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An Update On Implant-Associated Malignancies And Their Biocompatibility, Grace C Keane Tahmaseb, Alexandra M Keane, Jose A Foppiani, Terence M Myckatyn

2020-Current year OA Pubs

Implanted medical devices are widely used across various medical specialties for numerous applications, ranging from cardiovascular supports to orthopedic prostheses and cosmetic enhancements. However, recent observations have raised concerns about the potential of these implants to induce malignancies in the tissues surrounding them. There have been several case reports documenting the occurrence of cancers adjacent to these devices, prompting a closer examination of their safety. This review delves into the epidemiology, clinical presentations, pathological findings, and hypothesized mechanisms of carcinogenesis related to implanted devices. It also explores how the surgical domain and the intrinsic properties and biocompatibility of the implants …

Large-Scale Annotated Dataset For Cochlear Hair Cell Detection And Classification., Christopher J Buswinka, David B Rosenberg, Rubina G Simikyan, Richard T Osgood, Katharine Fernandez, Hidetomi Nitta, Yushi Hayashi, Leslie W Liberman, Emily Nguyen, Erdem Yildiz, Jinkyung Kim, Amandine Jarysta, Justine Renauld, Ella Wesson, Haobing Wang, Punam Thapa, Pierrick Bordiga, Noah Mcmurtry, Juan Llamas, Siân R Kitcher, Ana I López-Porras, Runjia Cui, Ghazaleh Behnammanesh, Jonathan E Bird, Angela Ballesteros, A Catalina Vélez-Ortega, Albert S B Edge, Michael R Deans, Ksenia Gnedeva, Brikha R Shrestha, Uri Manor, Bo Zhao, Anthony J Ricci, Basile Tarchini, Martín L Basch, Ruben Stepanyan, Lukas D Landegger, Mark A Rutherford, M Charles Liberman, Bradley J Walters, Corné J Kros, Guy P Richardson, Lisa L Cunningham, Artur A Indzhykulian

Faculty Research 2024

Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5-15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. …

Xpo1 Blockade With Kpt-330 Promotes Apoptosis In Cutaneous T-Cell Lymphoma By Activating The P53-P21 And P27 Pathways, Nitin Chakravarti, Amy Boles, Rachel Burzinski, Paola Sindaco, Colleen Isabelle, Kathleen Mcconnell, Anjali Mishra, Pierluigi Porcu

Kimmel Cancer Center Faculty Papers

Dysregulated nuclear-cytoplasmic trafficking has been shown to play a role in oncogenesis in several types of solid tumors and hematological malignancies. Exportin 1 (XPO1) is responsible for the nuclear export of several proteins and RNA species, mainly tumor suppressors. KPT-330, a small molecule inhibitor of XPO1, is approved for treating relapsed multiple myeloma and diffuse large B-cell lymphoma. Cutaneous T-cell lymphoma (CTCL) is an extranodal non-Hodgkin lymphoma with an adverse prognosis and limited treatment options in advanced stages. The effect of therapeutically targeting XPO1 with KPT-330 in CTCL has not been established. We report that XPO1 expression is upregulated in …

Six-Year Follow-Up And Subgroup Analyses Of A Phase 2 Trial Of Venetoclax For Del(17p) Chronic Lymphocytic Leukemia, Stephan Stilgenbauer, Eugen Tausch, Andrew W Roberts, Matthew S Davids, Barbara Eichhorst, Michael Hallek, Peter Hillmen, Christof Schneider, Johannes Schetelig, Sebastian Böttcher, Arnon P Kater, Yanwen Jiang, Michelle Boyer, Relja Popovic, Majd T Ghanim, Michael Moran, Wendy J Sinai, Xifeng Wang, Nabanita Mukherjee, Brenda Chyla, William G Wierda, John F Seymour

Faculty, Staff and Student Publications

Chromosome 17p deletion (del[17p]) is associated with poor prognosis in patients with chronic lymphocytic leukemia (CLL). Venetoclax is approved for treatment of previously untreated and relapsed/refractory (R/R) CLL, including patients with del(17p), based on the open-label, multicenter, phase 2 M13-982 trial (NCT01889186). Here, we detail the 6-year follow-up analysis for M13-982. A total of 158 patients with previously untreated (n = 5) or R/R (n = 153) del(17p) CLL received 400 mg venetoclax daily after initial ramp-up until progressive disease. After a median follow-up of 70 months, the best objective response rate (ORR) was 77% (21% complete remission …

Associations Between Stress, Health Behaviors, And Quality Of Life In Young Couples During The Transition To Survivorship: Protocol For A Measurement Burst Study, Dalnim Cho, Michael Roth, Susan K Peterson, Kristofer Jennings, Seokhun Kim, Shiao-Pei Weathers, Sairah Ahmed, J Andrew Livingston, Carlos Barcenas, Y Nancy You, Kathrin Milbury

Faculty, Staff and Student Publications

BACKGROUND: Cancer is a life-threatening, stressful event, particularly for young adults due to delays and disruptions in their developmental transitions. Cancer treatment can also cause adverse long-term effects, chronic conditions, psychological issues, and decreased quality of life (QoL) among young adults. Despite numerous health benefits of health behaviors (eg, physical activity, healthy eating, no smoking, no alcohol use, and quality sleep), young adult cancer survivors report poor health behavior profiles. Determining the associations of stress (either cancer-specific or day-to-day stress), health behaviors, and QoL as young adult survivors transition to survivorship is key to understanding and enhancing these survivors' health. …

Lipoprotein(A) Blood Levels And Cardiovascular Risk Reduction With Icosapent Ethyl, Michael Szarek, Deepak L Bhatt, Michael Miller, Eliot A Brinton, Terry A Jacobson, Jean-Claude Tardif, Christie M Ballantyne, R Preston Mason, Steven B Ketchum, Armando Lira Pineda, Ralph T Doyle, Ph Gabriel Steg, Reduce-It Investigators

Faculty, Staff and Students Publications

Background: Elevated lipoprotein(a) (Lp[a]) concentrations are associated with increased cardiovascular event risk even in the presence of well-controlled low-density lipoprotein cholesterol levels, but few treatments are documented to reduce this residual risk.

Objectives: The aim of this post hoc analysis of REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was to explore the cardiovascular benefit of icosapent ethyl (IPE) across a range of Lp(a) levels.

Methods: A total of 8,179 participants receiving statin therapy with established cardiovascular disease or age ≥50 years with diabetes and ≥1 additional risk factor, fasting triglyceride 1.69 to 5.63 mmol/L, and low-density lipoprotein cholesterol …

Lipoprotein(A) And Long-Term Cardiovascular Risk In A Multi-Ethnic Pooled Prospective Cohort, Nathan D Wong, Wenjun Fan, Xingdi Hu, Christie Ballantyne, Ron C Hoodgeveen, Michael Y Tsai, Auris Browne, Matthew J Budoff

Faculty, Staff and Students Publications

Background: Lipoprotein(a) (Lp[a]) is a causal genetic risk factor for atherosclerotic cardiovascular disease (ASCVD). There are limited long-term follow-up data from large U.S. population cohorts.

Objectives: This study examined the relationship of Lp(a) with ASCVD outcomes in a large, pooled, multi-ethnic U.S.

Methods: The study included data on Lp(a) and ASCVD outcomes from 5 U.S.

Prospective studies: MESA (Multi-Ethnic Study of Atherosclerosis), CARDIA (Coronary Artery Risk Development in Young Adults), JHS (Jackson Heart Study), FHS-OS (Framingham Heart Study-Offspring), and ARIC (Atherosclerosis Risk In Communities). Lp(a) levels were classified on the basis of cohort-specific percentiles. Multivariable Cox regression related Lp(a) with …

Large-Scale Annotated Dataset For Cochlear Hair Cell Detection And Classification, Christopher J Buswinka, Jinkyung Kim, Anthony J Ricci, Mark A Rutherford, Et Al.

2020-Current year OA Pubs

Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5-15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. …

Immunophenotypic Predictors Of Influenza Vaccine Immunogenicity In Pediatric Hematopoietic Cell Transplant Recipients., Justin Z. Amarin, Daniel E. Dulek, Joshua Simmons, Haya Hayek, James D. Chappell, Cindy Hager Nochowicz, Carrie L. Kitko, Jennifer E. Schuster, Flor M. Muñoz, Claire E. Bocchini, Elizabeth A. Moulton, Susan E. Coffin, Jason L. Freedman, Monica I. Ardura, Rachel L. Wattier, Gabriela Maron, Michael Grimley, Grant Paulsen, Lara Danziger-Isakov, Paul A. Carpenter, Janet A. Englund, Natasha B. Halasa, Andrew J. Spieker, Spyros A. Kalams

Manuscripts, Articles, Book Chapters and Other Papers

Pediatric hematopoietic cell transplant (HCT) recipients exhibit poor serologic responses to influenza vaccination early after transplant. To facilitate the optimization of influenza vaccination timing, we sought to identify B- and T-cell subpopulations associated with influenza vaccine immunogenicity in this population. We used mass cytometry to phenotype peripheral blood mononuclear cells collected from pediatric HCT recipients enrolled in a multicenter influenza vaccine trial comparing high- and standard-dose formulations over 3 influenza seasons (2016-2019). We fit linear regression models to estimate relationships between immune cell subpopulation numbers before vaccination and prevaccination to postvaccination geometric mean fold rises in antigen-specific (A/H3N2, A/H1N1, and …

Structural Variants Involving Mllt10 Fusion Are Associated With Adverse Outcomes In Pediatric Acute Myeloid Leukemia., Oussama Abla, Rhonda E. Ries, Tim Triche, Robert B. Gerbing, Betsy Hirsch, Susana Raimondi, Todd Cooper, Jason E. Farrar, Nathaniel Buteyn, Lauren M. Harmon, Hong Wen, Aniruddha J. Deshpande, E Anders Kolb, Alan S. Gamis, Richard Aplenc, Todd Alonzo, Soheil Meshinchi

Manuscripts, Articles, Book Chapters and Other Papers

MLLT10 gene rearrangements with KMT2A occur in pediatric acute myeloid leukemia (AML) and confer poor prognosis, but the prognostic impact of MLLT10 in partnership with other genes is unknown. We conducted a retrospective study with 2080 children and young adults with AML registered on the Children's Oncology Group AAML0531 (NCT00372593) and AAML1031 trials (NCT01371981). Transcriptome profiling and/or karyotyping were performed to identify leukemia-associated fusions associated with prognosis. Collectively, 127 patients (6.1%) were identified with MLLT10 fusions: 104 (81.9%) with KMT2A::MLLT10, 13 (10.2%) with PICALM::MLLT10, and 10 (7.9%) X::MLLT10: (2 each of DDX3X and TEC), with 6 partners (DDX3Y, CEP164, SCN2B, …

Rapidly Improving Ards Differs Clinically And Biologically From Persistent Ards, Patricia L Valda Toro, Andrew Willmore, Nelson E Wu, Kevin L Delucchi, Alejandra Jauregui, Pratik Sinha, Kathleen D Liu, Carolyn M Hendrickson, Aartik Sarma, Lucile P A Neyton, Aleksandra Leligdowicz, Charles R Langelier, Hanjing Zhuo, Chayse Jones, Kirsten N Kangelaris, Antonio D Gomez, Michael A Matthay, Carolyn S Calfee

2020-Current year OA Pubs

BACKGROUND: Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes.

METHODS: We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted …

Predictive And Prognostic Biomarkers And Tumor Antigens For Targeted Therapy In Urothelial Carcinoma, Aditya Eturi, Amman Bhasin, Kevin Zarrabi, William Tester

Department of Medical Oncology Faculty Papers

Urothelial carcinoma (UC) is the fourth most prevalent cancer amongst males worldwide. While patients with non-muscle-invasive disease have a favorable prognosis, 25% of UC patients present with locally advanced disease which is associated with a 10-15% 5-year survival rate and poor overall prognosis. Muscle-invasive bladder cancer (MIBC) is associated with about 50% 5 year survival when treated by radical cystectomy or trimodality therapy; stage IV disease is associated with 10-15% 5 year survival. Current therapeutic modalities for MIBC include neoadjuvant chemotherapy, surgery and/or chemoradiation, although patients with relapsed or refractory disease have a poor prognosis. However, the rapid success of …

An Approach To Identify Gene-Environment Interactions And Reveal New Biological Insight In Complex Traits, Xiaofeng Zhu, Yihe Yang, Noah Lorincz-Comi, Gen Li, Amy R Bentley, Paul S De Vries, Michael Brown, Alanna C Morrison, Charles N Rotimi, W James Gauderman, Dabeeru C Rao, Hugues Aschard

Faculty, Staff and Student Publications

There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. to address this issue, the Gene-Lifestyle Interactions Working Group within the Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium has been spearheading efforts to investigate G × E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identify and confirm 5 loci …

An Approach To Identify Gene-Environment Interactions And Reveal New Biological Insight In Complex Traits, Xiaofeng Zhu, Yihe Yang, Noah Lorincz-Comi, Gen Li, Amy R Bentley, Paul S De Vries, Michael Brown, Alanna C Morrison, Charles N Rotimi, W James Gauderman, Dabeeru C Rao, Hugues Aschard, Charge Gene-Lifestyle Interactions Working Group

2020-Current year OA Pubs

There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the Gene-Lifestyle Interactions Working Group within the Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium has been spearheading efforts to investigate G × E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identify and confirm 5 loci …

The Dual-Targeted Fusion Inhibitor Clofazimine Binds To The S2 Segment Of The Sars-Cov-2 Spike Protein, Matthew Freidel, Pratiti Vakhariya, Shalinder Sardarni, Roger Armen

College of Pharmacy Faculty Papers

Clofazimine and Arbidol have both been reported to be effective in vitro SARS-CoV-2 fusion inhibitors. Both are promising drugs that have been repurposed for the treatment of COVID-19 and have been used in several previous and ongoing clinical trials. Small-molecule bindings to expressed constructs of the trimeric S2 segment of Spike and the full-length SARS-CoV-2 Spike protein were measured using a Surface Plasmon Resonance (SPR) binding assay. We demonstrate that Clofazimine, Toremifene, Arbidol and its derivatives bind to the S2 segment of the Spike protein. Clofazimine provided the most reliable and highest-quality SPR data for binding with S2 over the …

Diffuse Hemispheric Glioma With H3 P.K28m (K27m) Mutation: Unusual Non-Midline Presentation Of Diffuse Midline Glioma, H3 K27m-Altered?, Kliment Donev, Vanitha Sundararajan, Derek Johnson, Jagadheshwar Balan, Meagan Chambers, Vera A Paulson, Kathryn P Scherpelz, Zied Abdullaev, Martha Quezado, Patrick J Cimino, Drew Pratt, Ediel Valerio, João Vıctor Alves De Castro, Dirce Maria Carraro, Giovana Tardin Torrezan, Beatriz Martins Wolff, Leslie Domenici Kulikowski, Felipe D'Almeida Costa, Kenneth Aldape, Cristiane M Ida

Neuroscience Articles

Diffuse midline glioma, H3 K27-altered (DMG-H3 K27) is an aggressive group of diffuse gliomas that predominantly occurs in pediatric patients, involves midline structures, and displays loss of H3 p.K28me3 (K27me3) expression by immunohistochemistry and characteristic genetic/epigenetic profile. Rare examples of a diffuse glioma with an H3 p.K28M (K27M) mutation and without involvement of the midline structures, so-called "diffuse hemispheric glioma with H3 p.K28M (K27M) mutation" (DHG-H3 K27), have been reported. Herein, we describe 2 additional cases of radiologically confirmed DHG-H3 K27 and summarize previously reported cases. We performed histological, immunohistochemical, molecular, and DNA methylation analysis and provided clinical follow-up in …

Sars-Cov-2 Omicron Ba.1 Variant Infection Of Human Colon Epithelial Cells, Avan Antia, David M Alvarado, Qiru Zeng, Luis A Casorla-Perez, Deanna L Davis, Naomi M Sonnek, Matthew A Ciorba, Siyuan Ding

2020-Current year OA Pubs

The Omicron variant of SARS-CoV-2, characterized by multiple subvariants including BA.1, XBB.1.5, EG.5, and JN.1, became the predominant strain in early 2022. Studies indicate that Omicron replicates less efficiently in lung tissue compared to the ancestral strain. However, the infectivity of Omicron in the gastrointestinal tract is not fully defined, despite the fact that 70% of COVID-19 patients experience digestive disease symptoms. Here, using primary human colonoids, we found that, regardless of individual variability, Omicron infects colon cells similarly or less effectively than the ancestral strain or the Delta variant. The variant induced limited type III interferon expression and showed …

Glycemia And Gluconeogenesis With Metformin And Liraglutide: A Randomized Trial In Youth-Onset Type 2 Diabetes, Katrina B Dietsche, Sheela N Magge, Sydney A Dixon, Faith S Davis, Andrea Krenek, Aruba Chowdhury, Lilian Mabundo, Michael Stagliano, Amber B Courville, Shanna Yang, Sara Turner, Hongyi Cai, Kannan Kasturi, Arthur S Sherman, Joon Ha, Eileen Shouppe, Mary Walter, Peter J Walter, Kong Y Chen, Robert J Brychta, Cody Peer, Yi Zeng, William Figg, Fran Cogen, D Elizabeth Estrada, Shaji Chacko, Stephanie T Chung

Children’s Nutrition Research Center Staff Publications

OBJECTIVE: Elevated rates of gluconeogenesis are an early pathogenic feature of youth-onset type 2 diabetes (Y-T2D), but targeted first-line therapies are suboptimal, especially in African American (AA) youth. We evaluated glucose-lowering mechanisms of metformin and liraglutide by measuring rates of gluconeogenesis and β-cell function after therapy in AA Y-T2D.

METHODS: In this parallel randomized clinical trial, 22 youth with Y-T2D-age 15.3 ± 2.1 years (mean ± SD), 68% female, body mass index (BMI) 40.1 ± 7.9 kg/m2, duration of diagnosis 1.8 ± 1.3 years-were randomized to metformin alone (Met) or metformin + liraglutide (Lira) (Met + Lira) and evaluated before …

Sleep And Circadian Biomarkers Of Postoperative Delirium (Sleep-Pod): Protocol For A Prospective And Observational Cohort Study, Elizabeth Sugg, Elizabeth Gleeson, Sarah N Baker, Peng Li, Chenlu Gao, Ariel Mueller, Hao Deng, Shiqian Shen, Esteban Franco-Garcia, Richa Saxena, Erik S Musiek, Oluwaseun Akeju, Zhongcong Xie, Kun Hu, Lei Gao

2020-Current year OA Pubs

INTRODUCTION: Surgical patients over 70 experience postoperative delirium (POD) complications in up to 50% of procedures. Sleep/circadian disruption has emerged as a potential risk factor for POD in epidemiological studies. This protocol presents a single-site, prospective observational study designed to examine the relationship between sleep/circadian regulation and POD and how this association could be moderated or mediated by Alzheimer's disease (AD) pathology and genetic risk for AD.

METHODS AND ANALYSIS: Study staff members will screen for eligible patients (age ≥70) seeking joint replacement or spinal surgery at Massachusetts General Hospital (MGH). At the inclusion visit, patients will be asked a …

Antiviral Cellular Therapy For Enhancing T-Cell Reconstitution Before Or After Hematopoietic Stem Cell Transplantation (Aces): A Two-Arm, Open Label Phase Ii Interventional Trial Of Pediatric Patients With Risk Factor Assessment, Michael D Keller, Jeffrey J Bednarski, Et Al.

2020-Current year OA Pubs

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST …

Advanced Nano-Drug Delivery Systems In The Treatment Of Ischemic Stroke, Jiajie Zhang, Zhong Chen, Qi Chen

Faculty, Staff and Student Publications

In recent years, the frequency of strokes has been on the rise year by year and has become the second leading cause of death around the world, which is characterized by a high mortality rate, high recurrence rate, and high disability rate. Ischemic strokes account for a large percentage of strokes. A reperfusion injury in ischemic strokes is a complex cascade of oxidative stress, neuroinflammation, immune infiltration, and mitochondrial damage. Conventional treatments are ineffective, and the presence of the blood-brain barrier (BBB) leads to inefficient drug delivery utilization, so researchers are turning their attention to nano-drug delivery systems. Functionalized nano-drug …

Transposable Elements Regulate Thymus Development And Function, Jean-David Larouche, Céline M Laumont, Assya Trofimov, Krystel Vincent, Leslie Hesnard, Sylvie Brochu, Caroline Côté, Juliette F Humeau, Éric Bonneil, Joel Lanoix, Chantal Durette, Patrick Gendron, Jean-Philippe Laverdure, Ellen R Richie, Sébastien Lemieux, Pierre Thibault, Claude Perreault

Faculty, Staff and Student Publications

Transposable elements (TEs) are repetitive sequences representing ~45% of the human and mouse genomes and are highly expressed by medullary thymic epithelial cells (mTECs). In this study, we investigated the role of TEs on T-cell development in the thymus. We performed multiomic analyses of TEs in human and mouse thymic cells to elucidate their role in T-cell development. We report that TE expression in the human thymus is high and shows extensive age- and cell lineage-related variations. TE expression correlates with multiple transcription factors in all cell types of the human thymus. Two cell types express particularly broad TE repertoires: …

Cdk8/Cdk19 Promotes Mitochondrial Fission Through Drp1 Phosphorylation And Can Phenotypically Suppress Pink1 Deficiency In Drosophila, Jenny Zhe Liao, Hyung-Lok Chung, Claire Shih, Kenneth Kin Lam Wong, Debdeep Dutta, Zelha Nil, Catherine Grace Burns, Oguz Kanca, Ye-Jin Park, Zhongyuan Zuo, Paul C Marcogliese, Katherine Sew, Hugo J Bellen, Esther M Verheyen

Faculty, Staff and Students Publications

Cdk8 in Drosophila is the orthologue of vertebrate CDK8 and CDK19. These proteins have been shown to modulate transcriptional control by RNA polymerase II. We found that neuronal loss of Cdk8 severely reduces fly lifespan and causes bang sensitivity. Remarkably, these defects can be rescued by expression of human CDK19, found in the cytoplasm of neurons, suggesting a non-nuclear function of CDK19/Cdk8. Here we show that Cdk8 plays a critical role in the cytoplasm, with its loss causing elongated mitochondria in both muscles and neurons. We find that endogenous GFP-tagged Cdk8 can be found in both the cytoplasm and nucleus. …

Fourteen-Day Vonoprazan-Based Bismuth Quadruple Therapy For H Pylori Eradication In An Area With High Clarithromycin And Levofloxacin Resistance: A Prospective Randomized Study (Vq-Hp Trial), Nuttapat Tungtrongchitr, Phubordee Bongkotvirawan, Sarita Ratana-Amornpin, Sith Siramolpiwat, Thanee Eiamsitrakoon, Pornpen Gamnarai, Arti Wongcha-Um, Yoshio Yamaoka, Kammal Kumar Pawa, Ratha-Korn Vilaichone

Faculty, Staff and Students Publications

Potassium-competitive acid blockers (P-CABs) provide potent acid inhibition, yet studies on P-CAB-based quadruple therapy for H. pylori eradication are limited. We theorized that integrating bismuth subsalicylate into a quadruple therapy regimen could enhance eradication rates. However, data on the efficacy of vonoprazan bismuth quadruple therapy are notably scarce. Therefore, the aim of this study was to evaluate the efficacy of vonoprazan-based bismuth quadruple therapy in areas with high clarithromycin and levofloxacin resistance. This was a prospective, single-center, randomized trial conducted to compare the efficacy of 7-day and 14-day vonoprazan-based bismuth quadruple therapy for H. pylori eradication between June 1, 2021, …

Cellular Geometry And Epithelial-Mesenchymal Plasticity Intersect With Piezo1 In Breast Cancer Cells, Choon Leng So, Mélanie Robitaille, Francisco Sadras, Michael H Mccullough, Michael J G Milevskiy, Geoffrey J Goodhill, Sarah J Roberts-Thomson, Gregory R Monteith

2020-Current year OA Pubs

Differences in shape can be a distinguishing feature between different cell types, but the shape of a cell can also be dynamic. Changes in cell shape are critical when cancer cells escape from the primary tumor and undergo major morphological changes that allow them to squeeze between endothelial cells, enter the vasculature, and metastasize to other areas of the body. A shift from rounded to spindly cellular geometry is a consequence of epithelial-mesenchymal plasticity, which is also associated with changes in gene expression, increased invasiveness, and therapeutic resistance. However, the consequences and functional impacts of cell shape changes and the …

Ml241 Antagonizes Erk 1/2 Activation And Inhibits Rotavirus Proliferation, Jinlan Wang, Xiaoqing Hu, Jinyuan Wu, Xiaochen Lin, Rong Chen, Chenxing Lu, Xiaopeng Song, Qingmei Leng, Yan Li, Xiangjing Kuang, Jinmei Li, Lida Yao, Xianqiong Tang, Jun Ye, Guangming Zhang, Maosheng Sun, Yan Zhou, Hongjun Li

Faculty, Staff and Student Publications

Rotavirus (RV) is the main pathogen that causes severe diarrhea in infants and children under 5 years of age. No specific antiviral therapies or licensed anti-rotavirus drugs are available. It is crucial to develop effective and low-toxicity anti-rotavirus small-molecule drugs that act on novel host targets. In this study, a new anti-rotavirus compound was selected by ELISA, and cell activity was detected from 453 small-molecule compounds. The anti-RV effects and underlying mechanisms of the screened compounds were explored. In vitro experimental results showed that the small-molecule compound ML241 has a good effect on inhibiting rotavirus proliferation and has low cytotoxicity …

Tissue-Specific Atlas Of Trans-Models For Gene Regulation Elucidates Complex Regulation Patterns, Robert Dagostino, Assaf Gottlieb

Faculty, Staff and Student Publications

BACKGROUND: Deciphering gene regulation is essential for understanding the underlying mechanisms of healthy and disease states. While the regulatory networks formed by transcription factors (TFs) and their target genes has been mostly studied with relation to cis effects such as in TF binding sites, we focused on trans effects of TFs on the expression of their transcribed genes and their potential mechanisms.

RESULTS: We provide a comprehensive tissue-specific atlas, spanning 49 tissues of TF variations affecting gene expression through computational models considering two potential mechanisms, including combinatorial regulation by the expression of the TFs, and by genetic variants within the …

Eye Infection Risks From Pseudomonas Aeruginosa Via Hand Soap And Eye Drops, Anna Gitter, Kristina D Mena, Karla S Mendez, Fuqing Wu, Charles P Gerba

Faculty, Staff and Student Publications

Eye infections from bacterial contamination of bulk-refillable liquid soap dispensers and artificial tear eye drops continue to occur, resulting in adverse health outcomes that include impaired vision or eye enucleation. Pseudomonas aeruginosa (P. aeruginosa), a common cause of eye infections, can grow in eye drop containers and refillable soap dispensers to high numbers. To assess the risk of eye infection, a quantitative microbial risk assessment for P. aeruginosa was conducted to predict the probability of an eye infection for two potential exposure scenarios: (i) individuals using bacteria-contaminated eye drops and (ii) contact lens wearers washing their hands with …

Topmed Imputed Genomics Enhances Genomic Atlas Of The Human Proteome In Brain, Cerebrospinal Fluid, And Plasma, Heng Yi, Qijun Yang, Charlie Repaci, Cheolmin Matthew Lee, Gyujin Heo, Jigyasha Timsina, Priyanka Gorijala, Chengran Yang, John Budde, Lihua Wang, Carlos Cruchaga, Yun Ju Sung

2020-Current year OA Pubs

Comprehensive expression quantitative trait loci studies have been instrumental for understanding tissue-specific gene regulation and pinpointing functional genes for disease-associated loci in a tissue-specific manner. Compared to gene expressions, proteins more directly affect various biological processes, often dysregulated in disease, and are important drug targets. We previously performed and identified tissue-specific protein quantitative trait loci in brain, cerebrospinal fluid, and plasma. We now enhance this work by analyzing more proteins (1,300 versus 1,079) and an almost twofold increase in high quality imputed genetic variants (8.4 million versus 4.4 million) by using TOPMed reference panel. We identified 38 genomic regions associated …

Emerging Variants Develop Total Escape From Potent Monoclonal Antibodies Induced By Ba4/5 Infection, Chang Liu, Raksha Das, Aiste Dijokaite-Guraliuc, Daming Zhou, Alexander J Mentzer, Piyada Supasa, Muneeswaran Selvaraj, Helen M E Duyvesteyn, Thomas G Ritter, Nigel Temperton, Paul Klenerman, Susanna J Dunachie, Neil G Paterson, Mark A Williams, David R Hall, Elizabeth E Fry, Juthathip Mongkolsapaya, Jingshan Ren, David I Stuart, Gavin R Screaton

Faculty, Staff and Student Publications

The rapid evolution of SARS-CoV-2 is driven in part by a need to evade the antibody response in the face of high levels of immunity. Here, we isolate spike (S) binding monoclonal antibodies (mAbs) from vaccinees who suffered vaccine break-through infections with Omicron sub lineages BA.4 or BA.5. Twenty eight potent antibodies are isolated and characterised functionally, and in some cases structurally. Since the emergence of BA.4/5, SARS-CoV-2 has continued to accrue mutations in the S protein, to understand this we characterize neutralization of a large panel of variants and demonstrate a steady attrition of neutralization by the panel of …