Digital Commons Network^™

Feasibility And Value Of Genomic Profiling In Cancer Of Unknown Primary: Real-World Evidence From Prospective Profiling Study, Ryan W Huey, Aakash Tushar Shah, Honey V Reddi, Priyadarsini Dasari, James T Topham, Hyunsoo Hwang, Nishat Dhillon, Anneleis Willett, Brandon G Smaglo, Jeannelyn S Estrella, Asif Rashid, Aurelio Matamoros, Michael J Overman, Linda Choquette, Greg Omerza, Kevin Kelly, Xuemei Wang, Jonathan M Loree, Jens Rueter, Gauri R Varadhachary, Kanwal Raghav

Faculty, Staff and Student Publications

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (October 2016-September 2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients of which GAs with US Food and Drug Administration-approved genomically matched therapy were seen in 25 (40.9%) patients. A change in therapy was recommended and implemented (primary endpoint of the study) in 16 (10.1%) and …

Successful Treatment Of Non-Langerhans Cell Histiocytosis With The Mek Inhibitor Trametinib: A Multicenter Analysis, Ashley Aaroe, Razelle Kurzrock, Gaurav Goyal, Aaron M Goodman, Harsh Patel, Gordon Ruan, Gary Ulaner, Jason Young, Ziyi Li, Derek Dustin, Ronald S Go, Eli L Diamond, Filip Janku

Faculty, Staff and Student Publications

Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs), for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with a favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed the outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at 4 major US …

A Comprehensive Report Of Intrinsically Disordered Regions In Inherited Retinal Diseases, Karen E Lee, Jose S Pulido, Mariana M Da Palma, Rebecca Procopio, Robert B Hufnagel, Margaret Reynolds

2020-Current year OA Pubs

BACKGROUND/PURPOSE: A comprehensive review of the degree of disorder in all genes in the Retinal Information Network (RetNet) Database is implicated in inherited retinal diseases (IRDs). Their association with a missense variation was evaluated.

METHODS: IRD genes from RetNet were included in this study. Publicly available data on the genome aggregation database (gnomAD) were used to analyze the number of total and pathogenic missense variants. Metapredict, an accurate and high-performance predictor that reproduces consensus disorder scores, was used to calculate disorder.

MAIN OUTCOME MEASURES: The main outcome measures were percent disorder, percent pathogenicity, number of total missense variants, and percent …

A Biologic-Device Combination Product Delivering Tumor-Derived Antigens Elicits Immunogenic Cell Death-Associated Immune Responses Against Glioblastoma, Christopher Cultrara, Christopher Uhl, Kenneth Kirby, Essam Abed Elrazaq, Amelia Zellander, David W. Andrews, Charles B. Scott, Lorenzo Galluzzi, Mark A. Exley, Jenny Zilberberg

Department of Neurosurgery Faculty Papers

Background IGV-001 is a personalized, autologous cancer cell-based immunotherapy conceived to deliver a tumor-derived antigenic payload in the context of immunostimulatory signals to patients with glioblastoma (GBM). IGV-001 consists of patient-derived GBM cells treated with an antisense oligodeoxynucleotide against insulin-like growth factor 1 receptor (IGF1R) and placed in proprietary biodiffusion chambers (BDCs). The BDCs are then exposed to 5–6 Gy radiation and implanted at abdominal sites for ~48 hours. IGV-001 has previously been shown to be generally safe with promising clinical activity in newly diagnosed GBM patients.

Methods Mouse (m) or human (h) variants of IGV-001 …

Fan1 Removes Triplet Repeat Extrusions Via A Pcna- And Rfc-Dependent Mechanism, Ashutosh S. Phadte, Mayuri Bhatia, Hope Ebert, Haaris Abdullah, Essam Abed Elrazaq, Konstantin E. Komolov, Anna Pluciennik

Department of Biochemistry and Molecular Biology Faculty Papers

Human genome-wide association studies have identified FAN1 and several DNA mismatch repair (MMR) genes as modifiers of Huntington’s disease age of onset. In animal models, FAN1 prevents somatic expansion of CAG triplet repeats, whereas MMR proteins promote this process. To understand the molecular basis of these opposing effects, we evaluated FAN1 nuclease function on DNA extrahelical extrusions that represent key intermediates in triplet repeat expansion. Here, we describe a strand-directed, extrusion-provoked nuclease function of FAN1 that is activated by RFC, PCNA, and ATP at physiological ionic strength. Activation of FAN1 in this manner results in DNA cleavage in the vicinity …

Traf3-Ewsr1 Signaling Axis Acts As A Checkpoint On Germinal Center Responses, Yanchuan Li, Lele Zhu, Chun-Jung Ko, Jin-Young Yang, Hongjiao Wang, Ganiraju Manyam, Jing Wang, Xuhong Cheng, Shuli Zhao, Zuliang Jie

Faculty, Staff and Student Publications

The formation of germinal centers (GCs) is crucial for humoral immunity and vaccine efficacy. Constant stimulation through microbiota drives the formation of constitutive GCs in Peyer's patches (PPs), which generate B cells that produce antibodies against gut antigens derived from commensal bacteria and infectious pathogens. However, the molecular mechanism that regulates this persistent process is poorly understood. We report that Ewing Sarcoma Breakpoint Region 1 (EWSR1) is a brake to constitutive GC generation and immunoglobulin G (IgG) production in PPs, vaccination-induced GC formation, and IgG responses. Mechanistically, EWSR1 suppresses Bcl6 upregulation after antigen encounter, thereby negatively regulating induced GC B …

Metabolic Liver Cancer: Associations Of Rare And Common Germline Variants In One-Carbon Metabolism And Dna Methylation Genes, Samuel O Antwi, Michael Heckman, Launia White, Irene Yan, Vivekananda Sarangi, Kimberly P Lauer, Joseph Reddy, Fowsiyo Ahmed, Swathi Veliginti, Ellis D Mejías Febres, Rikita I Hatia, Ping Chang, Laura Izquierdo-Sanchez, Loreto Boix, Angela Rojas, Jesus M Banales, Maria Reig, Per Stål, Manuel Romero Gómez, Amit G Singal, Donghui Li, Manal M Hassan, Lewis R Roberts, Tushar Patel

Faculty, Staff and Student Publications

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in …

Metabolic Liver Cancer: Associations Of Rare And Common Germline Variants In One-Carbon Metabolism And Dna Methylation Genes, Samuel O Antwi, Michael Heckman, Launia White, Irene Yan, Vivekananda Sarangi, Kimberly P Lauer, Joseph Reddy, Fowsiyo Ahmed, Swathi Veliginti, Ellis D Mejías Febres, Rikita I Hatia, Ping Chang, Laura Izquierdo-Sanchez, Loreto Boix, Angela Rojas, Jesus M Banales, Maria Reig, Per Stål, Manuel Romero Gómez, Amit G Singal, Donghui Li, Manal M Hassan, Lewis R Roberts, Tushar Patel

Faculty, Staff and Student Publications

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in …

Csf1r Regulates Schizophrenia-Related Stress Response And Vascular Association Of Microglia/Macrophages, Ling Yan, Yanli Li, Fengmei Fan, Mengzhuang Gou, Fangling Xuan, Wei Feng, Keerthana Chithanathan, Wei Li, Junchao Huang, Hongna Li, Wenjin Chen, Baopeng Tian, Zhiren Wang, Shuping Tan, Alexander Zharkovsky, L Elliot Hong, Yunlong Tan, Li Tian

Faculty, Staff and Student Publications

BACKGROUND: Microglia are known to regulate stress and anxiety in both humans and animal models. Psychosocial stress is the most common risk factor for the development of schizophrenia. However, how microglia/brain macrophages contribute to schizophrenia is not well established. We hypothesized that effector molecules expressed in microglia/macrophages were involved in schizophrenia via regulating stress susceptibility.

METHODS: We recruited a cohort of first episode schizophrenia (FES) patients (n = 51) and age- and sex-paired healthy controls (HCs) (n = 46) with evaluated stress perception. We performed blood RNA-sequencing (RNA-seq) and brain magnetic resonance imaging, and measured plasma level of colony stimulating …

Proteomic Profiling Across Breast Cancer Cell Lines And Models, Marian Kalocsay, Matthew J Berberich, Robert A Everley, Maulik K Nariya, Mirra Chung, Benjamin Gaudio, Chiara Victor, Gary A Bradshaw, Robyn J Eisert, Marc Hafner, Peter K Sorger, Caitlin E Mills, Kartik Subramanian

Faculty, Staff and Student Publications

We performed quantitative proteomics on 60 human-derived breast cancer cell line models to a depth of ~13,000 proteins. The resulting high-throughput datasets were assessed for quality and reproducibility. We used the datasets to identify and characterize the subtypes of breast cancer and showed that they conform to known transcriptional subtypes, revealing that molecular subtypes are preserved even in under-sampled protein feature sets. All datasets are freely available as public resources on the LINCS portal. We anticipate that these datasets, either in isolation or in combination with complimentary measurements such as genomics, transcriptomics and phosphoproteomics, can be mined for the purpose …

Multiomics Analyses Reveal Dars1-As1/Ybx1-Controlled Posttranscriptional Circuits Promoting Glioblastoma Tumorigenesis/Radioresistance, Caishang Zheng, Yanjun Wei, Qiang Zhang, Ming Sun, Yunfei Wang, Jiakai Hou, Peng Zhang, Xiangdong Lv, Dan Su, Yujie Jiang, Joy Gumin, Nidhi Sahni, Baoli Hu, Wenyi Wang, Xi Chen, Daniel J Mcgrail, Chaolin Zhang, Suyun Huang, Han Xu, Junjie Chen, Frederick F Lang, Jian Hu, Yiwen Chen

Faculty, Staff and Student Publications

The glioblastoma (GBM) stem cell-like cells (GSCs) are critical for tumorigenesis/therapeutic resistance of GBM. Mounting evidence supports tumor-promoting function of long noncoding RNAs (lncRNAs), but their role in GSCs remains poorly understood. By combining CRISPRi screen with orthogonal multiomics approaches, we identified a lncRNA DARS1-AS1-controlled posttranscriptional circuitry that promoted the malignant properties of GBM cells/GSCs. Depleting DARS1-AS1 inhibited the proliferation of GBM cells/GSCs and self-renewal of GSCs, prolonging survival in orthotopic GBM models. DARS1-AS1 depletion also impaired the homologous recombination (HR)-mediated double-strand break (DSB) repair and enhanced the radiosensitivity of GBM cells/GSCs. Mechanistically, DARS1-AS1 interacted with YBX1 to promote …

Combined Crispri And Proteomics Screening Reveal A Cohesin-Ctcf-Bound Allele Contributing To Increased Expression Of Ruvbl1 And Prostate Cancer Progression, Yijun Tian, Dandan Dong, Zixian Wang, Lang Wu, Jong Y Park, Gong-Hong Wei, Liang Wang

Faculty, Staff and Student Publications

Genome-wide association studies along with expression quantitative trait locus (eQTL) mapping have identified hundreds of single-nucleotide polymorphisms (SNPs) and their target genes in prostate cancer (PCa), yet functional characterization of these risk loci remains challenging. To screen for potential regulatory SNPs, we designed a CRISPRi library containing 9,133 guide RNAs (gRNAs) to cover 2,166 candidate SNP loci implicated in PCa and identified 117 SNPs that could regulate 90 genes for PCa cell growth advantage. Among these, rs60464856 was covered by multiple gRNAs significantly depleted in screening (FDR < 0.05). Pooled SNP association analysis in the PRACTICAL and FinnGen cohorts showed significantly higher PCa risk for the rs60464856 G allele (p value = 1.2 × 10

Moving The Pendulum For Glioblastoma Treatment: One Injection At A Time, Xizi Wu, Christopher Alvarez-Breckenridge

Faculty, Staff and Student Publications

Despite advances, glioblastoma is characterized by exceptionally high rates of recurrence and resistance to therapy. This commentary remarks on the recently published article by Maruyama et al, which reports the PMDA review of G47Δ injection for malignant glioma, in which the efficacy and safety results of G47Δ were evaluated and approval conditions clarified.

Facs-Based Genome-Wide Crispr Screens Define Key Regulators Of Dna Damage Signaling Pathways, Min Huang, Fuwen Yao, Litong Nie, Chao Wang, Dan Su, Huimin Zhang, Siting Li, Mengfan Tang, Xu Feng, Bin Yu, Zhen Chen, Shimin Wang, Ling Yin, Lisha Mou, Traver Hart, Junjie Chen

Faculty, Staff and Student Publications

DNA damage-activated signaling pathways are critical for coordinating multiple cellular processes, which must be tightly regulated to maintain genome stability. To provide a comprehensive and unbiased perspective of DNA damage response (DDR) signaling pathways, we performed 30 fluorescence-activated cell sorting (FACS)-based genome-wide CRISPR screens in human cell lines with antibodies recognizing distinct endogenous DNA damage signaling proteins to identify critical regulators involved in DDR. We discovered that proteasome-mediated processing is an early and prerequisite event for cells to trigger camptothecin- and etoposide-induced DDR signaling. Furthermore, we identified PRMT1 and PRMT5 as modulators that regulate ATM protein level. Moreover, we discovered …

Mavs Signaling Is Required For Preventing Persistent Chikungunya Heart Infection And Chronic Vascular Tissue Inflammation, Maria G Noval, Sophie N Spector, Eric Bartnicki, Franco Izzo, Navneet Narula, Stephen T Yeung, Payal Damani-Yokota, M Zahidunnabi Dewan, Valeria Mezzano, Bruno A Rodriguez-Rodriguez, Cynthia Loomis, Kamal M Khanna, Kenneth A Stapleford

Faculty, Staff and Student Publications

Chikungunya virus (CHIKV) infection has been associated with severe cardiac manifestations, yet, how CHIKV infection leads to heart disease remains unknown. Here, we leveraged both mouse models and human primary cardiac cells to define the mechanisms of CHIKV heart infection. Using an immunocompetent mouse model of CHIKV infection as well as human primary cardiac cells, we demonstrate that CHIKV directly infects and actively replicates in cardiac fibroblasts. In immunocompetent mice, CHIKV is cleared from cardiac tissue without significant damage through the induction of a local type I interferon response from both infected and non-infected cardiac cells. Using mice deficient in …

Novel Murine Glioblastoma Models That Reflect The Immunotherapy Resistance Profile Of A Human Disease, Chao-Hsien Chen, Renee L Chin, Genevieve P Hartley, Spencer T Lea, Brian J Engel, Cheng-En Hsieh, Rishika Prasad, Jason Roszik, Takashi Shingu, Gregory A Lizee, Amy B Heimberger, Steven W Millward, Jian Hu, David S Hong, Michael A Curran

Faculty, Staff and Student Publications

BACKGROUND: The lack of murine glioblastoma models that mimic the immunobiology of human disease has impeded basic and translational immunology research. We, therefore, developed murine glioblastoma stem cell lines derived from Nestin-CreERT2QkL/L; Trp53L/L; PtenL/L (QPP) mice driven by clinically relevant genetic mutations common in human glioblastoma. This study aims to determine the immune sensitivities of these QPP lines in immunocompetent hosts and their underlying mechanisms.

METHODS: The differential responsiveness of QPP lines was assessed in the brain and flank in untreated, anti-PD-1, or anti-CTLA-4 treated mice. The impact of genomic landscape on the responsiveness of each tumor was measured through …

Proteogenomic Analysis Of Chemo-Refractory High-Grade Serous Ovarian Cancer, Shrabanti Chowdhury, Jacob J Kennedy, Richard G Ivey, Oscar D Murillo, Noshad Hosseini, Xiaoyu Song, Francesca Petralia, Anna Calinawan, Sara R Savage, Anna B Berry, Boris Reva, Umut Ozbek, Azra Krek, Weiping Ma, Felipe Da Veiga Leprevost, Jiayi Ji, Seungyeul Yoo, Chenwei Lin, Uliana J Voytovich, Yajue Huang, Sun-Hee Lee, Lindsay Bergan, Travis D Lorentzen, Mehdi Mesri, Henry Rodriguez, Andrew N Hoofnagle, Zachary T Herbert, Alexey I Nesvizhskii, Bing Zhang, Jeffrey R Whiteaker, David Fenyo, Wilson Mckerrow, Joshua Wang, Stephan C Schürer, Vasileios Stathias, X Steven Chen, Mary Helen Barcellos-Hoff, Timothy K Starr, Boris J Winterhoff, Andrew C Nelson, Samuel C Mok, Scott H Kaufmann, Charles Drescher, Marcin Cieslik, Pei Wang, Michael J Birrer, Amanda G Paulovich

Faculty, Staff and Student Publications

To improve the understanding of chemo-refractory high-grade serous ovarian cancers (HGSOCs), we characterized the proteogenomic landscape of 242 (refractory and sensitive) HGSOCs, representing one discovery and two validation cohorts across two biospecimen types (formalin-fixed paraffin-embedded and frozen). We identified a 64-protein signature that predicts with high specificity a subset of HGSOCs refractory to initial platinum-based therapy and is validated in two independent patient cohorts. We detected significant association between lack of Ch17 loss of heterozygosity (LOH) and chemo-refractoriness. Based on pathway protein expression, we identified 5 clusters of HGSOC, which validated across two independent patient cohorts and patient-derived xenograft (PDX) …

Phf8-Glul Axis In Lipid Deposition And Tumor Growth Of Clear Cell Renal Cell Carcinoma., Song Peng, Ze Wang, Peng Tang, Shuo Wang, Yiqiang Huang, Qiubo Xie, Yapeng Wang, Xintao Tan, Tang Tang, Xuzhi Yan, Jing Xu, Weihua Lan, Luofu Wang, Dianzheng Zhang, Bin Wang, Tiejun Pan, Jun Qin, Jun Jiang, Qiuli Liu

PCOM Scholarly Works

For clear cell renal cell carcinoma (ccRCC), lipid deposition plays important roles in the development, metastasis, and drug resistance. However, the molecular mechanisms underlying lipid deposition in ccRCC remain largely unknown. By conducting an unbiased CRISPR-Cas9 screening, we identified the epigenetic regulator plant homeodomain finger protein 8 (PHF8) as an important regulator in ccRCC lipid deposition. Moreover, PHF8 is regulated by von Hippel-Lindau (VHL)/hypoxia-inducible factor (HIF) axis and essential for VHL deficiency-induced lipid deposition. PHF8 transcriptionally up-regulates glutamate-ammonia ligase (GLUL), which promotes the lipid deposition and ccRCC progression. Mechanistically, by forming a complex with c-MYC, PHF8 up-regulates TEA domain transcription …

Genetic Insights Into Resting Heart Rate And Its Role In Cardiovascular Disease, Yordi J Van De Vegte, Ruben N Eppinga, M Yldau Van Der Ende, Yanick P Hagemeijer, Yuvaraj Mahendran, Elias Salfati, Albert V Smith, Vanessa Y Tan, Dan E Arking, Ioanna Ntalla, Emil V Appel, Claudia Schurmann, Jennifer A Brody, Rico Rueedi, Ozren Polasek, Gardar Sveinbjornsson, Cecile Lecoeur, Claes Ladenvall, Jing Hua Zhao, Aaron Isaacs, Lihua Wang, Jian'an Luan, Shih-Jen Hwang, Nina Mononen, Kirsi Auro, Anne U Jackson, Lawrence F Bielak, Linyao Zeng, Nabi Shah, Maria Nethander, Archie Campbell, Tuomo Rankinen, Sonali Pechlivanis, Lu Qi, Wei Zhao, Federica Rizzi, Toshiko Tanaka, Antonietta Robino, Massimiliano Cocca, Leslie Lange, Martina Müller-Nurasyid, Carolina Roselli, Weihua Zhang, Marcus E Kleber, Xiuqing Guo, Henry J Lin, Francesca Pavani, Tessel E Galesloot, Raymond Noordam, Yuri Milaneschi, Katharina E Schraut, Marcel Den Hoed, Frauke Degenhardt, Stella Trompet, Marten E Van Den Berg, Giorgio Pistis, Yih-Chung Tham, Stefan Weiss, Xueling S Sim, Hengtong L Li, Peter J Van Der Most, Ilja M Nolte, Leo-Pekka Lyytikäinen, M Abdullah Said, Daniel R Witte, Carlos Iribarren, Lenore Launer, Susan M Ring, Paul S De Vries, Peter Sever, Allan Linneberg, Erwin P Bottinger, Sandosh Padmanabhan, Bruce M Psaty, Nona Sotoodehnia, Ivana Kolcic, Dcct/Edic Research Group, David O Arnar, Daniel F Gudbjartsson, Hilma Holm, Beverley Balkau, Claudia T Silva, Christopher H Newton-Cheh, Kjell Nikus, Perttu Salo, Karen L Mohlke, Patricia A Peyser, Heribert Schunkert, Mattias Lorentzon, Jari Lahti, Dabeeru C Rao, Marilyn C Cornelis, Jessica D Faul, Jennifer A Smith, Katarzyna Stolarz-Skrzypek, Stefania Bandinelli, Maria Pina Concas, Gianfranco Sinagra, Thomas Meitinger, Melanie Waldenberger, Moritz F Sinner, Konstantin Strauch, Graciela E Delgado, Kent D Taylor, Jie Yao, Luisa Foco, Olle Melander, Jacqueline De Graaf, Renée De Mutsert, Eco J C De Geus, Åsa Johansson, Peter K Joshi, Lars Lind, Andre Franke, Peter W Macfarlane, Kirill V Tarasov, Nicholas Tan, Stephan B Felix, E-Shyong Tai, Debra Q Quek, Harold Snieder, Johan Ormel, Martin Ingelsson, Cecilia Lindgren, Andrew P Morris, Olli T Raitakari, Torben Hansen, Themistocles Assimes, Vilmundur Gudnason, Nicholas J Timpson, Alanna C Morrison, Patricia B Munroe, David P Strachan, Niels Grarup, Ruth J F Loos, Susan R Heckbert, Peter Vollenweider, Caroline Hayward, Kari Stefansson, Philippe Froguel, Leif Groop, Nicholas J Wareham, Cornelia M Van Duijn, Mary F Feitosa, Christopher J O'Donnell, Mika Kähönen, Markus Perola, Michael Boehnke, Sharon L R Kardia, Jeanette Erdmann, Colin N A Palmer, Claes Ohlsson, David J Porteous, Johan G Eriksson, Claude Bouchard, Susanne Moebus, Peter Kraft, David R Weir, Daniele Cusi, Luigi Ferrucci, Sheila Ulivi, Giorgia Girotto, Adolfo Correa, Stefan Kääb, Annette Peters, John C Chambers, Jaspal S Kooner, Winfried März, Jerome I Rotter, Andrew A Hicks, J Gustav Smith, Lambertus A L M Kiemeney, Dennis O Mook-Kanamori, Brenda W J H Penninx, Ulf Gyllensten, James F Wilson, Stephen Burgess, Johan Sundström, Wolfgang Lieb, J Wouter Jukema, Mark Eijgelsheim, Edward L M Lakatta, Ching-Yu Cheng, Marcus Dörr, Tien-Yin Wong, Charumathi Sabanayagam, Albertine J Oldehinkel, Harriette Riese, Terho Lehtimäki, Niek Verweij, Pim Van Der Harst

Faculty, Staff and Student Publications

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample …

Alternative Splicing Of Ceacam1 By Hypoxia-Inducible Factor-1Α Enhances Tolerance To Hepatic Ischemia In Mice And Humans, Kenneth J Dery, Hidenobu Kojima, Shoichi Kageyama, Kentaro Kadono, Hirofumi Hirao, Brian Cheng, Yuan Zhai, Douglas G Farmer, Fady M Kaldas, Xiaoyi Yuan, Holger K Eltzschig, Jerzy W Kupiec-Weglinski

Faculty, Staff and Student Publications

Although alternative splicing (AS) drives transcriptional responses and cellular adaptation to environmental stresses, its contributions in organ transplantation have not been appreciated. We have shown that carcinoembryonic antigen-related cell adhesion molecule (Ceacam1; CD66a), a transmembrane biliary glycoprotein expressed in epithelial, endothelial, and immune cells, determines donor liver transplant quality. Here, we studied how AS of Ceacam1 affects ischemia-reperfusion injury (IRI) in mouse and human livers. We found that the short cytoplasmic isoform Ceacam1-S increased during early acute and late resolution phases of warm IRI injury in mice. Transfection of Ceacam1-deficient mouse hepatocytes with adenoviral Ceacam1-S mitigated hypoxia-induced loss of …

Genetic Insights Into Resting Heart Rate And Its Role In Cardiovascular Disease, Yordi J Van De Vegte, Lihua Wang, Dabeeru C Rao, Et Al.

2020-Current year OA Pubs

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample …

Skp2-Mediated Mlkl Degradation Confers Cisplatin-Resistant In Non-Small Cell Lung Cancer Cells, Huiling Zhou, Li Zhou, Qing Guan, Xuyang Hou, Cong Wang, Lijun Liu, Jian Wang, Xinfang Yu, Wei Li, Haidan Liu

Faculty, Staff and Students Publications

Non-small cell lung cancer (NSCLC) is the most prevalent type of cancer and the leading cause of cancer-related death. Chemotherapeutic resistance is a major obstacle in treating NSCLC patients. Here, we discovered that the E3 ligase Skp2 is overexpressed, accompanied by the downregulation of necroptosis-related regulator MLKL in human NSCLC tissues and cell lines. Knockdown of Skp2 inhibited viability, anchorage-independent growth, and in vivo tumor development of NSCLC cells. We also found that the Skp2 protein is negatively correlated with MLKL in NSCLC tissues. Moreover, Skp2 is increased and accompanied by an upregulation of MLKL ubiquitination and degradation in cisplatin-resistant …

Cross-Cultural Applicability Of Eye-Tracking In Assessing Attention To Emotional Faces In Preschool-Aged Children, Sara S Nozadi, Andrea Aguiar, Ruofei Du, Elizabeth A Enright, Susan L Schantz, Curtis Miller, Brandon Rennie, Mallery Quetawki, Debra Mackenzie, Johnnye L Lewis

Pediatrics Research and Scholarship

Humans show an attention bias toward emotional versus neutral information, which is considered an adaptive pattern of information processing. Deviations from this pattern have been observed in children with socially withdrawn behaviors, with most research being conducted in controlled settings among children from urban areas. The goal of the current study was to examine the cross-cultural applicability of two eye-tracking-based measures in assessing attention biases and their relations to children's symptoms of socially withdrawn behaviors in two independent and diverse samples of preschool children. The cross-cultural comparison was conducted between the Navajo Birth Cohort study (NBCS), an indigenous cohort with …

2022 American College Of Rheumatology Guideline For Exercise, Rehabilitation, Diet, And Additional Integrative Interventions For Rheumatoid Arthritis, Bryant R England, Benjamin J Smith, Nancy A Baker, Jennifer L Barton, Carol A Oatis, Gordon Guyatt, Allen Anandarajah, Kristine Carandang, Karmela Kim Chan, Deb Constien, Eileen Davidson, Carole V Dodge, Anita Bemis-Dougherty, Sotiria Everett, Nadine Fisher, Liana Fraenkel, Susan M Goodman, Janet Lewis, Victoria Menzies, Larry W Moreland, Iris Navarro-Millan, Sarah Patterson, Lawrence Rick Phillips, Neha Shah, Namrata Singh, Daniel White, Rawan Alheresh, Kamil E Barbour, Thomas Bye, Dana Guglielmo, Rebecca Haberman, Tate Johnson, Anatole Kleiner, Chris Y Lane, Linda C Li, Hiral Master, Daniel Pinto, Janet L Poole, Kimberly Steinbarger, Daniel Sztubinski, Louise Thoma, Vlad Tsaltskan, Marat Turgunbaev, Courtney Wells, Amy S Turner, Jonathan R Treadwell

Pediatrics Research and Scholarship

OBJECTIVE: To develop initial American College of Rheumatology (ACR) guidelines on the use of exercise, rehabilitation, diet, and additional interventions in conjunction with disease-modifying antirheumatic drugs (DMARDs) as part of an integrative management approach for people with rheumatoid arthritis (RA).

METHODS: An interprofessional guideline development group constructed clinically relevant Population, Intervention, Comparator, and Outcome (PICO) questions. A literature review team then completed a systematic literature review and applied the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the certainty of evidence. An interprofessional Voting Panel (n = 20 participants) that included 3 individuals with RA achieved consensus …

The Antiviral Effects Of A Mek1/2 Inhibitor Promote Tumor Regression In A Preclinical Model Of Human Papillomavirus Infection-Induced Tumorigenesis, Adrian J. Luna, Jesse M. Young, Rosa T. Sterk, Virginie Bondu, Fred A. Schultz, Donna F. Kusewitt, Huining Kang, Michelle A. Ozbun

Pathology Research and Scholarship

Human papillomaviruses (HPVs) are a significant public health concern due to their widespread transmission, morbidity, and oncogenic potential. Despite efficacious vaccines, millions of unvaccinated individuals and those with existing infections will develop HPV-related diseases for the next two decades and beyond. The continuing burden of HPV-related diseases is exacerbated by the lack of effective therapies or cures for infections, highlighting the need to identify and develop antivirals. The experimental murine papillomavirus type 1 (MmuPV1) model provides opportunities to study papillomavirus pathogenesis in cutaneous epithelium, the oral cavity, and the anogenital tract. However, to date the MmuPV1 infection model has not …

Association Of Amnioinfusion Volume At The Time Of Surgery For Twin-Twin Transfusion Syndrome And Latency To Delivery., Braxton Forde, Foong-Yen Lim, David N Mckinney, Mounira Habli, Kara B Markham, Mallory Hoffman, Sammy Tabbah, Marc Oria, Jose L Peiro

Women’s Health Articles

OBJECTIVE: To evaluate the impact of amnioinfusion and other peri-operative factors on pregnancy outcomes in the setting of Twin-twin transfusion syndrome (TTTS) treated via fetoscopic laser photocoagulation (FLP).

METHODS: Retrospective study of TTTS treated via FLP from 2010 to 2019. Pregnancies were grouped by amnioinfusion volume during FLP (< 1 L vs. ≥1 L). The primary outcome was latency from surgery to delivery. An amnioinfusion statistic (AIstat) was created for each surgery based on the volume of fluid infused and removed and the preoperative deepest vertical pocket. Regression analysis was planned to assess the association of AIstat with latency.

RESULTS: Patients with amnioinfusion of ≥1 L at the time of FLP had decreased latency from surgery to delivery (61 ± 29.4 vs. 73 ± 28.8 days with amnioinfusion < 1 L, p < 0.001) and increased preterm prelabor rupture of membranes (PPROM) < 34 weeks (44.7% vs. 33.5%, p = 0.042). Amnioinfusion ≥1 L was associated with an increased risk of delivery < 32 weeks (aRR 2.6, 95% CI 1.5-4.5), 30 weeks (aRR 2.4, 95% CI 1.5-3.8), and 28 weeks (aRR 1.9, 95% CI 1.1-2.3). Cox-proportional regression revealed that AIstat was inversely associated with latency (HR 1.1, 95% CI 1.1-1.2).

CONCLUSION: Amnioinfusion ≥1 L during FLP was associated with decreased latency after surgery and increased PPROM < 34 weeks.

Major Cardiovascular Events After Covid-19, Event Rates Post-Vaccination, Antiviral Or Anti-Inflammatory Therapy, And Temporal Trends: Rationale And Methodology Of The Corona-Vte-Network Study, Behnood Bikdeli, Candrika D Khairani, Darsiya Krishnathasan, Antoine Bejjani, Andre Armero, Anthony Tristani, Julia Davies, Nicole Porio, Ali A Assi, Victor Nauffal, Umberto Campia, Zaid Almarzooq, Eric Wei, Aditya Achanta, Sirus J Jesudasen, Bruce C Tiu, Geno J. Merli, Orly Leiva, John Fanikos, Aditya Sharma, Alec Vishnevsky, Judith Hsia, Mark R Nehler, James Welker, Marc P Bonaca, Brett J Carroll, Zhou Lan, Samuel Z Goldhaber, Gregory Piazza

Division of Cardiology Faculty Papers

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with excess risk of cardiovascular and thrombotic events in the early post-infection period and during convalescence. Despite the progress in our understanding of cardiovascular complications, uncertainty persists with respect to more recent event rates, temporal trends, association between vaccination status and outcomes, and findings within vulnerable subgroups such as older adults (aged 65 years or older), or those undergoing hemodialysis. Sex-informed findings, including results among pregnant and breastfeeding women, as well as adjusted comparisons between male and female adults are similarly understudied.

METHODS: Adult patients, aged ≥18 years, with polymerase chain reaction-confirmed COVID-19 …

Graft-Versus-Host Disease: Teaching Old Drugs New Tricks At Less Cost, Shatha Farhan, Shernan G. Holtan

Hematology/Oncology Articles

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). Currently, more patients can receive SCT. This is attributed to the use of reduced intensity regimens and the use of different GVHD prophylaxis that breaks the barrier of human leukocyte antigen, allowing an increase in the donor pool. Once an area with relatively few clinical trial options, there has been an increase in interest in GVHD prophylaxis and treatment, which has led to many US Food and Drug Administration (FDA) approvals. Although there is considerable excitement over novel therapies, many patients may not …

A First-In-Human, Dose-Escalation Study Of The Methionine Aminopeptidase 2 Inhibitor M8891 In Patients With Advanced Solid Tumors, Michael A. Carducci, Ding Wang, Christina Habermehl, Matthias Bödding, Felix Rohdich, Floriane Lignet, Klaus Duecker, Oleksandr Karpenko, Linda Pudelko, Claude Gimmi, Patricia Lorusso

Hematology/Oncology Articles

Methionine aminopeptidase 2 (MetAP2) is essential to endothelial cell growth and proliferation during tumor angiogenesis. M8891 is a novel orally bioavailable, potent, selective, reversible MetAP2 inhibitor with antiangiogenic and antitumor activity in preclinical studies. The safety, tolerability, pharmacokinetics, and pharmacodynamics of M8891 monotherapy were assessed in a phase I, first-in-human, multicenter, open-label, single-arm, dose-escalation study (NCT03138538). Patients with advanced solid tumors received 7-80 mg M8891 once daily in 21-day cycles. The primary endpoint was dose-limiting toxicity (DLT) during cycle 1, with the aim to determine the maximum tolerated dose (MTD). Twenty-seven patients were enrolled across six dose levels. Two DLTs …

Human Microbiome Variation Associated With Race And Ethnicity Emerges As Early As 3 Months Of Age, Elizabeth K. Mallott, Alexandra R. Sitarik, Leslie D. Leve, Camille Cioffi, Carlos A. Camargo, Kohei Hasegawa, Seth R. Bordenstein

Public Health Sciences Articles

Human microbiome variation is linked to the incidence, prevalence, and mortality of many diseases and associates with race and ethnicity in the United States. However, the age at which microbiome variability emerges between these groups remains a central gap in knowledge. Here, we identify that gut microbiome variation associated with race and ethnicity arises after 3 months of age and persists through childhood. One-third of the bacterial taxa that vary across caregiver-identified racial categories in children are taxa reported to also vary between adults. Machine learning modeling of childhood microbiomes from 8 cohort studies (2,756 samples from 729 children) distinguishes …