Digital Commons Network^™

Contemporary Outcomes Of Octa-Nonagenarians With Newly Diagnosed Acute Myeloid Leukemia, Jayastu Senapati, Hagop M Kantarjian, Tapan M Kadia, Jeannot Kekedjian, Gautam Borthakur, Naval Daver, Courtney D Dinardo, Elias Jabbour, Prithviraj Bose, Nicholas J Short, Musa Yilmaz, Nitin Jain, Naveen Pemmaraju, Hussein A Abbas, Ghayas C Issa, Abhishek Maiti, Guillermo Montalban Bravo, Indraneel Deshmukh, Elizabeth Shpall, Partow Kebriaei, Uday Popat, Sanam Loghavi, Beenu Thakral, Guilin Tang, Fadi G Haddad, Yesid Alvarado, Guillermo Garcia Manero, Farhad Ravandi

Faculty, Staff and Student Publications

Background: Octa-nonagenarians with acute myeloid leukemia (AML) represent a high-risk group due to frequently poor performance status, adverse genomics (e.g., TP53 mutations, complex karyotype), a high incidence of secondary AML, and inability to undergo an allogeneic stem cell transplantation. Evaluating their outcomes with modern treatment approaches is important.

Methods: This retrospective study analyzed outcomes of patients ≥80 years old with newly diagnosed AML treated at our center from 2013-2023.

Results: A total of 289 patients (median age, 83 years; range, 80-95 years) were included. Venetoclax containing low-intensity therapy was administered to 107 patients (37.0%). AML subtypes included de novo (123, …

Role Of Immunosuppressive Jnk Pathway In The Tumor Microenvironment Among Tnbc Subtypes In Ibcsg Trial 22–00, Andrea Joaquin Garcia, Takashi Semba, Mattia Rediti, Daniel J Mcgrail, Xuemei Xie, Xiaoping Wang, Dileep R Rampa, David Venet, Laurence Buisseret, Samira Majjaj, Roswitha Kammler, Marco Colleoni, Sherene Loi, Giuseppe Viale, Meredith M Regan, Françoise Rothé, Christos Sotiriou, Naoto T Ueno

Faculty, Staff and Student Publications

Phosphorylation of the JNK (pJNK) protein promotes an immunosuppressive tumor microenvironment (TME), enhancing aggressiveness in inflammatory triple-negative breast cancer (TNBC). This study evaluated the role of JNK signaling using a gene signature. RNA sequencing was performed on 347 TNBC tumors from the phase 3 International Breast Cancer Study Group (IBCSG) 22-00 trial, which evaluated adjuvant low-dose cyclophosphamide and methotrexate (CM). Immune-related tumors were identified by TNBC subtype or tumor-infiltrating lymphocytes (TILs). Associations between JNK and outcomes were analyzed using Cox models. Low pJNK levels were associated with better disease-free survival (DFS) in immune-related tumors. These tumors also had lower Treg …

Restoring Translational Control With Novel Small Molecule Activators Of Pp2a In Cancer Cells, Kayla A. Jonas

Theses & Dissertations

Hyperactivation of eIF4E-dependent translation in tumor cells is required for robust expression of oncogenic proteins and maintenance of the transformed phenotype. eIF4E binds to the 7-methylguanylate structure at the 5’ end of cellular mRNAs and nucleates the formation of the translation initiation complex, eIF4F, which recruits the preinitiation complex and resolves secondary structure in the mRNA. The ability of eIF4E to promote eIF4F assembly is negatively regulated by the translational repressor, 4E-BP1, and tumorigenesis depends on functional inactivation of 4E-BP1. A major mechanism of 4E-BP1 inactivation involves inhibitory phosphorylation by mTOR which prevents eIF4E binding. Functional inactivation can also occur …

Effects Of Body Armor On Respiratory Muscle Fatigue And Muscle Blood Flow During Progressive Treadmill Marching, Kathryn Bell

UNLV Theses, Dissertations, Professional Papers, and Capstones

Introduction: Torso-borne loads such as body armor are essential for modern military operations but impose mechanical and metabolic strain. These physiological stressors can trigger the inspiratory metaboreflex, which redirects blood flow from locomotor to respiratory muscles, further reducing muscle oxygen and endurance. While aerobic fitness has been shown to alleviate these effects, the interaction between sex, aerobic capacity, and oxygenation under load is not well understood. This study examined the physiological effects of torso-borne load carriage on respiratory muscle fatigue, skeletal muscle oxygenation, and exercise performance to volitional exhaustion and the degree to which sex and aerobic capacity influence these …

An Analysis Of The Influence Of Human Disease Pathogens On Core Behaviors Of The Black-Legged Tick, Emily F. Marinko

UNLV Theses, Dissertations, Professional Papers, and Capstones

Ixodes scapularis, the black-legged or deer tick, is a vector for several different disease-causing microbes, including the causative agent of Lyme disease. As such, it is a major health concern for people living within its range in the eastern half of the United States, a habitation area that is increasing due to climate change. Despite its medical relevance as a disease vector, there is still much to learn about the basic behavior of these arachnids in the wild. Thus, the major hypothesis of this thesis is that ticks that are infected with specific human disease-causing microbes behave differently than those …

Sox2 Regulates Foregut Squamous Epithelial Homeostasis And Is Lost During Barrett’S Esophagus Development, Ramon U Jin, Yuanwei Xu, T Mamie Lih, Yang-Zhe Huang, Toni M Nittolo, Blake E Sells, Olivia M Dres, Jean S Wang, Qing K Li, Hui Zhang, Jason C Mills

Faculty, Staff and Students Publications

Esophageal adenocarcinoma is increasingly prevalent and is thought to arise from Barrett's esophagus (BE), a metaplastic condition in which chronic acid and bile reflux transforms the esophageal squamous epithelium into a gastric-intestinal glandular mucosa. The molecular determinants driving this metaplasia are poorly understood. We developed a human BE organoid biobank that recapitulates BE's molecular heterogeneity. Bulk and single-cell transcriptomics, supported by patient tissue analysis, revealed that BE differentiation reflects a balance between SOX2 (foregut/esophageal) and CDX2 (hindgut/intestinal) transcription factors. Using squamous-specific inducible Sox2-KO (Krt5CreER/+ Sox2Δ/Δ ROSA26tdTomato/+) mice, we observed increased basal proliferation, reduced squamous differentiation, and expanded metaplastic glands at …

What Are The Predictors Of Malignancy In Inflammatory Bowel Disease?, Zülal İstemi̇han, Bi̇lger Çavuş, Ali̇ Emre Bardak, Ayşe Merve Kirkoğlu, Cansu Kiziltaş, Rüveyda Si̇lay, İbrahi̇m Volkan Şenkal, Zi̇ya İmanov, Kenan Nuri̇yev, Aynure Rüstemzade, Sezen Genç, Mi̇ne Güllüoğlu, Asli Çi̇fci̇başi Örmeci̇, Kadi̇r Demi̇r, Fati̇h Beşişik, Sabahatti̇n Kaymakoğlu, Fi̇li̇z Akyüz

Turkish Journal of Medical Sciences

Background/aimː This study aims to investigate the prevalence of malignancy in patients with inflammatory bowel disease (IBD) followed up in a tertiary reference center.

Materials and methodsː IBD patients with at least 6 months of follow-up from the gastroenterology clinic between 2000 and 2022 wereevaluated retrospectively in a tertiary center. Patient information was obtained from the patient registration system.

Resultsː There were 697 patients in the study, 320 (45.9%) of these were female. The mean age of the patients at IBD diagnosis was 33.4± 13.1 years. The mean follow-up time was 93.1 ± 64.8 (median 84, IQR (25–75) (36–144)) months. …

Incidence Of And Risk Factors For Hyperoxemia Among Potentially Critically Ill Patients Treated In The Wards: A Retrospective Study, Mehmet Nuri̇ Yakar, Doğukan Şenberber, Ozan Balkabak, Nurgazy Shermatov, Kaan Köşker, Seli̇n Elden, Emel İbi̇şoğlu, Begüm Ergan, Volkan Hanci, Necati̇ Gökmen

Turkish Journal of Medical Sciences

Background/aim: The literature shows a link between hyperoxemia and poor outcomes, whereas this association remains unclear in hospital wards. This study aims to determine the incidence of hyperoxemia in hospital wards and its risk factors.

Materials and methods: Patients aged ≥ 18 years who underwent an evaluation by an intensivist between 1 January 2020 and 31 December 2020, while receiving treatment in hospital wards, were included in the study following ethics committee approval. Patients with hypoxemia (partial pressure of oxygen [PaO2] < 60 mmHg), a condition related to Coronavirus disease 2019, a hospital stay < 1 day, or missing data were excluded. Patients were divided into two groups: normoxemia (60 mmHg ≤ PaO2 < 120 mmHg) and hyperoxemia.

Results: The incidence of hyperoxemia was 42.2%. Patients with hyperoxemia had longer hospital stays and higher intensive care unit …

Comparison Of Novel Diard-Hbv Dna Qpcr Kit With The Artus Hbv Qs-Rgq Kit For Quantification Of Hbv Dna In Clinical Samples, Ülker Çuhaci, Hande Toptan, Bengül Durmaz, Mehmet Köroğlu, Riza Durmaz

Turkish Journal of Medical Sciences

Background/aim: Hepatitis B virus (HBV) leads to widespread chronic infections that may result in long-term complications such as cirrhosis and hepatocellular carcinoma. The use of sensitive molecular methods for HBV DNA quantitation has provided significant contributions for diagnosis and monitoring of disease. The current study aimed to evaluate the diagnostic performances of a novel DiaRD HBV qPCR kit (novel kit) in comparison with the artus HBV QS-RGQ kit (comparator kit).

Materials and methods: A total of 288 plasma samples—105 HBV DNA-positive and 183 HBV DNA-negative—were tested using both kits. The diagnostic and quantitative results of the novel kit were compared …

Highly Oligomeric Drp1 Strategic Positioning At Mitochondria-Sarcoplasmic Reticulum Contacts In Adult Murine Heart Through Actin Anchoring, Celia Fernandez-Sanz, Sergio De La Fuente, Zuzana Nichtova, Marilen Federico, Stephane Duvezin-Caubet, Sebastian Lanvermann, Hui-Ying Tsai, Yanguo Xin, György Csordás, Wang Wang, Arnaud Mourier, Shey-Shing Sheu

Department of Medicine Faculty Papers

Mitochondrial fission and fusion appear to be relatively infrequent in cardiac cells compared to other cell types; however, the proteins involved in these events are highly expressed in adult cardiomyocytes (ACM). Therefore, these proteins likely have additional non-canonical roles. We have previously shown that DRP1 not only participates in mitochondrial fission processes but also regulates mitochondrial bioenergetics in cardiac tissue. However, it is still unknown where the DRP1 that does not participate in mitochondrial fission is located and what its role is at those non-fission spots. Therefore, this manuscript will clarify whether oligomeric DRP1 is located at the SR–mitochondria interface, …

Proteomics-Based Aging Clocks In Midlife Or Late-Life And Their Associated Risk Of Dementia, Sanaz Sedaghat, Saeun Park, Rob F Walker, Shuo Wang, Jialing Liu, Timothy M Hughes, Behnam Sabayan, Weihong Tang, Josef Coresh, James S Pankow, Keenan A Walker, Ramon Casanova, Ruth Dubin, Rajat Deo, Jerome I Rotter, Alexis C Wood, Peter Ganz, Pamela L Lutsey, Weihua Guan, Anna Prizment

Children’s Nutrition Research Center Staff Publications

Background: Biological age can be quantified by composite proteomic scores, called proteomics-based aging clocks (PACs). We investigated whether a discrepancy between chronological and biological age in midlife and late-life is associated with cognition and dementia risk.

Methods: We used two longitudinal population-based studies: the Atherosclerosis Risk in Communities (ARIC) Study and the Multi-Ethnic Study of Atherosclerosis (MESA). PACs were created in ARIC at midlife (mean age: 58 years, 57% female, n = 11,758) and late-life (mean age: 77 years, 56% female, n = 4934) using elastic net regression models in two-thirds of dementia-free participants and validated in the remaining one-third …

Multidimensional Analysis Of B7 Homolog 3 Rna Expression In Small Cell Lung Cancer Molecular Subtypes, Carl M Gay, Taofeek K Owonikoko, Lauren A Byers, Noura J Choudhury, Sajid Ahmed, Zachary Cain, Xiaozhong Qian, Matthew Brentnall, Simon Heeke, Ming Poi, Sharon Wu, Charles M Rudin

Faculty, Staff and Student Publications

Purpose: B7 homolog 3 (B7-H3) is a promising target for antibody-drug conjugates, with ifinatamab deruxtecan demonstrating an objective response rate of 54.8% in previously treated extensive-stage small cell lung cancer (SCLC). This analysis aimed to characterize B7-H3 RNA expression with reference to SCLC molecular subtypes (SCLC-A, SCLC-N, SCLC-P, and SCLC-I) and immune-related parameters.

Experimental design: Tumor RNA expression and mutational burden for 1,721 patients with SCLC were derived from a real-world database (Caris Life Sciences). A predominant molecular subtype was assigned based on RNA expression using a gene-ratio classifier. PD-L1 expression was assessed by IHC (antibody 22C3; positive cutoff: tumor …

Large-Scale Crispr Screening In Primary Human 3d Gastric Organoids Enables Comprehensive Dissection Of Gene-Drug Interactions, Yuan-Hung Lo, Hudson T Horn, Mo-Fan Huang, Wei-Chieh Yu, Chia-Mei Young, Qing Liu, Madeline Tomaske, Martina Towers, Antonia Dominguez, Michael C Bassik, Dung-Fang Lee, Lei S Qi, Jonathan S Weissman, Jin Chen, Calvin J Kuo

Faculty, Staff and Student Publications

Understanding how genes influence drug responses is critical for advancing personalized cancer treatments. However, identifying these gene-drug interactions in a physiologically relevant human system remains a challenge, as it requires a model that reflects the complexity and heterogeneity among individuals. Here we show that large-scale CRISPR-based genetic screens, including knockout, interference (CRISPRi), activation (CRISPRa), and single-cell approaches, can be applied in primary human 3D gastric organoids to systematically identify genes that affect sensitivity to cisplatin. Our screens uncover genes that modulate cisplatin response. By combining CRISPR perturbations with single-cell transcriptomics, we resolve how genetic alterations interact with cisplatin at the …

Co-Targeting Bcl-Xl With Mcl-1 Induces Lethal Mitochondrial Dysfunction In Diffuse Mesothelioma, Yuan Xu, Cristian G Medina, Deborah R Surman, Lacey E Dobrolecki, Monica Vilchis, Maheshwari Ramineni, Susan G Hilsenbeck, Yanming Li, Naren Li, Siqi Wu, Jaylon C Aggison, Xi Chen, Yi Zhu, Ying H Shen, R Taylor Ripley

Faculty, Staff and Students Publications

Diffuse mesothelioma (DM) is a rare but highly aggressive and treatment resistant neoplasm with low survival rates. Effective therapeutic strategies are limited, and resistance to treatment is a major obstacle. Myeloid Cell Leukemia (MCL)-1 and B-cell leukemia (BCL)-xL are anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins that block cell-intrinsic apoptosis through interactions on the mitochondrial outer membrane which contribute to therapeutic resistance.

We investigated whether B-cell homology domain (BH)-3 profiles were consistent between intra-patient fresh tumor sample, patient-derived cells (PDC), and patient-derived xenografts (PDX) by BH3 profiling; we observed striking consistency which enabled cross model comparisons. Next, we co-targeted BCL-xl …

Transcriptional Remodeling Shapes Therapeutic Vulnerability To Necroptosis In Acute Lymphoblastic Leukemia, Anna Saorin, Anna Dehler, Bartimée Galvan, Fabio Steffen, Marine Ray, Dong Lu, Xin Yu, James Kim, Aneta Drakul, Samanta Kisele, Jin Wang, Jean-Pierre Bourquin, Beat C Bornhauser

Faculty, Staff and Students Publications

Insufficient eradication of cancer cells and survival of drug tolerant clones are major relapse driving forces. Underlying molecular mechanisms comprise activated prosurvival and antiapoptotic signaling, leading to insufficient apoptosis and drug resistance. The identification of programmed cell death pathways alternative to apoptosis opens up possibilities to antagonize apoptosis escape routes. We have earlier shown that acute lymphoblastic leukemia (ALL) harbors a distinct propensity to undergo cell death by receptor-interacting protein kinase 1 (RIPK1)-dependent necroptosis, activated by small-molecule second mitochondria-derived activators of caspase (SMAC) mimetics. Despite demonstrated safety and tolerability of SMAC mimetics in clinical trials, their efficacy as single agent …

One Tracer, Dual Platforms: Unlocking Versatility Of Fluorescent Probes In Tr-Fret And Nanobret Target Engagement Assays, Erika Y Monroy, Xin Yu, Dong Lu, Xiaoli Qi, Jin Wang

Faculty, Staff and Students Publications

Target engagement assays are essential for drug discovery, utilizing Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) and Nano Bioluminescence Resonance Energy Transfer (NanoBRET) as complementary methods for biochemical and cellular evaluation. Traditional platforms require distinct fluorescent tracers, increasing costs and complexity. This study systematically evaluates the cross-platform performance of T2-BODIPY-FL and T2-BODIPY-589, tracers developed for receptor-interacting protein kinase 1 (RIPK1) target engagement in TR-FRET and NanoBRET applications, respectively. Our results demonstrate both tracers effectively bridge biochemical and cellular assays, providing reliable measurements. T2-BODIPY-589 demonstrates superior performance in NanoBRET (Z’ up to 0.80) and acceptable functionality in TR-FRET (Z’=0.53). Conversely, T2-BODIPY-FL performs …

Advanced Specificity And Sensitivity Studies Relative To A Research Use Only Transcription-Mediated Amplification-Based Assay For Treponema Pallidum Rna Detection, Trinity Krueger, Grace Kadonsky, Elizabeth Thelen, Amanda Zapp, Josephine Moore, Ahmet Muslu, Allan Pillay, Irene A Stafford, Erik Munson

Faculty, Staff and Student Publications

Preliminary experimentation has suggested that a research-use-only real-time transcription-mediated amplification assay for Treponema pallidum (RUO T. pallidum TMA) yields instances of T. pallidum nucleic acid detection that coincide with non-treponemal serology in men who have sex with men (MSM) at increased risk for sexually transmitted infection. To further characterize the specificity of RUO T. pallidum TMA testing, 3,586 rectal swab specimens reported as “not detected” by the assay generated a mean endpoint FAM fluorescence of 637.5 units. Introduction of Treponema denticola, Treponema phagedenis, and Treponema refringens nucleic acid into matrices generated mean endpoint FAM fluorescence ranging from 620.7 …

Ribosome Deficiency Induces Salmonella Filamentation Within Host Cells, Zhihui Lyu, Cierra Wilson, Kalyn Weiss, Spencer Lewis, Kurt Fredrick, William Margolin, Jiqiang Ling

Faculty, Staff and Student Publications

The ribosome is the central hub for protein synthesis and is heavily targeted by antibiotics. Ribosomal mutations, antibiotic treatment, and nutrient starvation can alter translational efficiency and lead to stressed cells. Ribosome deficiency plays a critical role in stress responses and disease progression; yet, how it affects bacteria-host interactions remains poorly understood. In this study, we show that a ribosome-deficient strain exhibits a surprising morphological change from rod shape to filamentous in Salmonella cells growing inside host macrophages. Such filamentation depends on an acidic condition within macrophages and in a defined medium mimicking macrophage conditions. Further genetic analyses revealed that …

Csf-Exosomal Mirnas And Delayed Cerebral Ischemia: Insights Into Pathophysiology But No Definitive Biomarkers, Chathathayil M Shafeeque, Devin W Mcbride, Yuanqing Yan, Hussein A Zeineddine, John P Hagen, H Alex Choi, Jude P Savarraj, Ari Dienel, Spiros L Blackburn, Peeyush Kumar Thankamani

Faculty, Staff and Student Publications

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is notoriously known for its high mortality and morbidity. Approximately one-third of the patients who survive aneurysm rupture are reported to develop delayed cerebral ischemia (DCI), which contributes to a poor clinical outcome. Currently, there are no biomarkers for identifying which aSAH patients are at risk of developing DCI. We aimed to determine the feasibility of cerebrospinal fluid (CSF) exosomal microRNAs (miRNAs) for predicting DCI post-aSAH.

Methods: aSAH patients were prospectively enrolled, and CSF samples were collected at two time points (< 24 h and 72 h post-aSAH) from individuals undergoing external ventricular drainage. Exosomal miRNAs were isolated from the CSF for analysis. In the initial group of patients (discovery cohort), an exploratory analysis was conducted using a CSF panel containing 84 miRNAs, assessed by quantitative real-time PCR (RT-qPCR). Based on this analysis, 27 miRNAs were selected for further evaluation in a second group of patients (validation cohort). Among these, 10 miRNAs had previously been reported in SAH-related CSF studies, supporting their relevance for continued investigation.

Results: In this study, RT-qPCR analysis of 84 miRNAs in CSF samples from …

Reduced Computed Tomography Scan Speed Improves Alignment Errors For Patients Undergoing Thoracic Stereotactic Body Radiation Therapy, Ramaswamy Sadagopan, Rachael M Martin-Paulpeter, Christopher R Peeler, Xiaochun Wang, Paige Nitsch, Julianne M Pollard-Larkin

Faculty, Staff and Student Publications

Objectives: We investigated the performance of a slow computed tomography (CT) protocol to reduce alignment errors arising from motion when using CT-on-rail (CTOR) for image guidance for patients receiving thoracic stereotactic body radiation therapy (SBRT).

Methods: A Quasar lung phantom with a moving tumor was programmed with three breathing rates and three motion amplitudes. MIP and average 4DCT images were used for contouring and alignment, respectively. Ten CTOR images were obtained for each of the breathing rates and amplitudes, under both CT protocols. We used in-house CAT software for image guidance, centering the tumor in the lung window …

Identification Of Alkynyl Nicotinamide Hsn748 As A Ret Solvent-Front Mutant Inhibitor With Intracranial Efficacy, Ujjwol Khatri, Neetu Dayal, Kofi B Owusu, Mandeep Kaur Hunjan, Shriya Pandey, Haley Anne Harper, Carli Mcmahan, Bennett D Elzey, Tao Shen, Xueqing Hu, Kurt W Evans, Ahmed El-Sheikh, Seong Jun Jo, Frederick W Holtsberg, M Javad Aman, Funda Meric-Bernstam, Sukyung Woo, Herman O Sintim, Jie Wu

Faculty, Staff and Student Publications

RET solvent-front G810C/R/S mutations confer resistance to the currently approved RET protein tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib. Moreover, RET fusion-positive lung adenocarcinoma frequently metastasizes to the brain. To address these challenges, it is imperative to develop a RET TKI that is effective against solvent-front mutations and exhibits intracranial activity. We synthesized alkynyl nicotinamide-based RET TKIs and tested their efficacy in cell cultures in inhibiting selpercatinib/pralsetinib-resistant RET solvent-front mutants G810C/R/S found in cancer patients, and in BaF3/KIF5B-RET(G810C) cell-derived subcutaneous and intracranial tumors in vivo. We also evaluated alkynyl nicotinamide RET TKIs in KIF5B-RET-induced lung tumors in immune competent …

Defining Treatment-Resistant Bipolar Depression: Recommendations From The Isbd Task Force, Eduard Vieta, Roger S Mcintyre, Trisha Suppes, Tamsyn E Van Rheenen, Balwinder Singh, Kamilla Woznica Miskowiak, Allan H Young, Lakshmi N Yatham, Kyooseob Ha, Michael Berk, Holly A Swartz, Chantal Henry, Maja Pantovic Stefanovic, Gerard Anmella Diaz, Aysegul Ozerdem, Wiesław J Cubała, Diego Hidalgo-Mazzei, Mauricio Tohen, Isabella Pacchiarotti, Paula Villela Nunes, Carlos Lopez-Jaramillo, Ana Gonzalez-Pinto, Paolo Brambilla, Robert Post, Jair C Soares, Michael Bauer, Ana C Andreazza, Xavier Justes Fradera, Montserrat Cosials-Lopez, Giovanna Fico

Faculty, Staff and Student Publications

Objective: Despite the availability of approved treatments, a substantial proportion of patients with bipolar disorder experience treatment-resistant bipolar depression (TRBD), characterized by persistent depressive symptoms unresponsive to standard therapies. However, a universally accepted definition of TRBD is lacking. This consensus document, developed by the International Society for Bipolar Disorders (ISBD) Task Force on TRBD, aims to provide a standardized definition of TRBD to facilitate clinical trials, research, and treatment strategies.

Methods: The Task Force employed a literature review, clinical trials analysis, and expert consensus meetings to define TRBD.

Results: TRBD was defined as the failure to achieve a significant and …

Defining Treatment-Resistant Bipolar Depression: Recommendations From The Isbd Task Force, Eduard Vieta, Roger S Mcintyre, Trisha Suppes, Tamsyn E Van Rheenen, Balwinder Singh, Kamilla Woznica Miskowiak, Allan H Young, Lakshmi N Yatham, Kyooseob Ha, Michael Berk, Holly A Swartz, Chantal Henry, Maja Pantovic Stefanovic, Gerard Anmella Diaz, Aysegul Ozerdem, Wiesław J Cubała, Diego Hidalgo-Mazzei, Mauricio Tohen, Isabella Pacchiarotti, Paula Villela Nunes, Carlos Lopez-Jaramillo, Ana Gonzalez-Pinto, Paolo Brambilla, Robert Post, Jair C Soares, Michael Bauer, Ana C Andreazza, Xavier Justes Fradera, Montserrat Cosials-Lopez, Giovanna Fico

Faculty, Staff and Student Publications

Objective: Despite the availability of approved treatments, a substantial proportion of patients with bipolar disorder experience treatment-resistant bipolar depression (TRBD), characterized by persistent depressive symptoms unresponsive to standard therapies. However, a universally accepted definition of TRBD is lacking. This consensus document, developed by the International Society for Bipolar Disorders (ISBD) Task Force on TRBD, aims to provide a standardized definition of TRBD to facilitate clinical trials, research, and treatment strategies.

Methods: The Task Force employed a literature review, clinical trials analysis, and expert consensus meetings to define TRBD.

Results: TRBD was defined as the failure to achieve a significant and …

An Exciting Future For Microbial Molecular Biology And Physiology, Andrew A Bridges, Leah Guthrie, Mckenzie Lehman, Elizabeth H Kellogg, Samantha Wellington Miranda, Andrew Pountain, Anthony L Shiver, Andrew Varble, Molecular Biology And Physiology Community Of The Council On Microbial Sciences, Heidi B Kaplan, Elizabeth A Shank, Gisela Storz

Faculty, Staff and Student Publications

Continuous advances in technologies ranging from deep sequencing and genetic manipulation to mass spectrometry, single cell imaging, and structural biology have led to previously unimaginable advances in our understanding of microbial physiology and the molecular mechanisms underlying microbial responses in a multitude of environments. Simultaneously, these advances are revealing how much more there is to learn. At the 2024 virtual retreat of the Molecular Biology and Physiology (MBP) Community of the Council on Microbial Sciences (COMS) of the American Society for Microbiology (ASM), eight early-career investigators, along with retreat attendees, discussed some of these astounding advances, as well as the …

Established And Emerging Asthma Biomarkers With A Focus On Biologic Trials: A Narrative Review, Philip F Lavere, Kaitlin M Phillips, Nicola A Hanania, Muhammad Adrish

Faculty, Staff and Students Publications

Chronic airway inflammation with variable airflow obstruction is clinical asthma, and it arises from distinct molecular and pathological mechanisms called endotypes. Biomarkers allow for precise endotype characterization and have been used in clinical trials to design, monitor, and evaluate outcomes for asthma biologic therapies. This review will highlight the central and evolving role of biomarkers for past, present, and future asthma, with a focus on regulatory-approved biologic therapies and emerging biomarkers. Established biomarkers, including serum immunoglobulin E (IgE), blood eosinophils, the fraction of exhaled nitric oxide (FeNO), and serum periostin, helped elucidate the complex pathophysiology of the eosinophilic type 2 …

Macrophage Phagocytosis Of Human Norovirus-Infected Cells In An Ex Vivo Human Enteroid-Macrophage Coculture Model, Ngan Fung Li, Sue E Crawford, Sydney R Mittiga, Cristian Coarfa, Hoa Nguyen-Phuc, Budi Utama, Sarah E Blutt, Sasirekha Ramani, Mary K Estes

Faculty, Staff and Students Publications

Human norovirus (HuNoV) causes acute gastroenteritis in immunocompetent hosts and chronic infection in immunocompromised individuals. Many recent studies of replication and innate immune responses following HuNoV infection have utilized epithelium-only human intestinal enteroids (HIEs), which lack immune cells. Here, we utilized an ex vivo enteroid-macrophage coculture model consisting of HIEs and different subtypes of human peripheral blood mononuclear cell-derived macrophages to better recapitulate in vivo gut biology and explore the role of macrophages in HuNoV replication and pathogenesis. We show that HuNoV infection in HIEs polarized on Transwells leads to bilateral release of the viral genome, with predominant apical virus …

Molecular Inflammatory Expression Profiles Associated With The Frequency Of Pain In Individuals With Sickle Cell Disease, Lana Mucalo Katunaric, Shuang Jia, Ashima Singh, Mark F. Roethle, Julie A. Panepinto, David C. Brousseau, Martin J. Hessner, Amanda M. Brandow

Department of Pediatrics Faculty Papers

Pain is the most common complication of sickle cell disease (SCD). The underlying biology of SCD pain is not well understood, which is a barrier to novel, effective analgesic and preventive therapies. A wide variability in the phenotypic expression of pain exists among individuals with SCD, despite the inheritance of a similar defective hemoglobin gene. This interindividual pain variability further complicates the ability to understand the biology and effectively treat pain. We sought to discover a biological signature comprising differentially expressed genes unique to SCD that could differentiate between individuals with varied pain frequency. We conducted plasma-induced transcription analysis from …

Assessing The Muc5b Promoter Variant In A Large Cohort Of Systemic Sclerosis-Associated Interstitial Lung Disease, Carlos Rosa-Baez, Carlos Rangel-Pelaez, Inmaculada Rodriguez-Martin, Martin Kerick, Alfredo Guillen-Del-Castillo, Carmen P Simeon-Aznar, José Luis Callejas, Alexandre E Voskuyl, Alexander Kreuter, Oliver Distler, Susanna M Proudman, Mandana Nikpour, Nicolas Hunzelmann, Jeska K De Vries-Bouwstra, Ariane L Herrick, Yannick Allanore, Lorenzo Beretta, Maureen D Mayes, Christopher P Denton, Shervin Assassi, Javier Martin, Marialbert Acosta-Herrera

Faculty, Staff and Student Publications

Objective: The common gain-of-function variant rs35705950, located in the promoter of MUC5B gene, has been strongly associated with interstitial lung diseases (ILDs) of different aetiology, such as idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated ILD (RA-ILD). In this study, we aimed to investigate the association of this variant and its nearby single nucleotide polymorphisms (SNPs) in the largest cohort of systemic sclerosis-associated ILD (SSc-ILD) to date.

Methods: Samples were collected from blood/saliva, followed by DNA extraction and genotyping using SNP arrays. Data for rs35705950 and additional 903 variants within 100 Kb were obtained using genomic imputation. Subsequently, we tested their …

Extracellular Vesicles For Clinical Diagnostics: From Bulk Measurements To Single-Vesicle Analysis, Hai Linh Tran, Wenshu Zheng, David A Issadore, Hyungsoon Im, Yoon-Kyoung Cho, Yuanqing Zhang, Dingbin Liu, Yang Liu, Bo Li, Fei Liu, David Tai Wai Wong, Jiashu Sun, Kun Qian, Mei He, Meihua Wan, Yong Zeng, Ke Cheng, Tony Jun Huang, Daniel T Chiu, Luke P Lee, Lei Zheng, Andrew K Godwin, Raghu Kalluri, Steven A Soper, Tony Y Hu

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) play a crucial role in intercellular communication, signaling pathways, and disease pathogenesis by transporting biomolecules such as DNA, RNA, proteins, and lipids derived from their cells of origin, and they have demonstrated substantial potential in clinical applications. Their clinical significance underscores the need for sensitive methods to fully harness their diagnostic potential. In this comprehensive review, we explore EV heterogeneity related to biogenesis, structure, content, origin, sample type, and function roles; the use of EVs as disease biomarkers; and the evolving landscape of EV measurement for clinical diagnostics, highlighting the progression from bulk measurement to single vesicle …

The Swib Domain-Containing Dna Topoisomerase I Of Chlamydia Trachomatis Mediates Dna Relaxation, Li Shen, Abigail R. Swoboda, Caitlynn Diggs, Shomita Ferdous, Andrew Terrebonne, Amanda Santos, Noel Wolf, Luis Lorenzo Carvajal, Guangming Zhong, Scot P. Ouellette, Yuk Ching Tse-Dinh

School of Graduate Studies Faculty Publications

Chlamydia trachomatis has a DNA topoisomerase I with a unique C-terminal domain (CTD) homologous to eukaryotic SWIB domains. This study focused on determining the function of the SWIB domain-containing TopA from C. trachomatis (CtTopA). We demonstrated that, despite the lack of sequence similarity at the CTDs between CtTopA and TopA from Escherichia coli (EcTopA), full-length CtTopA removed negative DNA supercoils in vitro and complemented the growth defect of a topA mutant of E. coli. CtTopA is less processive in DNA relaxation than EcTopA in dose-response and time course studies. An antibody generated against the SWIB domain of CtTopA specifically recognized …