Diseases Commons^™

Early Antibody Treatment, Inflammation, And Risk Of Post-Covid Conditions, Kelly A Gebo, Sonya L Heath, Yuriko Fukuta, Xianming Zhu, Sheriza Baksh, Allison G Abraham, Feben Habtehyimer, David Shade, Jessica Ruff, Malathi Ram, Oliver Laeyendecker, Reinaldo E Fernandez, Eshan U Patel, Owen R Baker, Shmuel Shoham, Edward R Cachay, Judith S Currier, Jonathan M Gerber, Barry Meisenberg, Donald N Forthal, Laura L Hammitt, Moises A Huaman, Adam Levine, Giselle S Mosnaim, Bela Patel, James H Paxton, Jay S Raval, Catherine G Sutcliffe, Shweta Anjan, Thomas Gniadek, Seble Kassaye, Janis E Blair, Karen Lane, Nichol A Mcbee, Amy L Gawad, Piyali Das, Sabra L Klein, Andrew Pekosz, Evan M Bloch, Daniel Hanley, Arturo Casadevall, Aaron A R Tobian, David J Sullivan, Cssc-004 Consortium

Faculty, Staff and Students Publications

Post-COVID conditions (PCCs) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about treatment, inflammation, and PCC. Among 882 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of COVID-19 convalescent plasma (CCP) vs control plasma with available biospecimens and symptom data, the association between early CCP treatment, cytokine levels, and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14, and day 90 using a multiplexed sandwich immunoassay (Meso Scale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. …

Enolase Inhibitors As Early Lead Therapeutics Against Trypanosoma Brucei, Colm P Roster, Danielle Lavigne, Jillian E Milanes, Emily Knight, Heidi D Anderson, Sabrina Pizarro, Elijah M Harding, Meredith T Morris, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian Dominy, Daniel C Whitehead, Md Nasir Uddin, Steven W Millward, James C Morris

Faculty, Staff and Student Publications

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei, serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO (TbENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) …

Determining Call-To-Entry Rate And Recruitment Barriers In Clinical Studies For Community Clinics Serving Low-Income Populations: A Cohort Study, Elizabeth M Vaughan, Salim Virani, Mahmoud Al Rifai, Victor J Cardenas, Craig A Johnston, Laura Porterfield, Zuleica Santiago Delgado, Susan L Samson, Vanessa Schick, Aanand D Naik

Faculty, Staff and Student Publications

BACKGROUND: Recruitment for clinical studies is challenging. to overcome barriers, investigators have previously established call-to-entry rates to assist in planning. However, rates specific to low-income minority populations are needed to account for additional barriers to enrolment these individuals face.

OBJECTIVE: to obtain a call-to-entry rate in a low-income uninsured Hispanic population with chronic disease.

METHODS: We used data from four of our randomised clinical studies to determine the call-to-entry rate for individuals (n=1075) with or at risk for type 2 diabetes: participants needed/potential participants contacted=recruitment rate (yield). Research staff contacted potential participants to enrol in a study that evaluated 6 …

Localized Cardiac Small Molecule Trajectories And Persistent Chemical Sequelae In Experimental Chagas Disease, Zongyuan Liu, Rebecca Ulrich Vonbargen, April L Kendricks, Kate Wheeler, Ana Carolina Leão, Krithivasan Sankaranarayanan, Danya A Dean, Shelley S Kane, Ekram Hossain, Jeroen Pollet, Maria Elena Bottazzi, Peter J Hotez, Kathryn M Jones, Laura-Isobel Mccall

Faculty, Staff and Students Publications

Post-infectious conditions present major health burdens but remain poorly understood. In Chagas disease (CD), caused by Trypanosoma cruzi parasites, antiparasitic agents that successfully clear T. cruzi do not always improve clinical outcomes. In this study, we reveal differential small molecule trajectories between cardiac regions during chronic T. cruzi infection, matching with characteristic CD apical aneurysm sites. Incomplete, region-specific, cardiac small molecule restoration is observed in animals treated with the antiparasitic benznidazole. In contrast, superior restoration of the cardiac small molecule profile is observed for a combination treatment of reduced-dose benznidazole plus an immunotherapy, even with less parasite burden reduction. Overall, …

Identification Of Chronic Wasting Disease Prions In Decaying Tongue Tissues From Exhumed White-Tailed Deer, Paulina Soto, Francisca Bravo-Risi, Rebeca Benavente, Stuart Lichtenberg, Mitch Lockwood, J Hunter Reed, Rodrigo Morales

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) prions cause fatal neuropathies in farmed and free-ranging cervids. The deposition of prions in natural and humanmade environmental components has been implicated as a major mechanism mediating CWD spread in wild and captive populations. Prions can be deposited in the environment through excreta, tissues, and carcasses from pre-clinical and clinical animals. Furthermore, burial of CWD-positive animals may reduce but not completely mitigate prion spread from carcasses into the surrounding environment. Here, we analyzed exhumed, decaying deer carcasses for the presence of CWD prions. By analyzing tongue tissues through the protein misfolding cyclic amplification (PMCA) technique, we …

White Matter Integrity Abnormalities In Healthy Overweight Individuals Revealed By Whole Brain Meta-Analysis Of Diffusion Tensor Imaging Studies, Xiaodong Cheng, Wenchang Wang, Chen Sun, Yana Sun, Cong Zhou

Faculty, Staff and Student Publications

OBJECTIVE: This study aimed to conduct a coordinate-based meta-analysis (CBMA) to investigate white matter (WM) abnormalities in healthy individuals with overweight or obesity.

METHODS: A systematic literature search using Web of Science and PubMed datasets was performed. Original investigations that used diffusion tensor imaging (DTI) to explore fractional anisotropy (FA) differences between healthy overweight/obese individuals and normal weight controls were collected. The meta-analysis was conducted using the seed-based

RESULTS: The analysis included five studies comprising 232 overweight/obese individuals and 219 healthy normal weight controls. The findings showed that overweight/obese individuals exhibited reduced fractional anisotropy (FA) in specific regions, namely, the …

Further Refinement Of The Differentially Methylated Distant Lung-Specific Foxf1 Enhancer In A Neonate With Alveolar Capillary Dysplasia, Przemyslaw Szafranski, Rijutha P Garimella, Haresh Mani, Ryan Hartman, Gail Deutsch, Alan Silk, Alan Benheim, Paweł Stankiewicz

Faculty, Staff and Students Publications

Heterozygous SNVs or CNV deletions involving the FOXF1 gene, or its distant enhancer, are causative for 80-90% of cases of alveolar capillary dysplasia with misalignment of pulmonary veins. Recently, we proposed bimodal structure and parental functional dimorphism of the lung-specific FOXF1 enhancer, with Unit 1 having higher activity on the paternal chr16 and Unit 2 on the maternal chr16. Here, we describe a novel unusually sized pathogenic de novo copy-number variant deletion involving a portion of the FOXF1 enhancer on maternal chr16 that implies narrowing Unit 2 to an essential ~ 9-kb segment. Using a restrictase-based assay, we found that …

Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey

Faculty, Staff and Student Publications

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 …

Braf D594a Mutation Defines A Unique Biological And Immuno-Modulatory Subgroup Associated With Functional Cd8+ T Cell Infiltration In Colorectal Cancer, Wenjing Li, Chenyi Zhao, Wenhui Li, Yang Gong, Kaili Ma, Yujie Lu, Xiaowei Liu, Lianjun Zhang, Feng Guo

Faculty, Staff and Student Publications

BACKGROUND: BRAF non-V600 mutation occupies a relatively small but critical subset in colorectal cancer (CRC). However, little is known about the biological functions and impacts of BRAF class III mutation in CRC. Here, we aim to explore how D594A mutation impacts on biological behaviors and immune related signatures in murine CRC cells.

METHODS: BRAF V600E (class I), G469V (class II) and D594A (class III) mutant cell lines were established based on MC38 cells. The biological behaviors of cells were evaluated in respect of cell growth, cell proliferation, cell apoptosis, cell migration and invasion by the methods of colony-forming assay, CCK-8 …

Reprogramming Of Cis-Regulatory Networks During Skeletal Muscle Atrophy In Male Mice, Hongchun Lin, Hui Peng, Yuxiang Sun, Meijun Si, Jiao Wu, Yanlin Wang, Sandhya S Thomas, Zheng Sun, Zhaoyong Hu

Faculty, Staff and Students Publications

A comprehensive atlas of cis-regulatory elements and their dynamic activity is necessary to understand the transcriptional basis of cellular structure maintenance, metabolism, and responses to the environment. Here we show, using matched single-nucleus chromatin accessibility and RNA-sequencing from juvenile male C57BL6 mice, an atlas of accessible chromatin regions in both normal and denervated skeletal muscles. We identified cell-type-specific cis-regulatory networks, highlighting the dynamic regulatory circuits mediating transitions between myonuclear types. Through comparison of normal and perturbed muscle, we delineated the reprogramming of cis-regulatory networks in response to denervation, described the interplay of promoters/enhancers and target genes. We further unveil a …

Standardization Of An Antiviral Pipeline For Human Norovirus In Human Intestinal Enteroids Demonstrates Nitazoxanide Has No To Weak Antiviral Activity, Miranda A Lewis, Nicolás W Cortés-Penfield, Khalil Ettayebi, Ketki Patil, Gurpreet Kaur, Frederick H Neill, Robert L Atmar, Sasirekha Ramani, Mary K Estes

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs) are the leading cause of acute gastroenteritis. In immunocompetent hosts, symptoms usually resolve within 3 days; however, in immunocompromised persons, HuNoV infection can become persistent, debilitating, and sometimes life-threatening. There are no licensed therapeutics for HuNoV due to a near half-century delay in its cultivation. Treatment for chronic HuNoV infection in immunosuppressed patients anecdotally includes nitazoxanide, a broad-spectrum antimicrobial licensed for treatment of parasite-induced gastroenteritis. Despite its off-label use for chronic HuNoV infection, nitazoxanide has not been clearly demonstrated to be an effective treatment. In this study, we standardized a pipeline for antiviral testing using multiple human …

Hippo Pathway Knockdown Gene Therapy In The Heart, Todd R Heallen, James F Martin

The Texas Heart Institute Journal

No abstract provided.

Impairment Of Serine Transport Across The Blood-Brain Barrier By Deletion Of Slc38a5 Causes Developmental Delay And Motor Dysfunction, Inna Radzishevsky, Maali Odeh, Oded Bodner, Salman Zubedat, Lihi Shaulov, Maxim Litvak, Kayoko Esaki, Takeo Yoshikawa, Bella Agranovich, Wen-Hong Li, Alex Radzishevsky, Eyal Gottlieb, Avi Avital, Herman Wolosker

Faculty, Staff and Student Publications

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. …

Molecular And Sequencing Study And Identification Of Novel Sem-Type In Beta-Hemolytic Streptococci Involving The Upper Respiratory Tract In Iran, Sina Moghaddam, Samad Lotfollahzadeh, Taghi Zahraei Salehi, Ali Hassanpour, Hamid Tavanaei Manesh, Iraj Ashrafi Tamai

Faculty, Staff and Students Publications

BACKGROUND: Beta-hemolytic streptococci involving the upper respiratory tract cause strangles and strangles-like diseases in horses and cause severe economic damage to the equestrian club each year. Therefore, careful epidemiological study of these bacteria, evaluation of phylogenetic connections and SeM-typing can be useful to determine the source and epidemiological characteristics of the disease outbreak. Isolates were analyzed using molecular and phylogenetic methods and to determine antibiotic resistance pattern in Iranian isolates. Molecular and phylogenetic methods were used to evaluate Iranian streptococcal isolates, and the similarity of the Iranian SeM-97 sequence with other alleles was assessed using the Neighbor-joining method with the …

Orthostatic Hypotension, Hypertension Treatment, And Cardiovascular Disease: An Individual Participant Meta-Analysis, Stephen P Juraschek, Jiun-Ruey Hu, Jennifer L Cluett, Anthony M Ishak, Carol Mita, Lewis A Lipsitz, Lawrence J Appel, Nigel S Beckett, Ruth L Coleman, William C Cushman, Barry R Davis, Greg Grandits, Rury R Holman, Edgar R Miller, Ruth Peters, Jan A Staessen, Addison A Taylor, Lutgarde Thijs, Jackson T Wright, Kenneth J Mukamal

Faculty, Staff and Students Publications

IMPORTANCE: There are ongoing concerns about the benefits of intensive vs standard blood pressure (BP) treatment among adults with orthostatic hypotension or standing hypotension.

OBJECTIVE: To determine the effect of a lower BP treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease (CVD) or all-cause mortality in strata of baseline orthostatic hypotension or baseline standing hypotension.

DATA SOURCES: Individual participant data meta-analysis based on a systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022.

STUDY SELECTION: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) with …

Priorities And Progress In Gram-Positive Bacterial Infection Research By The Antibacterial Resistance Leadership Group: A Narrative Review, Sarah B Doernberg, Cesar A Arias, Deena R Altman, Ahmed Babiker, Helen W Boucher, C Buddy Creech, Sara E Cosgrove, Scott R Evans, Vance G Fowler, Stephanie A Fritz, Toshimitsu Hamasaki, Brendan J Kelly, Sixto M Leal, Catherine Liu, Thomas P Lodise, Loren G Miller, Jose M Munita, Barbara E Murray, Melinda M Pettigrew, Felicia Ruffin, Marc H Scheetz, Bo Shopsin, Truc T Tran, Nicholas A Turner, Derek J Williams, Smitha Zaharoff, Thomas L Holland

Faculty, Staff and Student Publications

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, …

Sptan1/Numb Axis Senses Cell Density To Restrain Cell Growth And Oncogenesis Through Hippo Signaling, Dongxue Su, Yuxi Li, Weiji Zhang, Huan Gao, Yao Cheng, Yongqiang Hou, Junhong Li, Yi Ye, Zhangjian Lai, Zhe Li, Haitao Huang, Jiaxin Li, Jinhuan Li, Mengyu Cheng, Cheng Nian, Na Wu, Zhien Zhou, Yunzhi Xing, Yu Zhao, He Liu, Jiayu Tang, Qinghua Chen, Lixin Hong, Wengang Li, Zhihai Peng, Bin Zhao, Randy L Johnson, Pingguo Liu, Wanjin Hong, Lanfen Chen, Dawang Zhou

Faculty, Staff and Student Publications

The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and …

A Single Nanobody Neutralizes Multiple Epochally Evolving Human Noroviruses By Modulating Capsid Plasticity, Wilhelm Salmen, Liya Hu, Marina Bok, Natthawan Chaimongkol, Khalil Ettayebi, Stanislav V Sosnovtsev, Kaundal Soni, B Vijayalakshmi Ayyar, Sreejesh Shanker, Frederick H Neill, Banumathi Sankaran, Robert L Atmar, Mary K Estes, Kim Y Green, Viviana Parreño, B V Venkataram Prasad

Faculty, Staff and Students Publications

Acute gastroenteritis caused by human noroviruses (HuNoVs) is a significant global health and economic burden and is without licensed vaccines or antiviral drugs. The GII.4 HuNoV causes most epidemics worldwide. This virus undergoes epochal evolution with periodic emergence of variants with new antigenic profiles and altered specificity for histo-blood group antigens (HBGA), the determinants of cell attachment and susceptibility, hampering the development of immunotherapeutics. Here, we show that a llama-derived nanobody M4 neutralizes multiple GII.4 variants with high potency in human intestinal enteroids. The crystal structure of M4 complexed with the protruding domain of the GII.4 capsid protein VP1 revealed …

Revisiting Asthma Obstructive Sleep Apnea Overlap: Current Knowledge And Future Needs, Damini Saxena, Ikuyo Imayama, Muhammad Adrish

Faculty, Staff and Students Publications

Asthma and obstructive sleep apnea are highly prevalent conditions with a high cost burden. In addition to shared risk factors, existing data suggest a bidirectional relationship between asthma and OSA, where each condition can impact the other. Patients with asthma often complain of sleep fragmentation, nocturnal asthma symptoms, daytime sleepiness, and snoring. The prevalence of OSA increases with asthma severity, as evidenced by multiple large studies. Asthma may lower the threshold for arousal in OSA, resulting in the hypopnea with arousal phenotype. Epidemiologic studies in adults have shown that OSA is associated with worse asthma severity, increased frequency of exacerbation, …

Dna2 Nuclease Inhibition Confers Synthetic Lethality In Cancers With Mutant P53 And Synergizes With Parp Inhibitors, Helena Folly-Kossi, Joshua D Graves, Lidija A Wilhelms Garan, Fang-Tsyr Lin, Weei-Chin Lin

Faculty, Staff and Students Publications

UNLABELLED: The tumor suppressor p53 promotes tumor-suppressive activities including cell-cycle inhibition, apoptosis, senescence, autophagy, and DNA repair. However, somatic mutations in the TP53 gene are one of the most common alterations in human cancers. We previously showed that mutant p53 (mutp53) can bind TopBP1, an ATR activator, to attenuate its ATR-activating function. A partially defective ATR function caused by mutp53 makes cancer cells more vulnerable to inhibitors of other TopBP1-independent ATR activators, such as DNA2. DNA2 plays a role in homologous recombination (HR) repair by resecting DNA ends in double-strand breaks and preparing them for invasion of homologous duplex. Here …

Excretory/Secretory Products From Trichinella Spiralis Adult Worms Ameliorate Myocardial Infarction By Inducing M2 Macrophage Polarization In A Mouse Model, Lingqin Wu, Wenhui Yin, Jutai Wen, Shuying Wang, Huihui Li, Xiaoli Wang, Weixiao Zhang, Shuyao Duan, Qiuyu Zhu, Erhe Gao, Shili Wu, Bin Zhan, Rui Zhou, Xiaodi Yang

Faculty, Staff and Students Publications

BACKGROUND: Ischemia-induced inflammatory response is the main pathological mechanism of myocardial infarction (MI)-caused heart tissue injury. It has been known that helminths and worm-derived proteins are capable of modulating host immune response to suppress excessive inflammation as a survival strategy. Excretory/secretory products from Trichinella spiralis adult worms (Ts-AES) have been shown to ameliorate inflammation-related diseases. In this study, Ts-AES were used to treat mice with MI to determine its therapeutic effect on reducing MI-induced heart inflammation and the immunological mechanism involved in the treatment.

METHODS: The MI model was established by the ligation of the left anterior descending coronary artery, …

Tuberculosis Presentation And Outcomes In Older Hispanic Adults From Tamaulipas, Mexico, Belinda A Medrano, Miryoung Lee, Gretchen Gemeinhardt, Javier E Rodríguez-Herrera, Moncerrato García-Viveros, Blanca I Restrepo

Faculty, Staff and Student Publications

Older people are at high risk of developing and dying from pulmonary infections like tuberculosis (TB), but there are few studies among them, particularly in Hispanics. To address these gaps, we sought to identify host factors associated with TB and adverse treatment outcomes in older Hispanics by conducting a cross-sectional study of TB surveillance data from Tamaulipas, Mexico (2006-2013; n = 8381). Multivariable logistic regressions were assessed for older adults (OA ≥65 years) when compared to young (YA, 18-39 years) and middle-aged adults (40-64 years). We found that the OA had features associated with a less complicated TB (e.g., lower …

Top Caregiver Concerns In Rett Syndrome And Related Disorders: Data From The Us Natural History Study, Jeffrey L Neul, Timothy A Benke, Eric D Marsh, Bernhard Suter, Lori Silveira, Cary Fu, Sarika U Peters, Alan K Percy

Faculty, Staff and Students Publications

OBJECTIVE: Recent advances in the understanding of neurodevelopmental disorders such as Rett syndrome (RTT) have enabled the discovery of novel therapeutic approaches that require formal clinical evaluation of efficacy. Clinical trial success depends on outcome measures that assess clinical features that are most impactful for affected individuals. To determine the top concerns in RTT and RTT-related disorders we asked caregivers to list the top caregiver concerns to guide the development and selection of appropriate clinical trial outcome measures for these disorders.

METHODS: Caregivers of participants enrolled in the US Natural History Study of RTT and RTT-related disorders (n = 925) …

Immune-Depleted Tumor Microenvironment Is Associated With Poor Outcomes And Btk Inhibitor Resistance In Mantle Cell Lymphoma, Preetesh Jain, Krystle Nomie, Nikita Kotlov, Vitaiy Segodin, Holly Hill, Chi Young Ok, Ahmed Fetooh, Rashmi Kanagal-Shamanna, Francisco Vega, Alexander Bagaev, Nathan Fowler, Christopher R Flowers, Michael Wang

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is a generally aggressive B cell non-Hodgkin lymphoma (B-NHL). Outcomes of patients have improved in the era of Bruton’s tyrosine kinase inhibitors (BTKi). However, MCL patients can develop resistance to BTKi over time and can progress [1]. Ibrutinib resistance in MCL is correlated with an overexpression of OXPHOS, MYC and PI3K/AKT/m-TOR pathways. Somatic mutations in TP53, KMT2D, NSD2, SMARCA4, CCND1, TRAF2, NFKBIE genes are reported with ibrutinib resistance [2]. A few reports have also demonstrated that a decrease in T cell numbers [3, 4] or a downregulation of effector/cytotoxic …

Trio-Based Gwas Identifies Novel Associations And Subtype-Specific Risk Factors For Cleft Palate, Kelsey Robinson, Trenell J Mosley, Kenneth S Rivera-González, Christopher R Jabbarpour, Sarah W Curtis, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, David J Cutler, Michael P Epstein, Lord J J Gowans, Jacqueline T Hecht, Jeffrey C Murray, Gary M Shaw, Lina Moreno Uribe, Seth M Weinberg, Harrison Brand, Mary L Marazita, Robert J Lipinski, Elizabeth J Leslie

Faculty, Staff and Student Publications

Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n = 435), and subtype-specific risks for any cleft soft palate (CSP), (n = 259) and any cleft hard palate (CHP) (n = 125). We identified …

Usp1 Promotes Cholangiocarcinoma Progression By Deubiquitinating Parp1 To Prevent Its Proteasomal Degradation, Deng Yong Zhang, Yan Zhu, Qiong Wu, Shuoshuo Ma, Yang Ma, Zheng Chao Shen, Zhonglin Wang, Wanliang Sun, Yong Chun Zhou, Dongdong Wang, Shuo Zhou, Zhong Liu, Lawrence N Kwong, Zheng Lu

Faculty, Staff and Student Publications

Despite its involvement in various cancers, the function of the deubiquitinase USP1 (ubiquitin-specific protease 1) is unexplored in cholangiocarcinoma (CCA). In this study, we provide evidence that USP1 promotes CCA progression through the stabilization of Poly (ADP-ribose) polymerase 1 (PARP1), consistent with the observation that both USP1 and PARP1 are upregulated in human CCA. Proteomics and ubiquitylome analysis of USP1-overexpressing CCA cells nominated PARP1 as a top USP1 substrate. Indeed, their direct interaction was validated by a series of immunofluorescence, co-immunoprecipitation (CO-IP), and GST pull-down assays, and their interaction regions were identified using deletion mutants. Mechanistically, USP1 removes the ubiquitin …

Paired Liver:Plasma Pfas Concentration Ratios From Adolescents In The Teen-Labs Study And Derivation Of Empirical And Mass Balance Models To Predict And Explain Liver Pfas Accumulationn, Brittney O Baumert, Fabian C Fischer, Flemming Nielsen, Philippe Grandjean, Scott Bartell, Nikos Stratakis, Douglas I Walker, Damaskini Valvi, Rohit Kohli, Thomas Inge, Justin Ryder, Todd Jenkins, Stephanie Sisley, Stavra Xanthakos, Sarah Rock, Michele A La Merrill, David Conti, Rob Mcconnell, Lida Chatzi

Faculty, Staff and Students Publications

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity, however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentrations ratios were perfectly explained (r2 > 0.99) in a multi-linear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this …

Opposing Roles For The Α Isoform Of The Catalytic Subunit Of Protein Phosphatase 1 In Inside-Out And Outside-In Integrin Signaling In Murine Platelets, Tanvir Khatlani, Subhashree Pradhan, Kimberly Langlois, Deepika Subramanyam, Rolando E Rumbaut, K Vinod Vijayan

Faculty, Staff and Students Publications

Platelet activation during hemostasis and thrombosis is facilitated by agonist-induced inside–out and integrin αIIbβ3-initiated outside–in signaling via protein kinases and phosphatases. Pharmacological inhibitor studies suggest that the serine/threonine protein phosphatase 1 (PP1) promotes platelet activation. However, since phosphatase inhibitors block all the isoforms of the catalytic subunit of PP1 (PP1c), the role of specific PP1c isoform in platelet signaling remains unclear. Here, we employed a platelet-specific PP1cα−/− mice to explore the contribution of a major PP1 isoform in platelet functions. Loss of PP1cα moderately decreased activation of integrin αIIbβ3, binding of soluble fibrinogen, and aggregation to low-dose thrombin, ADP, and …

Mathematical Modeling Of Radiotherapy: Impact Of Model Selection On Estimating Minimum Radiation Dose For Tumor Control, Achyudhan R Kutuva, Jimmy J Caudell, Kosj Yamoah, Heiko Enderling, Mohammad U Zahid

Faculty, Staff and Student Publications

INTRODUCTION: Radiation therapy (RT) is one of the most common anticancer therapies. Yet, current radiation oncology practice does not adapt RT dose for individual patients, despite wide interpatient variability in radiosensitivity and accompanying treatment response. We have previously shown that mechanistic mathematical modeling of tumor volume dynamics can simulate volumetric response to RT for individual patients and estimation personalized RT dose for optimal tumor volume reduction. However, understanding the implications of the choice of the underlying RT response model is critical when calculating personalized RT dose.

METHODS: In this study, we evaluate the mathematical implications and biological effects of 2 …

Ccdc50 Promotes Tumor Growth Through Regulation Of Lysosome Homeostasis, Penghui Jia, Tian Tian, Zibo Li, Yicheng Wang, Yuxin Lin, Weijie Zeng, Yu Ye, Miao He, Xiangrong Ni, Ji'an Pan, Xiaonan Dong, Jian Huang, Chun-Mei Li, Deyin Guo, Panpan Hou

Faculty, Staff and Student Publications

The maintenance of lysosome homeostasis is crucial for cell growth. Lysosome-dependent degradation and metabolism sustain tumor cell survival. Here, we demonstrate that CCDC50 serves as a lysophagy receptor, promoting tumor progression and invasion by controlling lysosomal integrity and renewal. CCDC50 monitors lysosomal damage, recognizes galectin-3 and K63-linked polyubiquitination on damaged lysosomes, and specifically targets them for autophagy-dependent degradation. CCDC50 deficiency causes the accumulation of ruptured lysosomes, impaired autophagic flux, and superfluous reactive oxygen species, consequently leading to cell death and tumor suppression. CCDC50 expression is associated with malignancy, progression to metastasis, and poor overall survival in human melanoma. Targeting CCDC50 …