebiewska, Frezghi G Habte, Gerald A Grant, Ramasamy Paulmurugan, Kevin S Lee, Max Wintermark

Faculty, Staff and Student Publications

An orthotopically allografted mouse GL26 glioma model (Ccr2^RFP/wt-Cx3cr1^GFP/wt) was used to evaluate the effect of transient, focal opening of the Blood Brain Barrier (BBB) on the composition of tumor-associated macrophages and microglia (TAMs). BBB Opening was induced by Magnetic Resonance Imaging (MRI)-guided focused ultrasound (MRgFUS) combined with microbubbles. CX3CR1-GFP cells and CCR2-RFP cells in brain tumors were quantified in microscopic images. Tumors in animals treated with a single session of MRgFUS did not show significant changes in cell numbers when compared to tumors in animals not receiving FUS. However, tumors that received two or three sessions …

A Model For Gastrointestinal Tract Motility In A 4d Imaging Phantom Of Human Anatomy, Ergys Subashi, Paul Segars, Harini Veeraraghavan, Joseph Deasy, Neelam Tyagi

Faculty, Staff and Student Publications

BACKGROUND: Gastrointestinal (GI) tract motility is one of the main sources for intra/inter-fraction variability and uncertainty in radiation therapy for abdominal targets. Models for GI motility can improve the assessment of delivered dose and contribute to the development, testing, and validation of deformable image registration (DIR) and dose-accumulation algorithms.

PURPOSE: To implement GI tract motion in the 4D extended cardiac-torso (XCAT) digital phantom of human anatomy.

MATERIALS AND METHODS: Motility modes that exhibit large amplitude changes in the diameter of the GI tract and may persist over timescales comparable to online adaptive planning and radiotherapy delivery were identified based on …

Investigating Gene-Diet Interactions Impacting The Association Between Macronutrient Intake And Glycemic Traits, Kenneth E Westerman, Maura E Walker, Sheila M Gaynor, Jennifer Wessel, Daniel Dicorpo, Jiantao Ma, Alvaro Alonso, Stella Aslibekyan, Abigail S Baldridge, Alain G Bertoni, Mary L Biggs, Jennifer A Brody, Yii-Der Ida Chen, Joseé Dupuis, Mark O Goodarzi, Xiuqing Guo, Natalie R Hasbani, Adam Heath, Bertha Hidalgo, Marguerite R Irvin, W Craig Johnson, Rita R Kalyani, Leslie Lange, Rozenn N Lemaitre, Ching-Ti Liu, Simin Liu, Jee-Young Moon, Rami Nassir, James S Pankow, Mary Pettinger, Laura M Raffield, Laura J Rasmussen-Torvik, Elizabeth Selvin, Mackenzie K Senn, Aladdin H Shadyab, Albert V Smith, Nicholas L Smith, Lyn Steffen, Sameera Talegakwar, Kent D Taylor, Paul S De Vries, James G Wilson, Alexis C Wood, Lisa R Yanek, Jie Yao, Yinan Zheng, Eric Boerwinkle, Alanna C Morrison, Miriam Fornage, Tracy P Russell, Bruce M Psaty, Daniel Levy, Nancy L Heard-Costa, Vasan S Ramachandran, Rasika A Mathias, Donna K Arnett, Robert Kaplan, Kari E North, Adolfo Correa, April Carson, Jerome I Rotter, Stephen S Rich, Joann E Manson, Alexander P Reiner, Charles Kooperberg, Jose C Florez, James B Meigs, Jordi Merino, Deirdre K Tobias, Han Chen, Alisa K Manning

Faculty, Staff and Student Publications

Few studies have demonstrated reproducible gene-diet interactions (GDIs) impacting metabolic disease risk factors, likely due in part to measurement error in dietary intake estimation and insufficient capture of rare genetic variation. We aimed to identify GDIs across the genetic frequency spectrum impacting the macronutrient-glycemia relationship in genetically and culturally diverse cohorts. We analyzed 33,187 participants free of diabetes from 10 National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine program cohorts with whole-genome sequencing, self-reported diet, and glycemic trait data. We fit cohort-specific, multivariable-adjusted linear mixed models for the effect of diet, modeled as an isocaloric substitution of carbohydrate …

Conditional Concordance-Assisted Learning Under Matched Case-Control Design For Combining Biomarkers For Population Screening, Wen Li, Ruosha Li, Qingxiang Yan, Ziding Feng, Jing Ning

Faculty, Staff and Student Publications

Incorporating promising biomarkers into cancer screening practices for early-detection is increasingly appealing because of the unsatisfactory performance of current cancer screening strategies. The matched case-control design is commonly adopted in biomarker development studies to evaluate the discriminative power of biomarker candidates, with an intention to eliminate confounding effects. Data from matched case-control studies have been routinely analyzed by the conditional logistic regression, although the assumed logit link between biomarker combinations and disease risk may not always hold. We propose a conditional concordance-assisted learning method, which is distribution-free, for identifying an optimal combination of biomarkers to discriminate cases and controls. We …

Toward A Neural Semantic Parsing System For Ehr Question Answering, Sarvesh Soni, Kirk Roberts

Faculty, Staff and Student Publications

Clinical semantic parsing (SP) is an important step toward identifying the exact information need (as a machine-understandable logical form) from a natural language query aimed at retrieving information from electronic health records (EHRs). Current approaches to clinical SP are largely based on traditional machine learning and require hand-building a lexicon. The recent advancements in neural SP show a promise for building a robust and flexible semantic parser without much human effort. Thus, in this paper, we aim to systematically assess the performance of two such neural SP models for EHR question answering (QA). We found that the performance of these …

Genetic Loci Of Beta-Aminoisobutyric Acid Are Associated With Aging-Related Mild Cognitive Impairment, Einat Granot-Hershkovitz, Brian Spitzer, Yunju Yang, Wassim Tarraf, Bing Yu, Eric Boerwinkle, Myriam Fornage, Thomas H Mosley, Charles Decarli, Bruce S Kristal, Hector M González, Tamar Sofer

Faculty, Staff and Student Publications

We studied the genetic associations of a previously developed Metabolomic Risk Score (MRS) for Mild Cognitive Impairment (MCI) and beta-aminoisobutyric acid metabolite (BAIBA)-the metabolite highlighted by results from a genome-wide association study (GWAS) of the MCI-MRS, and assessed their association with MCI in datasets of diverse race/ethnicities. We first performed a GWAS for the MCI-MRS and BAIBA, in Hispanic/Latino adults (n = 3890) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We identified ten independent genome-wide significant (p value <5 × 10-8) variants associated with MCI-MRS or BAIBA. Variants associated with the MCI-MRS are located in the Alanine-Glyoxylate Aminotransferase 2 (AGXT2 gene), which is known to be associated with BAIBA metabolism. Variants associated with BAIBA are located in the AGXT2 gene and in the SLC6A13 gene. Next, we tested the variants' association with MCI in independent datasets of n = 3178 HCHS/SOL older individuals, n = 3775 European Americans, and n = 1032 African Americans from the Atherosclerosis Risk In Communities (ARIC) study. Variants were considered associated with MCI if their p value <0.05 in the meta-analysis of the three datasets and their direction of association was consistent with expectation. Rs16899972 and rs37369 from the AGXT2 region were associated with MCI. Mediation analysis supported the mediation effect of BAIBA between the two genetic variants and MCI (p value = 0.004 for causal mediated effect). In summary, genetic variants in the AGXT2 region are associated with MCI in Hispanic/Latino, African, and European American populations in the USA, and their effect is likely mediated by changes in BAIBA levels.

The Genomic Landscape Of Familial Glioma, Dong-Joo Choi, Georgina Armstrong, Brittney Lozzi, Prashanth Vijayaraghavan, Sharon E Plon, Terence C Wong, Eric Boerwinkle, Donna M Muzny, Hsiao-Chi Chen, Richard A Gibbs, Quinn T Ostrom, Beatrice Melin, Benjamin Deneen, Melissa L Bondy, Gliogene Consortium, Genomics England Research Consortium, Matthew N Bainbridge, Christopher I Amos, Jill S Barnholtz-Sloan, Jonine L Bernstein, Elizabeth B Claus, Richard S Houlston, Dora Il'yasova, Robert B Jenkins, Christoffer Johansen, Daniel Lachance, Rose Lai, Beatrice S Melin, Ryan T Merrell, Sara H Olson, Siegal Sadetzki, Joellen Schildkraut, Sanjay Shete, J C Ambrose, P Arumugam, R Bevers, M Bleda, F Boardman-Pretty, C R Boustred, H Brittain, M A Brown, M J Caulfield, G C Chan, A Giess, J N Griffin, A Hamblin, S Henderson, T J P Hubbard, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, A Kousathanas, L Lahnstein, A Lakey, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, M Mcentagart, F Minneci, J Mitchell, L Moutsianas, M Mueller, N Murugaesu, A C Need, P O'Donovan, C A Odhams, C Patch, D Perez-Gil, M B Pereira, J Pullinger, T Rahim, A Rendon, T Rogers, K Savage, K Sawant, R H Scott, A Siddiq, A Sieghart, S C Smith, A Sosinsky, A Stuckey, M Tanguy, A L Taylor Tavares, E R A Thomas, S R Thompson, A Tucci, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki

Faculty, Staff and Student Publications

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to …