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Association Of Gulf War Illness With Characteristics In Deployed Vs Non-Deployed Gulf War Era Veterans In The Cooperative Studies Program 2006/Million Veteran Program 029 Cohort: A Cross-Sectional Analysis, Linh M Duong, Alice B S Nono Djotsa, Jacqueline Vahey, Lea Steele, Rachel Quaden, Kelly M Harrington, Sarah T Ahmed, Renato Polimanti, Elani Streja, John Michael Gaziano, John Concato, Hongyu Zhao, Krishnan Radhakrishnan, Elizabeth R Hauser, Drew A Helmer, Mihaela Aslan, Elizabeth J Gifford

Center for Medical Ethics and Health Policy Staff Publications

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990-1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA's Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990-1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018-2019 survey, 35,902 respondents met study inclusion criteria, 13,107 …

Collaborative Interprofessional Health Science Student Led Realistic Mass Casualty Incident Simulation, Deborah L Mccrea, Robert C Coghlan, Tiffany Champagne-Langabeer, Stanley Cron

Faculty, Staff and Student Publications

In collaboration, a health science university and a fire department offered a mass casualty incident (MCI) simulation. The purpose of this study was to evaluate a cross-section of student health care providers to determine their working knowledge of an MCI. Students were given a pretest using the Emergency Preparedness Information Questionnaire (EPIQ) and the Simple Triage and Rapid Transport (START) Quiz. The EPIQ instrument related to knowledge of triage, first aid, bio-agent detection, critical reporting, incident command, isolation/quarantine/decontamination, psychological issues, epidemiology, and communications. The START Quiz gave 10 scenarios. Didactic online content was given followed by the simulation a few …

Risk Factors For Sars-Cov-2 Transmission In Close Contacts Of Adults At High Risk Of Infection Due To Occupation: Results From The Contact Tracing Strategy Of The Covida Epidemiological Surveillance Study In Bogotá, Colombia, In 2020-2021, Andrea Ramírez Varela, Sandra Contreras-Arrieta, Guillermo Tamayo-Cabeza, Leonardo Salas Zapata, Yuldor Caballero-Díaz, Luis Jorge Hernández Florez, Andrés Patiño Benavidez, Rachid Laajaj, Fernando De La Hoz, Giancarlo Buitrago Gutierrez, Silvia Restrepo, Eduardo Behrentz

Faculty, Staff and Student Publications

OBJECTIVES: To estimate the risk factors for SARS-CoV-2 transmission in close contacts of adults at high risk of infection due to occupation, participants of the CoVIDA study, in Bogotá D.C., Colombia.

SETTING: The CoVIDA study was the largest COVID-19 intensified sentinel epidemiological surveillance study in Colombia thus far, performing over 60 000 RT-PCR tests for SARS-CoV-2 infection. The study implemented a contact tracing strategy (via telephone call) to support traditional surveillance actions performed by the local health authority.

PARTICIPANTS: Close contacts of participants from the CoVIDA study.

PRIMARY AND SECONDARY OUTCOME MEASURES: SARS-CoV-2 testing results were obtained (RT-PCR with CoVIDA …

Multiomics Characterization Of Methicillin-Resistant Staphylococcus Aureus (Mrsa) Isolates With Heterogeneous Intermediate Resistance To Vancomycin (Hvisa) In Latin America, Betsy E Castro, Rafael Rios, Lina P Carvajal, Mónica L Vargas, Mónica P Cala, Lizeth León, Blake Hanson, An Q Dinh, Oscar Ortega-Recalde, Carlos Seas, Jose M Munita, Cesar A Arias, Sandra Rincon, Jinnethe Reyes, Lorena Diaz

Faculty, Staff and Student Publications

BACKGROUND: Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) compromise the clinical efficacy of vancomycin. The hVISA isolates spontaneously produce vancomycin-intermediate Staphylococcus aureus (VISA) cells generated by diverse and intriguing mechanisms.

OBJECTIVE: To characterize the biomolecular profile of clinical hVISA applying genomic, transcriptomic and metabolomic approaches.

METHODS: 39 hVISA and 305 VSSA and their genomes were included. Core genome-based Bayesian phylogenetic reconstructions were built and alterations in predicted proteins in VISA/hVISA were interrogated. Linear discriminant analysis and a Genome-Wide Association Study were performed. Differentially expressed genes were identified in hVISA-VSSA by RNA-sequencing. The undirected profiles of metabolites were determined by liquid chromatography and …

Control Of Sars-Cov-2 Infection By Mt1-Mmp-Mediated Shedding Of Ace2, Xuanming Guo, Jianli Cao, Jian-Piao Cai, Jiayan Wu, Jiangang Huang, Pallavi Asthana, Sheung Kin Ken Wong, Zi-Wei Ye, Susma Gurung, Yijing Zhang, Sheng Wang, Zening Wang, Xin Ge, Hiu Yee Kwan, Aiping Lyu, Kui Ming Chan, Nathalie Wong, Jiandong Huang, Zhongjun Zhou, Zhao-Xiang Bian, Shuofeng Yuan, Hoi Leong Xavier Wong

Faculty, Staff and Student Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2. The full-length membrane form of ACE2 (memACE2) undergoes ectodomain shedding to generate a shed soluble form (solACE2) that mediates SARS-CoV-2 entry via receptor-mediated endocytosis. Currently, it is not known how the physiological regulation of ACE2 shedding contributes to the etiology of COVID-19 in vivo. The present study identifies Membrane-type 1 Matrix Metalloproteinase (MT1-MMP) as a critical host protease for solACE2-mediated SARS-CoV-2 infection. SARS-CoV-2 infection leads to increased activation of MT1-MMP that is colocalized with ACE2 in human lung …

Clinical Cancer And Direct-To-Consumer Genetic Test Result-Sharing Behavior: Findings From Hints 2020, Sukh Makhnoon, Robert Yu, Susan K Peterson, Sanjay Shete

Faculty, Staff and Student Publications

INTRODUCTION: Sharing genetic test results with different stakeholders such as family members, healthcare providers and genetic counselors (HCP/GCs), spouses/partners, and friends is a health behavior of clinical importance in genomic medicine.

METHODS: Using nationally representative population-based data collected from the Health Information National Trends Survey (HINTS 5, cycle 4), we identified the prevalence and factors associated with genetic test result-sharing behavior for high-risk cancer tests, genetic health risk tests, and ancestry tests within four groups: HCP/GCs, first-degree relatives (FDRs), spouse/partner, and friend/other.

RESULTS: Overall, 68.4% of those who underwent high-risk cancer genetic testing shared their results with FDRs, whereas 89.9% …

Hif1a-Dependent Induction Of Alveolar Epithelial Pfkfb3 Dampens Acute Lung Injury, Christine U Vohwinkel, Nana Burns, Ethan Coit, Xiaoyi Yuan, Eszter K Vladar, Christina Sul, Eric P Schmidt, Peter Carmeliet, Kurt Stenmark, Eva S Nozik, Rubin M Tuder, Holger K Eltzschig

Faculty, Staff and Student Publications

Acute lung injury (ALI) is a severe form of lung inflammation causing acute respiratory distress syndrome in patients. ALI pathogenesis is closely linked to uncontrolled alveolar inflammation. We hypothesize that specific enzymes of the glycolytic pathway could function as key regulators of alveolar inflammation. Therefore, we screened isolated alveolar epithelia from mice exposed to ALI induced by injurious ventilation to assess their metabolic responses. These studies pointed us toward a selective role for isoform 3 of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3). Pharmacologic inhibition or genetic deletion of Pfkfb3 in alveolar epithelia (Pfkfb3loxP/loxP SPC-ER-Cre+ mice) was associated with profound increases in ALI during …

Human Health During Space Travel: State-Of-The-Art Review, Chayakrit Krittanawong, Nitin Kumar Singh, Richard A Scheuring, Emmanuel Urquieta, Eric M Bershad, Timothy R Macaulay, Scott Kaplin, Carly Dunn, Stephen F Kry, Thais Russomano, Marc Shepanek, Raymond P Stowe, Andrew W Kirkpatrick, Timothy J Broderick, Jean D Sibonga, Andrew G Lee, Brian E Crucian

Faculty, Staff and Student Publications

The field of human space travel is in the midst of a dramatic revolution. Upcoming missions are looking to push the boundaries of space travel, with plans to travel for longer distances and durations than ever before. Both the National Aeronautics and Space Administration (NASA) and several commercial space companies (e.g., Blue Origin, SpaceX, Virgin Galactic) have already started the process of preparing for long-distance, long-duration space exploration and currently plan to explore inner solar planets (e.g., Mars) by the 2030s. With the emergence of space tourism, space travel has materialized as a potential new, exciting frontier of business, hospitality, …

Period 2 Regulates Low-Dose Radioprotection Via Per2/Pgsk3Β/Β-Catenin/Per2 Loop, Aris T Alexandrou, Yixin Duan, Shanxiu Xu, Clifford Tepper, Ming Fan, Jason Tang, Jonathan Berg, Wassim Basheer, Tyler Valicenti, Paul F Wilson, Matthew A Coleman, Andrew T Vaughan, Loning Fu, David J Grdina, Jefferey Murley, Aijun Wang, Gayle Woloschak, Jian Jian Li

Faculty, Staff and Students Publications

During evolution, humans are acclimatized to the stresses of natural radiation and circadian rhythmicity. Radiosensitivity of mammalian cells varies in the circadian period and adaptive radioprotection can be induced by pre-exposure to low-level radiation (LDR). It is unclear, however, if clock proteins participate in signaling LDR radioprotection. Herein, we demonstrate that radiosensitivity is increased in mice with the deficient Period 2 gene (Per2def) due to impaired DNA repair and mitochondrial function in progenitor bone marrow hematopoietic stem cells and monocytes. Per2 induction and radioprotection are also identified in LDR-treated Per2wt mouse cells and in human skin (HK18) and breast (MCF-10A) …

Rare Diseases And Space Health: Optimizing Synergies From Scientific Questions To Care, Maria Puscas, Gabrielle Martineau, Gurjot Bhella, Penelope E Bonnen, Phil Carr, Robyn Lim, John Mitchell, Matthew Osmond, Emmanuel Urquieta, Jaime Flamenbaum, Giuseppe Iaria, Yann Joly, Étienne Richer, Joan Saary, David Saint-Jacques, Nicole Buckley, Etienne Low-Decarie

Faculty, Staff and Students Publications

Knowledge transfer among research disciplines can lead to substantial research progress. At first glance, astronaut health and rare diseases may be seen as having little common ground for such an exchange. However, deleterious health conditions linked to human space exploration may well be considered as a narrow sub-category of rare diseases. Here, we compare and contrast research and healthcare in the contexts of rare diseases and space health and identify common barriers and avenues of improvement. The prevalent genetic basis of most rare disorders contrasts sharply with the occupational considerations required to sustain human health in space. Nevertheless small sample …

Engineering Naturally Occurring Cd7- T Cells For The Immunotherapy Of Hematological Malignancies, Abdullah Freiwan, Jaquelyn T Zoine, Jeremy Chase Crawford, Abishek Vaidya, Stefan A Schattgen, Jacquelyn A Myers, Sagar L Patil, Mahsa Khanlari, Hiroto Inaba, Jeffery M Klco, Charles G Mullighan, Giedre Krenciute, Peter J Chockley, Swati Naik, Deanna M Langfitt, Maksim Mamonkin, Esther A Obeng, Paul G Thomas, Stephen Gottschalk, M Paulina Velasquez

Faculty, Staff and Students Publications

Chimeric antigen receptor (CAR) T-cell therapy targeting T-cell acute lymphoblastic leukemia (T-ALL) faces limitations such as antigen selection and limited T-cell persistence. CD7 is an attractive antigen for targeting T-ALL, but overlapping expression on healthy T cells leads to fratricide of CD7-CAR T cells, requiring additional genetic modification. We took advantage of naturally occurring CD7- T cells to generate CD7-CAR (CD7-CARCD7-) T cells. CD7-CARCD7- T cells exhibited a predominantly CD4+ memory phenotype and had significant antitumor activity upon chronic antigen exposure in vitro and in xenograft mouse models. Based on these encouraging results, we next explored the utility of CD7- …

Activation Of Basal Forebrain-To-Lateral Habenula Circuitry Drives Reflexive Aversion And Suppresses Feeding Behavior, Jessica L Swanson, Joshua Ortiz-Guzman, Snigdha Srivastava, Pey-Shyuan Chin, Sean W Dooling, Elizabeth Hanson Moss, Mikhail Y Kochukov, Patrick J Hunt, Jay M Patel, Brandon T Pekarek, Qingchun Tong, Benjamin R Arenkiel

Faculty, Staff and Student Publications

Environmental cues and internal states such as mood, reward, or aversion directly influence feeding behaviors beyond homeostatic necessity. The hypothalamus has been extensively investigated for its role in homeostatic feeding. However, many of the neural circuits that drive more complex, non-homeostatic feeding that integrate valence and sensory cues (such as taste and smell) remain unknown. Here, we describe a basal forebrain (BF)-to-lateral habenula (LHb) circuit that directly modulates non-homeostatic feeding behavior. Using viral-mediated circuit mapping, we identified a population of glutamatergic neurons within the BF that project to the LHb, which responds to diverse sensory cues, including aversive and food-related …

Molecular Markers In Maternal Blood Exosomes Allow Early Detection Of Fetal Alcohol Spectrum Disorders, Nune Darbinian, Armine Darbinyan, John Sinard, Gabriel Tatevosian, Nana Merabova, Faith D'Amico, Tarek Khader, Ahsun Bajwa, Diana Martirosyan, Alina K Gawlinski, Richa Pursnani, Huaqing Zhao, Shohreh Amini, Mary Morrison, Laura Goetzl, Michael E Selzer

Faculty, Staff and Student Publications

Prenatal alcohol exposure can cause developmental abnormalities (fetal alcohol spectrum disorders; FASD), including small eyes, face and brain, and neurobehavioral deficits. These cannot be detected early in pregnancy with available imaging techniques. Early diagnosis could facilitate development of therapeutic interventions. Banked human fetal brains and eyes at 9−22 weeks’ gestation were paired with maternal blood samples, analyzed for morphometry, protein, and RNA expression, and apoptotic signaling. Alcohol (EtOH)-exposed (maternal self-report) fetuses were compared with unexposed controls matched for fetal age, sex, and maternal race. Fetal brain-derived exosomes (FB-E) were isolated from maternal blood and analyzed for protein, RNA, and apoptotic …

Concurrent Mutations In Sf3b1 And Phf6 In Myeloid Neoplasms, Zhuang Zuo, L Jeffrey Medeiros, Sofia Garces, Mark J Routbort, Chi Young Ok, Sanam Loghavi, Rashmi Kanagal-Shamanna, Fatima Zahra Jelloul, Guillermo Garcia-Manero, Kelly S Chien, Keyur P Patel, Rajyalakshmi Luthra, C Cameron Yin

Faculty, Staff and Student Publications

It has been reported that gene mutations in SF3B1 and PHF6 are mutually exclusive. However, this observation has never been rigorously assessed. We report the clinicopathologic and molecular genetic features of 21 cases of myeloid neoplasms with double mutations in SF3B1 and PHF6, including 9 (43%) with myelodysplastic syndrome, 5 (24%) with acute myeloid leukemia, 4 (19%) with myeloproliferative neoplasms, and 3 (14%) with myelodysplastic/myeloproliferative neoplasms. Multilineage dysplasia with ring sideroblasts, increased blasts, and myelofibrosis are common morphologic findings. All cases but one had diploid or non-complex karyotypes. SF3B1 mutations were detected in the first analysis of all the …

Impact Of Covid-19 On A Worksite Weight Loss Program For Employees With Overweight And Obesity, Che Young Lee, Michael C Robertson, Kendahl Servino, Thuan Le, Margaret Raber, Katherine Oestman, Karen M Basen-Engquist

Faculty, Staff and Students Publications

OBJECTIVE: The COVID-19 pandemic has been shown to be negatively associated with physical activity engagement, adherence to healthy diet, and weight management among people with obesity. The current study examined COVID-19-related changes in weight, physical activity (PA), and diet among employees with obesity or overweight who participated in Vibrant Lives (VL), a worksite weight loss program.

METHODS: School district employees participated in the 6-month VL weight loss program and were categorized into non-COVID-era participants and COVID-era participants. Participants completed questionnaires about PA and dietary intake at baseline and follow-up. COVID-era participants reported the effects of pandemic on their behaviors. Changes …

Systemic Delivery Of Divalent Europium From Ligand Screening With Implications To Direct Imaging Of Hypoxia, Md Mamunur Rashid, Brooke A Corbin, Pavan Jella, Caitlyn J Ortiz, Md Abul Hassan Samee, Robia G Pautler, Matthew J Allen

Faculty, Staff and Students Publications

Hypoxia is a hallmark of many diseases, including cancer, arthritis, heart and kidney diseases, and diabetes, and it is often associated with disease aggressiveness and poor prognosis. Consequently, there is a critical need for imaging hypoxia in a noninvasive and direct way to diagnose, stage, and monitor the treatment and development of new therapies for these diseases. Eu-containing contrast agents for magnetic resonance imaging have demonstrated potential for in vivo imaging of hypoxia via changes in metal oxidation state from +2 to +3, but rapid oxidation in blood limits EuII-containing complexes to only studies compatible with direct injection to sites. …

Does Receiving A Sars-Cov-2 Antibody Test Result Change Covid-19 Protective Behaviors? Testing Risk Compensation In Undergraduate Students With A Randomized Controlled Trial, Christina Ludema, Molly S Rosenberg, Jonathan T Macy, Sina Kianersi, Maya Luetke, Chen Chen, Lilian Golzarri-Arroyo, Erin Ables, Kevin Maki, David B Allison

Children’s Nutrition Research Center Staff Publications

Background: Risk compensation, or matching behavior to a perceived level of acceptable risk, can blunt the effectiveness of public health interventions. One area of possible risk compensation during the SARS-CoV-2 pandemic is antibody testing. While antibody tests are imperfect measures of immunity, results may influence risk perception and individual preventive actions. We conducted a randomized control trial to assess whether receiving antibody test results changed SARS-CoV-2 protective behaviors.

Purpose: Assess whether objective information about antibody status, particularly for those who are antibody negative and likely still susceptible to SARS-CoV-2 infection, increases protective behaviors. Secondarily, assess whether a positive antibody test …

A Flexible-Hazards Cure Model With Application To Patients With Soft Tissue Sarcoma, Can Xie, Xuelin Huang, Ruosha Li, Peter W T Pisters

Faculty, Staff and Student Publications

In medical research, it is often of great interest to have an accurate estimation of cure rates by different treatment options and for different patient groups. If the follow-up time is sufficiently long and the sample size is large, the proportion of cured patients will make the Kaplan-Meier estimator of survival function have a flat plateau at its tail, whose value indicates the overall cure rate. However, it may be difficult to estimate and compare the cure rates for all the subsets of interest in this way, due to the limit of sample sizes and curse of dimensionality. In the …

Correlations Between Complex Human Phenotypes Vary By Genetic Background, Gender, And Environment, Michael Elgart, Matthew O Goodman, Carmen Isasi, Han Chen, Alanna C Morrison, Paul S De Vries, Huichun Xu, Ani W Manichaikul, Xiuqing Guo, Nora Franceschini, Bruce M Psaty, Stephen S Rich, Jerome I Rotter, Donald M Lloyd-Jones, Myriam Fornage, Adolfo Correa, Nancy L Heard-Costa, Ramachandran S Vasan, Ryan Hernandez, Robert C Kaplan, Susan Redline, Tamar Sofer

Faculty, Staff and Student Publications

We develop a closed-form Haseman-Elston estimator for genetic and environmental correlation coefficients between complex phenotypes, which we term HEc, that is as precise as GCTA yet ∼20× faster. We estimate genetic and environmental correlations between over 7,000 phenotype pairs in subgroups from the Trans-Omics in Precision Medicine (TOPMed) program. We demonstrate substantial differences in both heritabilities and genetic correlations for multiple phenotypes and phenotype pairs between individuals of self-reported Black, Hispanic/Latino, and White backgrounds. We similarly observe differences in many of the genetic and environmental correlations between genders. To estimate the contribution of genetics to the observed phenotypic correlation, we …

Xcvatr: Detection And Characterization Of Variant Impact On The Embeddings Of Single -Cell And Bulk Rna-Sequencing Samples, Arif Harmanci, Akdes Serin Harmanci, Tiemo J Klisch, Akash J Patel

Duncan NRI Faculty and Staff Publications

Background: RNA-sequencing has become a standard tool for analyzing gene activity in bulk samples and at the single-cell level. By increasing sample sizes and cell counts, this technique can uncover substantial information about cellular transcriptional states. Beyond quantification of gene expression, RNA-seq can be used for detecting variants, including single nucleotide polymorphisms, small insertions/deletions, and larger variants, such as copy number variants. Notably, joint analysis of variants with cellular transcriptional states may provide insights into the impact of mutations, especially for complex and heterogeneous samples. However, this analysis is often challenging due to a prohibitively high number of variants and …

Spatial Heterogeneity Of Infiltrating T Cells In High-Grade Serous Ovarian Cancer Revealed By Multi-Omics Analysis, Bin Yang, Xiong Li, Wei Zhang, Junpeng Fan, Yong Zhou, Wenting Li, Jingjing Yin, Xiaohang Yang, Ensong Guo, Xi Li, Yu Fu, Si Liu, Dianxing Hu, Xu Qin, Yingyu Dou, Rourou Xiao, Funian Lu, Zizhuo Wang, Tianyu Qin, Wei Wang, Qinghua Zhang, Shuaicheng Li, Ding Ma, Gordon B Mills, Gang Chen, Chaoyang Sun

Faculty, Staff and Student Publications

Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, represent a favorable prognostic factor in high-grade serous ovarian cancer (HGSOC) and other tumor lineages. Here, we analyze the spatial heterogeneity of different TIL subtypes in HGSOC. We integrated RNA sequencing, whole-genome sequencing, bulk T cell receptor (TCR) sequencing, as well as single-cell RNA/TCR sequencing to investigate the characteristics and differential composition of TILs across different HGSOC sites. Two immune "cold" patterns in ovarian cancer are identified: (1) ovarian lesions with low infiltration of mainly dysfunctional T cells and immunosuppressive Treg cells and (2) omental lesions infiltrated with non-tumor-specific bystander cells. Exhausted CD8 T …

Structural Insights Into Cardiolipin Replacement By Phosphatidylglycerol In A Cardiolipin-Lacking Yeast Respiratory Supercomplex, Elena G Govorunova, Oleg A Sineshchekov, Leonid S Brown, Ana-Nicoleta Bondar, John L Spudich

Faculty, Staff and Student Publications

Potassium-selective channelrhodopsins (KCRs) are light-gated K+ channels recently found in the stramenopile protist Hyphochytrium catenoides. When expressed in neurons, KCRs enable high-precision optical inhibition of spiking (optogenetic silencing). KCRs are capable of discriminating K+ from Na+ without the conventional K+ selectivity filter found in classical K+ channels. The genome of H. catenoides also encodes a third paralog that is more permeable for Na+ than for K+. To identify structural motifs responsible for the unusual K+ selectivity of KCRs, we systematically analyzed a series of chimeras and mutants of this protein. We found that mutations of three critical residues in the …

In-Depth Analysis Of Alternative Splicing Landscape In Multiple Myeloma And Potential Role Of Dysregulated Splicing Factors, Anil Aktas Samur, Mariateresa Fulciniti, Herve Avet-Loiseau, Michael A Lopez, Sanika Derebail, Jill Corre, Stephane Minvielle, Florence Magrangeas, Philippe Moreau, Kenneth C Anderson, Giovanni Parmigiani, Mehmet K Samur, Nikhil C Munshi

Faculty, Staff and Student Publications

Splicing changes are common in cancer and are associated with dysregulated splicing factors. Here, we analyzed RNA-seq data from 323 newly diagnosed multiple myeloma (MM) patients and described the alternative splicing (AS) landscape. We observed a large number of splicing pattern changes in MM cells compared to normal plasma cells (NPC). The most common events were alterations of mutually exclusive exons and exon skipping. Most of these events were observed in the absence of overall changes in gene expression and often impacted the coding potential of the alternatively spliced genes. To understand the molecular mechanisms driving frequent aberrant AS, we …

The Role Of Lncrnas In The Tumor Microenvironment And Immunotherapy Of Melanoma, Wencheng Zhou, Xuewen Xu, Ying Cen, Junjie Chen

Faculty, Staff and Student Publications

Melanoma is one of the most lethal tumors with highly aggressive and metastatic properties. Although immunotherapy and targeted therapy have certain therapeutic effects in melanoma, a significant proportion of patients still have drug resistance after treatment. Recent studies have shown that long noncoding RNAs (lncRNAs) are widely recognized as regulatory factors in cancer. They can regulate numerous cellular processes, including cell proliferation, metastasis, epithelial-mesenchymal transition (EMT) progression and the immune microenvironment. The role of lncRNAs in malignant tumors has received much attention, whereas the relationship between lncRNAs and melanoma requires further investigation. Our review summarizes tumor suppressive and oncogenic lncRNAs …

Accumulation Of Sublethal Radiation Damage And Its Effect On Cell Survival, Oleg N Vassiliev

Faculty, Staff and Student Publications

Objective. Determine the extent of sublethal radiation damage (SRD) in a cell population that received a given dose of radiation and the impact of this damage on cell survival. Approach. We developed a novel formalism to account for accumulation of SRD with increasing dose. It is based on a very general formula for cell survival that correctly predicts the basic properties of cell survival curves, such as the transition from the linear-quadratic to a linear dependence at high doses. Using this formalism we analyzed extensive experimental data for photons, protons and heavy ions to evaluate model parameters, quantify the extent …

Stabilization Of Mcl-1 By E3 Ligase Traf4 Confers Radioresistance, Ming Li, Feng Gao, Xiaoying Li, Yu Gan, Shuangze Han, Xinfang Yu, Haidan Liu, Wei Li

Faculty, Staff and Students Publications

The E3 ligase TNF receptor-associated factor 4 (TRAF4) is frequently overexpressed and closely related to poor prognosis in human malignancies. However, its effect on carcinogenesis and radiosensitivity in oral squamous cell carcinoma (OSCC) remains unclear. The present study found that TRAF4 was significantly upregulated in primary and relapsed OSCC tumor tissues. Depletion of TRAF4 markedly improved the sensitivity of OSCC cells to irradiation (IR) treatment, showing that tumor cell proliferation, colony formation and xenograft tumor growth were reduced. Mechanistically, IR promoted the interaction between TRAF4 and Akt to induce Akt K63-mediated ubiquitination and activation. TRAF4 knockout inhibited the phosphorylation of …

Ccl4 Regulates Eosinophil Activation In Eosiccl4 Regulates Eosinophil Activation In Eosinophilic Airway Inflammationnophilic Airway Inflammation, Hanh Hong Chu, Yoshiki Kobayashi, Dan Van Bui, Yasutaka Yun, Linh Manh Nguyen, Akitoshi Mitani, Kensuke Suzuki, Mikiya Asako, Akira Kanda, Hiroshi Iwai

Faculty, Staff and Student Publications

Eosinophilic chronic rhinosinusitis (ECRS) is a refractory airway disease accompanied by eosinophilic inflammation, the mechanisms of which are unknown. We recently found that CCL4/MIP-1β-a specific ligand for CCR5 receptors-was implicated in eosinophil recruitment into the inflammatory site and was substantially released from activated eosinophils. Moreover, it was found in nasal polyps from patients with ECRS, primarily in epithelial cells. In the present study, the role of epithelial cell-derived CCL4 in eosinophil activation was investigated. First, CCL4 expression in nasal polyps from patients with ECRS as well as its role of CCL4 in eosinophilic airway inflammation were investigated in an in …

Nuclear S6k1 Enhances Oncogenic Wnt Signaling By Inducing Wnt/Β-Catenin Transcriptional Complex Formation, Min Gyu Lee, Hwamok Oh, Jong Woo Park, Jueng Soo You, Jeung-Whan Han

Faculty, Staff and Student Publications

Ribosomal protein S6 kinase 1 (S6K1), a key downstream effector of the mammalian target of rapamycin (mTOR), regulates diverse functions, such as cell proliferation, cell growth, and protein synthesis. Because S6K1 was previously known to be localized in the cytoplasm, its function has been mainly studied in the cytoplasm. However, the nuclear localization and function of S6K1 have recently been elucidated and other nuclear functions are expected to exist but remain elusive. Here, we show a novel nuclear role of S6K1 in regulating the expression of the Wnt target genes. Upon activation of the Wnt signaling, S6K1 translocated from the …

Ex Vivo Drug Sensitivity Correlates With Clinical Response And Supports Personalized Therapy In Pediatric Aml, Debbie C Strachan, Christine J Gu, Ryosuke Kita, Erica K Anderson, Michelle A Richardson, George Yam, Graham Pimm, Jordan Roselli, Alyssa Schweickert, Maci Terrell, Raushan Rashid, Alan K Gonzalez, Hailey H Oviedo, Michelle C Alozie, Tamilini Ilangovan, Andrea N Marcogliese, Hiroomi Tada, Marianne T Santaguida, Alexandra M Stevens

Faculty, Staff and Students Publications

Acute myeloid leukemia (AML) is a heterogeneous disease that accounts for ~20% of all childhood leukemias, and more than 40% of children with AML relapse within three years of diagnosis. Although recent efforts have focused on developing a precise medicine-based approach towards treating AML in adults, there remains a critical gap in therapies designed specifically for children. Here, we present ex vivo drug sensitivity profiles for children with de novo AML using an automated flow cytometry platform. Fresh diagnostic blood or bone marrow aspirate samples were screened for sensitivity in response to 78 dose conditions by measuring the reduction in …

Research Infrastructure Core Facilities At Research Centers In Minority Institutions: Part I-Research Resources Management, Operation, And Best Practices, Paul B Tchounwou, Mohamad Malouhi, Elizabeth O Ofili, Emma Fernández-Repollet, Daniel F Sarpong, Richard Yanagihara, Renato J Aguilera, Cecilia Ayón, Xiaoxin Chen, Asok Dasmahapatra, Song Gao, Cimona V Hinton, Robert Holt, Vladimir Kolesnichenko, Michael D Powell, Fatima Merchant, Kinfe K Redda, Abiel Roche-Lima, Cecilia M Shikuma, Jacqueline J Stevens, Jose A Torres, Robert T Trotter, James Wachira, Paul Wang, Kristen J Wells, Jason White, Yanyuan Wu

Faculty, Staff and Student Publications

Funded by the National Institutes of Health (NIH), the Research Centers in Minority Institutions (RCMI) Program fosters the development and implementation of innovative research aimed at improving minority health and reducing or eliminating health disparities. Currently, there are 21 RCMI Specialized (U54) Centers that share the same framework, comprising four required core components, namely the Administrative, Research Infrastructure, Investigator Development, and Community Engagement Cores. The Research Infrastructure Core (RIC) is fundamentally important for biomedical and health disparities research as a critical function domain. This paper aims to assess the research resources and services provided and evaluate the best practices in …