Medical Specialties Commons^™

Repeated Out-Of-Africa Expansions Of Helicobacter Pylori Driven By Replacement Of Deleterious Mutations, Harry A Thorpe, Elise Tourrette, Koji Yahara, Filipa F Vale, Siqi Liu, Mónica Oleastro, Teresa Alarcon, Tsachi-Tsadok Perets, Saeid Latifi-Navid, Yoshio Yamaoka, Beatriz Martinez-Gonzalez, Ioannis Karayiannis, Timokratis Karamitros, Dionyssios N Sgouras, Wael Elamin, Ben Pascoe, Samuel K Sheppard, Jukka Ronkainen, Pertti Aro, Lars Engstrand, Lars Agreus, Sebastian Suerbaum, Kaisa Thorell, Daniel Falush

Faculty, Staff and Students Publications

Helicobacter pylori lives in the human stomach and has a population structure resembling that of its host. However, H. pylori from Europe and the Middle East trace substantially more ancestry from modern African populations than the humans that carry them. Here, we use a collection of Afro-Eurasian H. pylori genomes to show that this African ancestry is due to at least three distinct admixture events. H. pylori from East Asia, which have undergone little admixture, have accumulated many more non-synonymous mutations than African strains. European and Middle Eastern bacteria have elevated African ancestry at the sites of these mutations, implying …

Clinical And In Vitro Evidence Favoring Immunoglobulin Treatment Of A Chronic Norovirus Infection In A Patient With Common Variable Immunodeficiency, Jeroen J A Van Kampen, Virgil A S H Dalm, Pieter L A Fraaij, Bas B Oude Munnink, Claudia M E Schapendonk, Ray W Izquierdo-Lara, Nele Villabruna, Khalil Ettayebi, Mary K Estes, Marion P G Koopmans, Miranda De Graaf

Faculty, Staff and Students Publications

BACKGROUND: Immunocompromised individuals can become chronically infected with norovirus, but effective antiviral therapies are not yet available.

METHODS: Treatments with nitazoxanide, ribavirin, interferon alpha-2a, and nasoduodenally administered immunoglobulins were evaluated sequentially in an immunocompromised patient chronically infected with norovirus. In support, these components were also applied to measure norovirus inhibition in intestinal enteroid cultures in vitro. Viral RNA levels were determined in fecal and plasma samples during each treatment and viral genomes were sequenced.

RESULTS: None of the antivirals resulted in a reduction of viral RNA levels in feces or plasma. However, during ribavirin treatment, there was an increased accumulation …

De Novo Identification Of Microbial Contaminants In Low Microbial Biomass Microbiomes With Squeegee, Yunxi Liu, R A Leo Elworth, Michael D Jochum, Kjersti M Aagaard, Todd J Treangen

Faculty, Staff and Students Publications

Computational analysis of host-associated microbiomes has opened the door to numerous discoveries relevant to human health and disease. However, contaminant sequences in metagenomic samples can potentially impact the interpretation of findings reported in microbiome studies, especially in low-biomass environments. Contamination from DNA extraction kits or sampling lab environments leaves taxonomic "bread crumbs" across multiple distinct sample types. Here we describe Squeegee, a de novo contamination detection tool that is based upon this principle, allowing the detection of microbial contaminants when negative controls are unavailable. On the low-biomass samples, we compare Squeegee predictions to experimental negative control data and show that …

Assessing The Contribution Of Rare Genetic Variants To Phenotypes Of Chronic Obstructive Pulmonary Disease Using Whole-Genome Sequence Data, Wonji Kim, Julian Hecker, R Graham Barr, Eric Boerwinkle, Brian Cade, Adolfo Correa, Josée Dupuis, Sina A Gharib, Leslie Lange, Stephanie J London, Alanna C Morrison, George T O'Connor, Elizabeth C Oelsner, Bruce M Psaty, Ramachandran S Vasan, Susan Redline, Stephen S Rich, Jerome I Rotter, Bing Yu, Christoph Lange, Ani Manichaikul, Jin J Zhou, Tamar Sofer, Edwin K Silverman, Dandi Qiao, Michael H Cho, Nhlbi Trans-Omics In Precision Medicine (Topmed) Consortium And Topmed Lung Working Group

Faculty, Staff and Students Publications

Rationale: Genetic variation has a substantial contribution to chronic obstructive pulmonary disease (COPD) and lung function measurements. Heritability estimates using genome-wide genotyping data can be biased if analyses do not appropriately account for the nonuniform distribution of genetic effects across the allele frequency and linkage disequilibrium (LD) spectrum. In addition, the contribution of rare variants has been unclear.

Objectives: We sought to assess the heritability of COPD and lung function using whole-genome sequence data from the Trans-Omics for Precision Medicine program.

Methods: Using the genome-based restricted maximum likelihood method, we partitioned the genome into bins based on minor allele frequency …

Sars-Cov-2 Incubation Period According To Vaccination Status During The Fifth Covid-19 Wave In A Tertiary-Care Center In Spain: A Cohort Study, Jordi Cortés Martínez, Daewoo Pak, Gabriela Abelenda-Alonso, Klaus Langohr, Jing Ning, Alexander Rombauts, Mireia Colom, Yu Shen, Guadalupe Gómez Melis

Faculty, Staff and Student Publications

Background: The incubation period of an infectious disease is defined as the elapsed time between the exposure to the pathogen and the onset of symptoms. Although both the mRNA-based and the adenoviral vector-based vaccines have shown to be effective, there have been raising concerns regarding possible decreases in vaccine effectiveness for new variants and variations in the incubation period.

Methods: We conducted a unicentric observational study at the Hospital Universitari de Bellvitge, Barcelona, using a structured telephone survey performed by trained interviewers to estimate the incubation period of the SARS-CoV-2 Delta variant in a cohort of Spanish hospitalized patients. The …

Multi-Organ Segmentation Of Abdominal Structures From Non-Contrast And Contrast Enhanced Ct Images, Cenji Yu, Chidinma P Anakwenze, Yao Zhao, Rachael M Martin, Ethan B Ludmir, Joshua S Niedzielski, Asad Qureshi, Prajnan Das, Emma B Holliday, Ann C Raldow, Callistus M Nguyen, Raymond P Mumme, Tucker J Netherton, Dong Joo Rhee, Skylar S Gay, Jinzhong Yang, Laurence E Court, Carlos E Cardenas

Faculty, Staff and Student Publications

Manually delineating upper abdominal organs at risk (OARs) is a time-consuming task. To develop a deep-learning-based tool for accurate and robust auto-segmentation of these OARs, forty pancreatic cancer patients with contrast-enhanced breath-hold computed tomographic (CT) images were selected. We trained a three-dimensional (3D) U-Net ensemble that automatically segments all organ contours concurrently with the self-configuring nnU-Net framework. Our tool's performance was assessed on a held-out test set of 30 patients quantitatively. Five radiation oncologists from three different institutions assessed the performance of the tool using a 5-point Likert scale on an additional 75 randomly selected test patients. The mean (± …

Conducting A Supportive Oncology Clinical Trial During The Covid-19 Pandemic: Challenges And Strategies, Jie Deng, John N. Lukens, Joy C. Cohn, Erin Mcmenamin, Barbara Murphy, Bryan A. Spinelli, Niya Murphy, Alicia K. Steinmetz, Megan A. Landriau, Alexander Lin

Department of Physical Therapy Faculty Papers

The coronavirus disease 2019 (COVID-19) pandemic resulted in severe interruptions to clinical research worldwide. This global public health crisis required investigators and researchers to rapidly develop and implement new strategies and solutions to mitigate its negative impact on the progress of clinical trials. In this paper, we describe the challenges, strategies, and lessons learned regarding the continuation of a supportive oncology clinical trial during the pandemic. We hope to provide insight into the implementation of clinical trials during a public health emergency to be better prepared for future instances.

Trial registration: ClinicalTrials.gov, a service of the US National Institute of …

Omics Analyses Of A Somatic Trp53r245w/+ Breast Cancer Model Identify Cooperating Driver Events Activating Pi3k/Akt/Mtor Signaling, Xiaojie Yu, Yun Zhang, Shunbin Xiong, Joy M Mcdaniel, Chang Sun, Gilda P Chau, Jovanka Gencel-Augusto, Dhruv Chachad, Rhiannon L Morrissey, Xiayu Rao, Jing Wang, Guillermina Lozano

Faculty, Staff and Student Publications

Alterations of the tumor suppressor

Antibody-Drug Conjugates For The Treatment Of Her2-Positive Breast Cancer, Mariana K Najjar, Sara G Manore, Angelina T Regua, Hui-Wen Lo

Faculty, Staff and Student Publications

Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20–30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted …

A High-Resolution 3d Atlas Of The Spectrum Of Tuberculous Andcovid-19 Lung Lesions, Gordon Wells, Joel N Glasgow, Kievershen Nargan, Kapongo Lumamba, Rajhmun Madansein, Kameel Maharaj, Leon Y Perumal, Malcolm Matthew, Robert L Hunter, Hayden Pacl, Jacelyn E Peabody Lever, Denise D Stanford, Satinder P Singh, Prachi Bajpai, Upender Manne, Paul V Benson, Steven M Rowe, Stephan Le Roux, Alex Sigal, Muofhe Tshibalanganda, Carlyn Wells, Anton Du Plessis, Mpumelelo Msimang, Threnesan Naidoo, Adrie J C Steyn

Faculty, Staff and Student Publications

Our current understanding of the spectrum of TB and COVID-19 lesions in the human lung is limited by a reliance on low-resolution imaging platforms that cannot provide accurate 3D representations of lesion types within the context of the whole lung. To characterize TB and COVID-19 lesions in 3D, we applied micro/nanocomputed tomography to surgically resected, postmortem, and paraffin-embedded human lung tissue. We define a spectrum of TB pathologies, including cavitary lesions, calcium deposits outside and inside necrotic granulomas and mycetomas, and vascular rearrangement. We identified an unusual spatial arrangement of vasculature within an entire COVID-19 lobe, and 3D segmentation of …

A Randomized Pilot Study Of Oncology Massage To Treat Chemotherapy-Induced Peripheral Neuropathy, Gabriel Lopez, Cathy Eng, Michael Overman, David Ramirez, Wenli Liu, Curtiss Beinhorn, Pamela Sumler, Sarah Prinsloo, Yisheng Li, Minxing Chen, Eduardo Bruera, Lorenzo Cohen

Faculty, Staff and Student Publications

This pilot randomized controlled trial investigated massage therapy for symptomatic relief of chemotherapy-induced peripheral neuropathy (CIPN) to determine the ideal weekly frequency and number of weeks of providing massage. We evaluated the feasibility and initial efficacy of a Swedish massage protocol to treat lower extremity (LE) CIPN. Inclusion criteria: LE neuropathy attributed to oxaliplatin, paclitaxel, or docetaxel, with no other attributable causes; ≥ 6 months since last chemotherapy; self-reported neuropathy score ≥ 3, 0-10 scale; age ≥ 18. Participant randomization (2:2:1:1) to one of four groups: LE (2) or head/neck/shoulder (control; 1) massage 3 times (3X) a week for 4 …

Prevalence Of Sleep-Related Problems And Risks In A Community-Dwelling Older Adult Population: A Cross-Sectional Survey-Based Study, Nancy P Gordon, Jimmy H Yao, Leslea A Brickner, Joan C Lo

Faculty, Staff and Student Publications

BACKGROUND: Despite evidence of adverse health consequences of inadequate restorative sleep for older adults, assessment of sleep quantity, quality, and use of sleep aids is not routinely done. We aimed to characterize sleep problems, sleep risks, and advice received about sleep in a community-dwelling older adult population, overall and in subgroups with health conditions and functional difficulties.

METHODS: This cross-sectional study used weighted self-report data for 5074 Kaiser Permanente Northern California members aged 65-79y who responded to a 2017 or 2020 Member Health Survey. We estimated usual amount of sleep (< 6, 6 to < 7, ≥7 hours) and prevalence of sleep problems (frequent insomnia, frequent daytime fatigue, poor quality sleep, and potential sleep apnea (OSA) symptoms (frequent very loud snoring, apnea episodes)) for older adults overall, by self-rated health, and in subgroups reporting hypertension, diabetes, heart disease, frequent problems with balance/walking, and frequent memory problems. We also estimated percentages who regularly used sleep aids and had discussed sleep adequacy with a healthcare professional in the past year.

RESULTS: Approximately 30% of older adults usually got less …

Association Between Preoperative Hemodialysis Timing And Postoperative Mortality In Patients With End-Stage Kidney Disease, Vikram Fielding-Singh, Matthew W Vanneman, Tristan Grogan, Jacques P Neelankavil, Wolfgang C Winkelmayer, Tara I Chang, Vincent X Liu, Eugene Lin

Faculty, Staff and Students Publications

Importance: For patients with end-stage kidney disease treated with hemodialysis, the optimal timing of hemodialysis prior to elective surgical procedures is unknown.

Objective: To assess whether a longer interval between hemodialysis and subsequent surgery is associated with higher postoperative mortality in patients with end-stage kidney disease treated with hemodialysis.

Design, setting, and participants: Retrospective cohort study of 1 147 846 procedures among 346 828 Medicare beneficiaries with end-stage kidney disease treated with hemodialysis who underwent surgical procedures between January 1, 2011, and September 30, 2018. Follow-up ended on December 31, 2018.

Exposures: One-, two-, or three-day intervals between the most …

The Nogo Receptor Ngr2, A Novel Αvβ3 Integrin Effector, Induces Neuroendocrine Differentiation In Prostate Cancer, Fabio Quaglia, Shiv Ram Krishn, Khalid Sossey-Alaoui, Priyanka Shailendra Rana, Elzbieta Pluskota, Pyung Hun Park, Christopher D. Shields, Stephen Lin, Peter Mccue, Andrew V. Kossenkov, Yanqing Wang, David W. Goodrich, Sheng-Yu Ku, Himisha Beltran, William K. Kelly, Eva Corey, Maja Klose, Christine Bandtlow, Qin Liu, Dario C. Altieri, Edward F. Plow, Lucia R. Languino

Department of Cancer Biology Faculty Papers

Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, …

Polygenic Risk Score Improves The Accuracy Of A Clinical Risk Score For Coronary Artery Disease, Austin King, Lang Wu, Hong-Wen Deng, Hui Shen, Chong Wu

Faculty, Staff and Student Publications

BACKGROUND: The value of polygenic risk scores (PRSs) towards improving guideline-recommended clinical risk models for coronary artery disease (CAD) prediction is controversial. Here we examine whether an integrated polygenic risk score improves the prediction of CAD beyond pooled cohort equations. METHODS: An observation study of 291,305 unrelated White British UK Biobank participants enrolled from 2006 to 2010 was conducted. A case-control sample of 9499 prevalent CAD cases and an equal number of randomly selected controls was used for tuning and integrating of the polygenic risk scores. A separate cohort of 272,307 individuals (with follow-up to 2020) was used to examine …

High-Contrast Detection Of Somatostatin Receptor Subtype-2 For Fluorescence-Guided Surgery, Servando Hernandez Vargas, Solmaz Aghaamiri, Sukhen C Ghosh, Michael P Luciano, Luis C Borbon, Po Hien Ear, James R Howe, Jennifer M Bailey-Lundberg, Gregory D Simonek, Daniel M Halperin, Hop S Tran Cao, Naruhiko Ikoma, Martin J Schnermann, Ali Azhdarinia

Faculty, Staff and Student Publications

Dye design can influence the ability of fluorescently labeled imaging agents to generate tumor contrast and has become an area of significant interest in the field of fluorescence-guided surgery (FGS). Here, we show that the charge-balanced near-infrared fluorescent (NIRF) dye FNIR-Tag enhances the imaging properties of a fluorescently labeled somatostatin analogue.

Prognostic Performance Of Cystatin C In Covid-19: A Systematic Review And Meta-Analysis, Michal Matuszewski, Yurii Reznikov, Michal Pruc, Frank W Peacock, Alla Navolokina, Raúl Júarez-Vela, Lukasz Jankowski, Zubaid Rafique, Lukasz Szarpak

Faculty, Staff and Students Publications

Cystatin C is a specific biomarker of kidney function. We perform this meta-analysis to determine the association of Cystatin C with the COVID-19 severity. In this systematic review and meta-analysis, we searched PubMed, EMBASE, Cochrane library, and Web of Science for studies published until 2nd September 2022 that reported associations between Cystatin C levels and COVID-19 severity. The analysis was performed using a random-effects model to calculate pooled standard mean difference (SMD). Twenty-five studies were included in the meta-analysis. Pooled analysis showed statistically significant differences of Cystatin C levels among survive vs. decreased patients (0.998 ± 0.225 vs. 1.328 ± …

Elective Surgery System Strengthening: Development, Measurement, And Validation Of The Surgical Preparedness Index Across 1632 Hospitals In 119 Countries, Nihr Global Health Unit On Global Surgery, Covidsurg Collaborative

Faculty, Staff and Student Publications

BACKGROUND: The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index to support local elective surgical system strengthening and address growing backlogs.

METHODS: First, we performed an international consultation through a four-stage consensus process to develop a multidomain index for hospital-level assessment (surgical preparedness index; SPI). Second, we measured surgical preparedness across a global network of hospitals in high-income countries (HICs), …

Blockade Of Fgf2/Fgfr2 Partially Overcomes Bone Marrow Mesenchymal Stromal Cells Mediated Progression Of T-Cell Acute Lymphoblastic Leukaemia, Chen Tian, Yueyang Li, Lina Wang, Junqi Si, Yaxin Zheng, Junnan Kang, Yafei Wang, M James You, Guoguang Zheng

Faculty, Staff and Student Publications

The development of acute lymphoblastic leuakemia (ALL) is partly attributed to the effects of bone marrow (BM) microenvironment, especially mesenchymal stromal cells (MSCs), which interact bilaterally with leukaemia cells, leading to ALL progression. In order to find MSCs-based microenvironment targeted therapeutic strategies, Notch1-induced T-cell ALL (T-ALL) mice models were used and dynamic alterations of BM-MSCs with increased cell viability during T-ALL development was observed. In T-ALL mice derived stroma-based condition, leukaemia cells showed significantly elevated growth capacity indicating that MSCs participated in leukaemic niche formation. RNA sequence results revealed that T-ALL derived MSCs secreted fibroblast growth factor 2 (FGF2), which …

Metformin Increases Natural Killer Cell Functions In Head And Neck Squamous Cell Carcinoma Through Cxcl1 Inhibition, Mckenzie Crist, Benyamin Yaniv, Sarah Palackdharry, Maria A. Lehn, Mario Medvedovic, Timothy Stone, Shuchi Gulati, Vidhya Karivedu, Michael Borchers, Bethany Fuhrman, Audrey Crago, Joseph Curry, Ubaldo Martinez-Outschoorn, Vinita Takiar, Trisha M. Wise-Draper

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

BACKGROUND: Metformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692).

METHODS: Peripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell …

Characterization Of Bcma Expression In Circulating Rare Single Cells Of Patients With Plasma Cell Neoplasms, Libere J Ndacayisaba, Kate E Rappard, Stephanie N Shishido, Sonia M Setayesh, Guilin Tang, Pei Lin, Nicholas Matsumoto, Ching-Ju Hsu, Rafael Nevarez, Carmen Ruiz Velasco, Amin Naghdloo, Eric Yang, Kevin Kelly, James Hicks, Jeremy Mason, Robert Z Orlowski, Elisabet E Manasanch, Peter Kuhn

Faculty, Staff and Student Publications

B-cell maturation antigen (BCMA), a key regulator of B-cell proliferation and survival, is highly expressed in almost all cases of plasma cell neoplasms and B-lymphoproliferative malignancies. BCMA is a robust biomarker of plasma cells and a therapeutic target with substantial clinical significance. However, the expression of BCMA in circulating tumor cells of patients with hematological malignancies has not been validated for the detection of circulating plasma and B cells. The application of BCMA as a biomarker in single-cell detection and profiling of circulating tumor cells in patients' blood could enable early disease profiling and therapy response monitoring. Here, we report …

Antibiotic Exposure Does Not Impact Immune Checkpoint Blockade Response In Msi-H/Dmmr Metastatic Colorectal Cancer: A Single-Center Experience, Victoria Serpas Higbie, Jane Rogers, Hyunsoo Hwang, Wei Qiao, Lianchun Xiao, Arvind Dasari, Kerri Mola-Rudd, Van K Morris, Robert A Wolff, Kanwal Raghav, Ryan Huey, Christine Parseghian, Jason Willis, Scott Kopetz, Michael J Overman, Benny Johnson

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint blockade (ICB) has improved outcomes for patients with microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) tumors. However, not all MSI-H/dMMR patients will exhibit the same ICB efficacy. Previous studies suggest that concomitant antibiotic use while receiving ICB may result in poorer outcomes. We aimed to evaluate this association in patients with MSI-H/dMMR metastatic colorectal cancer (mCRC).

MATERIALS AND METHODS: A single-site, retrospective review of 57 patients with MSI-H/dMMR mCRC that received ICB was completed. Data collected included patient demographics, ICB information, and antibiotic use. Antibiotic exposure was considered from 90 days prior to ICB through 6 weeks …

Injury To The Posterior Horn Of The Lateral Meniscus From A Misplaced Tibial Tunnel For Anterior Cruciate Ligament Reconstruction: A Case Report, Amar S Vadhera, Jonathan S Lee, Harsh Singh, Safa Gursoy, Kyle N Kunze, Nikhil N Verma, Jorge Chahla

Department of Orthopaedic Surgery Faculty Papers

BACKGROUND Posterior meniscal root avulsions can cause meniscal extrusion, joint space narrowing, and progressive knee arthritis. Iatrogenic posterior meniscal root avulsions after malpositioning of the transtibial tunnels during anterior cruciate ligament (ACL) reconstruction can account for poor long-term outcomes seen in some patients following ACL reconstruction. Therefore, correct transtibial tunnel placement during ACL reconstruction is essential to avoid iatrogenic meniscal damage. CASE REPORT A 32-year-old man presented with 1 year of right knee pain and instability following a non-contact twisting injury sustained while playing soccer. An ACL tear with no meniscal involvement was diagnosed at an outside institution. A double-bundle …

A Comprehensive Review On Nutraceuticals: Therapy Support And Formulation Challenges, Vivek Puri, Manju Nagpal, Inderbir Singh, Manjinder Singh, Gitika Arora Dhingra, Kampanart Huanbutta, Divya Dheer, Ameya Sharma, Tanikan Sangnim

Faculty, Staff and Student Publications

Nutraceuticals are the nourishing components (hybrid of nutrition and pharmaceuticals) that are biologically active and possess capability for maintaining optimal health and benefits. These products play a significant role in human health care and its endurance, most importantly for the future therapeutic development. Nutraceuticals have received recognition due to their nutritional benefits along with therapeutic effects and safety profile. Nutraceuticals are globally growing in the field of services such as health care promotion, disease reduction, etc. Various drug nutraceutical interactions have also been elaborated with various examples in this review. Several patents on nutraceuticals in agricultural applications and in various …

Dll3 As An Emerging Target For The Treatment Of Neuroendocrine Neoplasms, James Yao, Emily Bergsland, Rahul Aggarwal, Ana Aparicio, Himisha Beltran, Judy S Crabtree, Christine L Hann, Toni Ibrahim, Lauren A Byers, Hironobu Sasano, John Umejiego, Marianne Pavel

Faculty, Staff and Student Publications

INTRODUCTION: Neuroendocrine neoplasms (NEN) are heterogeneous malignancies that can arise at almost any anatomical site and are classified as biologically distinct well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Current systemic therapies for advanced disease, including targeted therapies, chemotherapy, and immunotherapy, are associated with limited duration of response. New therapeutic targets are needed. One promising target is delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch receptor whose overexpression on the surface of NEN is associated with tumorigenesis.

METHODS: This article is a narrative review that highlights the role of DLL3 in NEN progression and prognosis, the …

Evaluation Of Mrna-1273 Vaccine In Children 6 Months To 5 Years Of Age, Evan J Anderson, C Buddy Creech, Vladimir Berthaud, Arin Piramzadian, Kimball A Johnson, Marcus Zervos, Fredric Garner, Carl Griffin, Khozema Palanpurwala, Mark Turner, Jeffrey Gerber, Richard L Bennett, Kashif Ali, Madhavi Ampajwala, Gary Berman, Jennifer Nayak, Carey Chronis, Barbara Rizzardi, William J Muller, Christopher A Smith, George Fuchs, Daniel Hsia, Joanne E Tomassini, Dianne Delucia, Caroline Reuter, Barbara Kuter, Xiaoping Zhao, Weiping Deng, Honghong Zhou, Daniela Ramirez Schrempp, Kelly Hautzinger, Bethany Girard, Karen Slobod, Roderick Mcphee, Rolando Pajon, Anne Aunins, Rituparna Das, Jacqueline M Miller, Sabine Schnyder Ghamloush, Kidcove Study Group

Faculty, Staff and Student Publications

BACKGROUND: The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children are unknown.

METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-μg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these …

Epacadostat Plus Pembrolizumab And Chemotherapy For Advanced Solid Tumors: Results From The Phase I/Ii Echo-207/Keynote-723 Study, John D Powderly, Samuel J Klempner, Aung Naing, Johanna Bendell, Ignacio Garrido-Laguna, Daniel V T Catenacci, Matthew H Taylor, James J Lee, Fred Zheng, Feng Zhou, Xiaohua Gong, Hema Gowda, Gregory L Beatty

Faculty, Staff and Student Publications

Background: Epacadostat, an oral, selective inhibitor of IDO1, has shown activity when administered with pembrolizumab. We evaluated the addition of chemotherapy to epacadostat and pembrolizumab in patients with advanced or metastatic solid tumors. One proposed mechanism of resistance to PD-1 checkpoint inhibition is through immunosuppression mediated by L-kynurenine. IDO1, indoleamine-2,3-dioxygenase 1 is the rate-limiting enzyme catalyzing the conversion of L-tryptophan to L-kynurenine. If IDO1 is a mechanism of tumor escape from checkpoint inhibition, then addition of an IDO1 inhibitor with a PD-1 checkpoint inhibitor could enable tumor response to immunotherapy.

Methods: Patients received one of 7 tumor-appropriate chemotherapy regimens. Pembrolizumab …

Microrna Analysis In Maternal Blood Of Pregnancies With Preterm Premature Rupture Of Membranes Reveals A Distinct Expression Profile, Michail Spiliopoulos, Andrew Haddad, Huda B Al-Kouatly, Saeed Haleema, Michael J Paidas, Sara N Iqbal, Robert I Glazer

Department of Obstetrics and Gynecology Faculty Papers

OBJECTIVE: To determine the expression profile of microRNAs in the peripheral blood of pregnant women with preterm premature rupture of membranes (PPROM) compared to that of healthy pregnant women.

STUDY DESIGN: This was a pilot study with case-control design in pregnant patients enrolled between January 2017 and June 2019. Patients with healthy pregnancies and those affected by PPROM between 20- and 33+6 weeks of gestation were matched by gestational age and selected for inclusion to the study. Patients were excluded for multiple gestation and presence of a major obstetrical complication such as preeclampsia, diabetes, fetal growth restriction and stillbirth. A …

Hormonal Therapies Up-Regulate Manf And Overcome Female Susceptibility To Immune Checkpoint Inhibitor Myocarditis, Yaohua Zhang, Chengcao Sun, Yajuan Li, Juan Qin, Kaushik Amancherla, Ying Jing, Qingsong Hu, Ke Liang, Zhao Zhang, Youqiong Ye, Lisa A Huang, Tina K Nguyen, Sergey D Egranov, Zilong Zhao, Andrew Wu, Yutao Xi, Jun Yao, Mien-Chie Hung, George A Calin, Jie Cheng, Bora Lim, Lorenz H Lehmann, Joe-Elie Salem, Douglas B Johnson, Michael A Curran, Dihua Yu, Leng Han, Radbod Darabi, Liuqing Yang, Javid J Moslehi, Chunru Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis …

The Single-Cell Immunogenomic Landscape Of B And Plasma Cells In Early-Stage Lung Adenocarcinoma, Dapeng Hao, Guangchun Han, Ansam Sinjab, Lorena Isabel Gomez-Bolanos, Rossana Lazcano, Alejandra Serrano, Sharia D Hernandez, Enyu Dai, Xuanye Cao, Jian Hu, Minghao Dang, Ruiping Wang, Yanshuo Chu, Xingzhi Song, Jianhua Zhang, Edwin R Parra, Jennifer A Wargo, Stephen G Swisher, Tina Cascone, Boris Sepesi, Andrew P Futreal, Mingyao Li, Steven M Dubinett, Junya Fujimoto, Luisa M Solis Soto, Ignacio I Wistuba, Christopher S Stevenson, Avrum Spira, Shabnam Shalapour, Humam Kadara, Linghua Wang

Faculty, Staff and Student Publications

Tumor-infiltrating B and plasma cells (TIB) are prevalent in lung adenocarcinoma (LUAD); however, they are poorly characterized. We performed paired single-cell RNA and B-cell receptor (BCR) sequencing of 16 early-stage LUADs and 47 matching multiregion normal tissues. By integrative analysis of ∼50,000 TIBs, we define 12 TIB subsets in the LUAD and adjacent normal ecosystems and demonstrate extensive remodeling of TIBs in LUADs. Memory B cells and plasma cells (PC) were highly enriched in tumor tissues with more differentiated states and increased frequencies of somatic hypermutation. Smokers exhibited markedly elevated PCs and PCs with distinct differentiation trajectories. BCR clonotype diversity …