Digital Commons Network^™

An Atlas Of Healthy And Injured Cell States And Niches In The Human Kidney, Blue B Lake, Amanda Knoten, Bo Zhang, Diane Salamon, Anitha Vijayan, Eric H Kim, Joseph P Gaut, Sanjay Jain, Et Al.

2020-Current year OA Pubs

Understanding kidney disease relies on defining the complexity of cell types and states, their associated molecular profiles and interactions within tissue neighbourhoods

Organization Of The Human Intestine At Single-Cell Resolution, John W Hickey, Zhengyan Zhang, Yiing Lin, Et Al.

2020-Current year OA Pubs

The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall health

An Rrna Fragment In Extracellular Vesicles Secreted By Human Airway Epithelial Cells Increases The Fluoroquinolone Sensitivity Of P. Aeruginosa, Katja Koeppen, Thomas H Hampton, Roxanna Barnaby, Carolyn Roche, Scott A Gerber, Young Ah Goo, Byoung-Kyu Cho, Danielle M Vermilyea, Deborah A Hogan, Bruce A Stanton

2020-Current year OA Pubs

Lung infections caused by antibiotic-resistant strains of

The Impact Of Essential Trace Elements On Ovarian Response And Reproductive Outcomes Following Single Euploid Embryo Transfer, Roberto Gonzalez-Martin, Andrea Palomar, Alicia Quiñonero, Nuria Pellicer, Rocio Fernandez-Saavedra, Estefania Conde-Vilda, Alberto J Quejido, Christine Whitehead, Richard T. Scott, Francisco Dominguez

Department of Medicine Faculty Papers

Essential trace elements are required in extremely small amounts and obtained through diet. This research focuses on detecting major trace elements in different biofluids of sixty women undergoing ICSI with PGT-A and SET/FET at IVI-RMA, New Jersey, and assessing their impact on their IVF outcomes. Urine, plasma, and follicular fluid samples were collected on the vaginal oocyte retrieval day to measure the concentrations of eight essential trace elements (copper, zinc, molybdenum, lithium, selenium, manganese, chromium, and iron) using ICP-MS. After analysis, ovarian response and preimplantation outcomes had significant positive associations with both copper alone and the copper/zinc ratio in the …

What Were The Information Voids? A Qualitative Analysis Of Questions Asked By Dear Pandemic Readers Between August 2020-August 2021, Rachael Piltch-Loeb, Richard James, Sandra S. Albrecht, Alison M. Buttenheim, Jennifer Beam Dowd, Aparna Kumar, Malia Jones, Lindsey J. Leininger, Amanda Simanek, Shoshana Aronowitz

College of Nursing Faculty Papers & Presentations

In the current infodemic, how individuals receive information (channel), who it is coming from (source), and how it is framed can have an important effect on COVID-19 related mitigation behaviors. In light of these challenges presented by the infodemic, Dear Pandemic (DP) was created to directly address persistent questions related to COVID-19 and other health topics in the online environment. This is a qualitative analysis of 3806 questions that were submitted by DP readers to a question box on the Dear Pandemic website between August 30, 2020 and August 29, 2021. Analyses resulted in four themes: the need for clarification …

Privacy Preserving Identification Of Population Stratification For Collaborative Genomic Research, Leonard Dervishi, Wenbiao Li, Anisa Halimi, Xiaoqian Jiang, Jaideep Vaidya, Erman Ayday

Faculty, Staff and Student Publications

The rapid improvements in genomic sequencing technology have led to the proliferation of locally collected genomic datasets. Given the sensitivity of genomic data, it is crucial to conduct collaborative studies while preserving the privacy of the individuals. However, before starting any collaborative research effort, the quality of the data needs to be assessed. One of the essential steps of the quality control process is population stratification: identifying the presence of genetic difference in individuals due to subpopulations. One of the common methods used to group genomes of individuals based on ancestry is principal component analysis (PCA). In this article, we …

Microrna-145 And Microrna-486 Are Potential Serum Biomarkers For Vascular Calcification, Sara Fernández-Villabrille, Beatriz Martín-Carro, Julia Martín-Vírgala, Cristina Alonso-Montes, Carmen Palomo-Antequera, Raúl García-Castro, Susana López-Ongil, Adriana S Dusso, José Luis Fernández-Martín, Manuel Naves-Díaz, Jorge B Cannata-Andía, Natalia Carrillo-López, Sara Panizo

2020-Current year OA Pubs

INTRODUCTION: MicroRNAs (miRs) regulate vascular calcification (VC), and their quantification may contribute to suspicion of the presence of VC.

METHODS: The study was performed in four phases. Phase 1: miRs sequencing of rat calcified and non-calcified aortas. Phase 2: miRs with the highest rate of change, plus miR-145 [the most abundant miR in vascular smooth muscle cells (VSMCs)], were validated in aortas and serum from rats with and without VC. Phase 3: the selected miRs were analyzed in epigastric arteries from kidney donors and recipients, and serum samples from general population. Phase 4: VSMCs were exposed to different phosphorus concentrations, …

A Phase I Study Of Milademetan (Ds3032b) In Combination With Low Dose Cytarabine With Or Without Venetoclax In Acute Myeloid Leukemia: Clinical Safety, Efficacy, And Correlative Analysis, Jayastu Senapati, Muharrem Muftuoglu, Jo Ishizawa, Hussein A Abbas, Sanam Loghavi, Gautam Borthakur, Musa Yilmaz, Ghayas C Issa, Samuel I Dara, Mahesh Basyal, Li Li, Kiran Naqvi, Rasoul Pourebrahim, Elias J Jabbour, Steven M Kornblau, Nicholas J Short, Naveen Pemmaraju, Guillermo Garcia-Manero, Farhad Ravandi, Joseph Khoury, Naval Daver, Hagop M Kantarjian, Michael Andreeff, Courtney D Dinardo

Faculty, Staff and Student Publications

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 …

A Phase I Study Of Milademetan (Ds3032b) In Combination With Low Dose Cytarabine With Or Without Venetoclax In Acute Myeloid Leukemia: Clinical Safety, Efficacy, And Correlative Analysis, Jayastu Senapati, Muharrem Muftuoglu, Jo Ishizawa, Hussein A Abbas, Sanam Loghavi, Gautam Borthakur, Musa Yilmaz, Ghayas C Issa, Samuel I Dara, Mahesh Basyal, Li Li, Kiran Naqvi, Rasoul Pourebrahim, Elias J Jabbour, Steven M Kornblau, Nicholas J Short, Naveen Pemmaraju, Guillermo Garcia-Manero, Farhad Ravandi, Joseph Khoury, Naval Daver, Hagop M Kantarjian, Michael Andreeff, Courtney D Dinardo

Faculty, Staff and Student Publications

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, …

G Protein-Coupled Receptor-Targeting Antibody-Drug Conjugates: Current Status And Future Directions, Peyton High, Kendra S Carmon

Faculty, Staff and Student Publications

In recent years, antibody-drug conjugates (ADCs) have emerged as promising anti-cancer therapeutic agents with several having already received market approval for the treatment of solid tumor and hematological malignancies. As ADC technology continues to improve and the range of indications treatable by ADCs increases, the repertoire of target antigens has expanded and will undoubtedly continue to grow. G protein-coupled receptors (GPCRs) are well-characterized therapeutic targets implicated in many human pathologies, including cancer, and represent a promising emerging target of ADCs. In this review, we will discuss the past and present therapeutic targeting of GPCRs and describe ADCs as therapeutic modalities. …

A Novel Peptide 'T14' Reflects Age And Photo-Aging In Human Skin, Sheila Rocha, Sara Garcia Ratés, Tumisang Moswete, Kristopher Kalleberg, Anna Villa, Jason P Harcup, Susan A Greenfield

Faculty, Staff and Student Publications

T14 is a 14mer peptide derived from the C-terminus of acetylcholinesterase (AChE). Once cleaved, it is independently bioactive of the parent molecule and enhances calcium influx in different cell types, in a range of scenarios: it binds to an allosteric site selectively on the alpha-7 receptor, where it modulates calcium influx and is thus a potential trophic agent, as already reported in a range of normal developmental scenarios. However, if inappropriately activated, this erstwhile beneficial effect converts to a toxic one, resulting in pathologies as disparate as Alzheimer’s and various metastatic cancers. Given that epidermal keratinocyte cells have the same …

Hdac1 Regulates The Chromatin Landscape To Control Transcriptional Dependencies In Chronic Lymphocytic Leukemia, Tzung-Huei Lai, Hatice Gulcin Ozer, Pierluigi Gasparini, Giovanni Nigita, Rosario Distefano, Lianbo Yu, Janani Ravikrishnan, Selen Yilmaz, Juan Gallegos, Sachet Shukla, Vinay Puduvalli, Jennifer Woyach, Rosa Lapalombella, James Blachly, John C Byrd, Deepa Sampath

Faculty, Staff and Student Publications

Chronic lymphocytic leukemia (CLL) is a quiescent B-cell malignancy that depends on transcriptional dysregulation for survival. The histone deacetylases are transcriptional regulators whose role within the regulatory chromatin and consequence on the CLL transcriptome is poorly characterized. Here, we profiled and integrated the genome-wide occupancy of HDAC1, BRD4, H3K27Ac, and H3K9Ac signals with chromatin accessibility, Pol2 occupancy, and target expression signatures in CLL cells. We identified that when HDAC1 was recruited within super-enhancers (SEs) marked by acetylated H3K27 and BRD4, it functioned as a transcriptional activator that drove the de novo expression of select genes to facilitate survival and progression …

Hyperphosphorylation Of The Group A Streptococcal Control Of Virulence Regulator Increases Promoter Occupancy Specifically At Virulence Factor-Encoding Genes, Nicola Horstmann, Chau Nguyen Tran, Anthony R Flores, Samuel A Shelburne

Faculty, Staff and Student Publications

The control of virulence two-component gene regulatory system (CovRS) is critical to the pathogenesis of many medically important streptococci. In emm1 group A streptococci (GAS), CovR directly binds the promoters of numerous GAS virulence factor-encoding genes. Elimination of CovS phosphatase activity increases CovR phosphorylation (CovR~P) levels and abrogates GAS virulence. Given the emm type-specific diversity of CovRS function, in this study we used chromatin immunoprecipitation sequencing (ChIP-seq) to define global CovR DNA occupancy in the wild-type emm3 strain MGAS10870 (medium CovR~P) and its CovS phosphatase-negative derivative 10870-CovS-T284A (high CovR~P). In the wild-type emm3 strain, 89% of the previously identified emm1 …

Neuraminidase Activity Modulates Cellular Coinfection During Influenza A Virus Multicycle Growth, Zijian Guo, Yuanyuan He, Jian Xu, Ananya N. Benegal, Steven L. Brody, Michael D. Vahey

2020-Current year OA Pubs

Infection of individual cells by multiple virions plays critical roles in the replication and spread of many viruses, but mechanisms that control cellular coinfection during multicycle viral growth remain unclear. Here, we investigate virus-intrinsic factors that control cellular coinfection by influenza A virus (IAV). Using quantitative fluorescence to track the spread of virions from single infected cells, we identify the IAV surface protein neuraminidase (NA) as a key determinant of cellular coinfection. We map this effect to NA's ability to deplete viral receptors from both infected and neighboring uninfected cells. In cases in which viral infectious potential is low, genetic …

The Long Non-Coding Rna Neat1 Is A Δnp63 Target Gene Modulating Epidermal Differentiation, Claudia Fierro, Veronica Gatti, Veronica La Banca, Sara De Domenico, Stefano Scalera, Giacomo Corleone, Maurizio Fanciulli, Francesca De Nicola, Alessandro Mauriello, Manuela Montanaro, George A Calin, Gerry Melino, Angelo Peschiaroli

Faculty, Staff and Student Publications

The transcription factor ΔNp63 regulates epithelial stem cell function and maintains the integrity of stratified epithelial tissues by acting as transcriptional repressor or activator towards a distinct subset of protein-coding genes and microRNAs. However, our knowledge of the functional link between ∆Np63 transcriptional activity and long non-coding RNAs (lncRNAs) expression is quite limited. Here, we show that in proliferating human keratinocytes ∆Np63 represses the expression of the lncRNA NEAT1 by recruiting the histone deacetylase HDAC1 to the proximal promoter of NEAT1 genomic locus. Upon induction of differentiation, ∆Np63 down-regulation is associated by a marked increase of NEAT1 RNA levels, resulting …

Design And Validation Of A Low-Cost Mobile Eeg-Based Brain-Computer Interface, Alexander Craik, Juan José González-España, Ayman Alamir, David Edquilang, Sarah Wong, Lianne Sánchez Rodríguez, Jeff Feng, Gerard E Francisco, Jose L Contreras-Vidal

Faculty, Staff and Student Publications

Objective: We designed and validated a wireless, low-cost, easy-to-use, mobile, dry-electrode headset for scalp electroencephalography (EEG) recordings for closed-loop brain–computer (BCI) interface and internet-of-things (IoT) applications.

Approach: The EEG-based BCI headset was designed from commercial off-the-shelf (COTS) components using a multi-pronged approach that balanced interoperability, cost, portability, usability, form factor, reliability, and closed-loop operation.

Main Results: The adjustable headset was designed to accommodate 90% of the population. A patent-pending self-positioning dry electrode bracket allowed for vertical self-positioning while parting the user’s hair to ensure contact of the electrode with the scalp. In the current prototype, five EEG electrodes were incorporated …

Integrative Genetic Approach Facilitates Precision Strategies For Acute Myocardial Infarction, Muzamil Khawaja, Rehma Siddiqui, Salim S Virani, Christopher I Amos, Dhrubajyoti Bandyopadhyay, Hafeez Ul Hassan Virk, Mahboob Alam, Hani Jneid, Chayakrit Krittanawong

Faculty, Staff and Students Publications

Acute myocardial infarction remains a significant cause of mortality worldwide and its burden continues to grow. Its pathophysiology is known to be complex and multifactorial, with several acquired and inherited risk factors. As advances in technology and medical therapy continue, there is now increasing recognition of the role that genetics play in the development and management of myocardial infarction. The genetic determinants of acute coronary syndrome are still vastly understudied, but the advent of whole-genome scanning and genome-wide association studies has significantly expanded the current understanding of genetics and simultaneously fostered hope that genetic profiling and gene-guided treatments could substantially …

On The Dependent Recognition Of Some Long Zinc Finger Proteins., Zheng Zuo, Timothy Billings, Michael Walker, Petko M. Petkov, Polly M Fordyce, Gary D Stormo

Faculty Research 2023

The human genome contains about 800 C2H2 zinc finger proteins (ZFPs), and most of them are composed of long arrays of zinc fingers. Standard ZFP recognition model asserts longer finger arrays should recognize longer DNA-binding sites. However, recent experimental efforts to identify in vivo ZFP binding sites contradict this assumption, with many exhibiting short motifs. Here we use ZFY, CTCF, ZIM3, and ZNF343 as examples to address three closely related questions: What are the reasons that impede current motif discovery methods? What are the functions of those seemingly unused fingers and how can we improve the motif discovery algorithms based …

Researching Covid To Enhance Recovery (Recover) Adult Study Protocol: Rationale, Objectives, And Design, Leora I Horwitz, Tanayott Thaweethai, Shari B Brosnahan, Mine S Cicek, Megan L Fitzgerald, Jason D Goldman, Rachel Hess, S L Hodder, Vanessa L Jacoby, Michael R Jordan, Jerry A Krishnan, Adeyinka O Laiyemo, Torri D Metz, Lauren Nichols, Rachel E Patzer, Anisha Sekar, Nora G Singer, Lauren E Stiles, Barbara S Taylor, Shifa Ahmed, Heather A Algren, Khamal Anglin, Lisa Aponte-Soto, Hassan Ashktorab, Ingrid V Bassett, Brahmchetna Bedi, Nahid Bhadelia, Christian Bime, Marie-Abele C Bind, Lora J Black, Andra L Blomkalns, Hassan Brim, Mario Castro, James Chan, Alexander W Charney, Benjamin K Chen, Li Qing Chen, Peter Chen, David Chestek, Lori B Chibnik, Dominic C Chow, Helen Y Chu, Rebecca G Clifton, Shelby Collins, Maged M Costantine, Sushma K Cribbs, Steven G Deeks, John D Dickinson, Sarah E Donohue, Matthew S Durstenfeld, Ivette F Emery, Kristine M Erlandson, Julio C Facelli, Rachael Farah-Abraham, Aloke V Finn, Melinda S Fischer, Valerie J Flaherman, Judes Fleurimont, Vivian Fonseca, Emily J Gallagher, Jennifer C Gander, Maria Laura Gennaro, Kelly S Gibson, Minjoung Go, Steven N Goodman, Joey P Granger, Frank L Greenway, John W Hafner, Jenny E Han, Michelle S Harkins, Kristine S P Hauser, James R Heath, Carla R Hernandez, On Ho, Matthew K Hoffman, Susan E Hoover, Carol R Horowitz, Harvey Hsu, Priscilla Y Hsue, Brenna L Hughes, Prasanna Jagannathan, Judith A James, Janice John, Sarah Jolley, S E Judd, Joy J Juskowich, Diane G Kanjilal, Elizabeth W Karlson, Stuart D Katz, J Daniel Kelly, Sara W Kelly, Arthur Y Kim, John P Kirwan, Kenneth S Knox, Andre Kumar, Michelle F Lamendola-Essel, Margaret Lanca, Joyce K Lee-Lannotti, R Craig Lefebvre, Bruce D Levy, Janet Y Lin, Brian P Logarbo, Jennifer K Logue, Michele T Longo, Carlos A Luciano, Karen Lutrick, Shahdi K Malakooti, Gail Mallett, Gabrielle Maranga, Jai G Marathe, Vincent C Marconi, Gailen D Marshall, Christopher F Martin, Jeffrey N Martin, Heidi T May, Grace A Mccomsey, Dylan Mcdonald, Hector Mendez-Figueroa, Lucio Miele, Murray A Mittleman, Sindhu Mohandas, Christian Mouchati, Janet M Mullington, Girish N Nadkarni, Erica R Nahin, Robert B Neuman, Lisa T Newman, Amber Nguyen, Janko Z Nikolich, Igho Ofotokun, Princess U Ogbogu, Anna Palatnik, Kristy T S Palomares, Tanyalak Parimon, Samuel Parry, Sairam Parthasarathy, Thomas F Patterson, Ann Pearman, Michael J Peluso, Priscilla Pemu, Christian M Pettker, Beth A Plunkett, Kristen Pogreba-Brown, Athena Poppas, J Zachary Porterfield, John G Quigley, Davin K Quinn, Hengameh Raissy, Candida J Rebello, Uma M Reddy, Rebecca Reece, Harrison T Reeder, Franz P Rischard, Johana M Rosas, Clifford J Rosen, Nadine G Rouphael, Dwight J Rouse, Adam M Ruff, Christina Saint Jean, Grecio J Sandoval, Jorge L Santana, Shannon M Schlater, Frank C Sciurba, Caitlin Selvaggi, Sudha Seshadri, Howard D Sesso, Dimpy P Shah, Eyal Shemesh, Zaki A Sherif, Daniel J Shinnick, Hyagriv N Simhan, Upinder Singh, Amber Sowles, Vignesh Subbian, Jun Sun, Mehul S Suthar, Larissa J Teunis, John M Thorp, Amberly Ticotsky, Alan T N Tita, Robin Tragus, Katherine R Tuttle, Alfredo E Urdaneta, P J Utz, Timothy M Vanwagoner, Andrew Vasey, Suzanne D Vernon, Crystal Vidal, Tiffany Walker, Honorine D Ward, David E Warren, Ryan M Weeks, Steven J Weiner, Jordan C Weyer, Jennifer L Wheeler, Sidney W Whiteheart, Zanthia Wiley, Natasha J Williams, Juan P Wisnivesky, John C Wood, Lynn M Yee, Natalie M Young, Sokratis N Zisis, Andrea S Foulkes

Faculty, Staff and Student Publications

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. …

On The Dependent Recognition Of Some Long Zinc Finger Proteins, Zheng Zuo, Timothy Billings, Michael Walker, Petko M Petkov, Polly M Fordyce, Gary D Stormo

2020-Current year OA Pubs

The human genome contains about 800 C2H2 zinc finger proteins (ZFPs), and most of them are composed of long arrays of zinc fingers. Standard ZFP recognition model asserts longer finger arrays should recognize longer DNA-binding sites. However, recent experimental efforts to identify in vivo ZFP binding sites contradict this assumption, with many exhibiting short motifs. Here we use ZFY, CTCF, ZIM3, and ZNF343 as examples to address three closely related questions: What are the reasons that impede current motif discovery methods? What are the functions of those seemingly unused fingers and how can we improve the motif discovery algorithms based …

Female Athlete Health Domains: A Supplement To The International Olympic Committee Consensus Statement On Methods For Recording And Reporting Epidemiological Data On Injury And Illness In Sport., Isabel S Moore, Kay M Crossley, Kari Bo, Margo Mountjoy, Kathryn E Ackerman, Juliana Da Silva Antero, Jorunn Sundgot Borgen, Wendy J Brown, Caroline S Bolling, Benjamin Clarsen, Wayne Derman, Paul Dijkstra, Amber Donaldson, Kirsty J Elliott-Sale, Carolyn A Emery, Lene Haakstad, Astrid Junge, Nonhlanhla S Mkumbuzi, Sophia Nimphius, Debbie Palmer, Mireille Van Poppel, Jane S Thornton, Rita Tomás, Phathokuhle C Zondi, Evert Verhagen

Family Medicine Publications

The IOC made recommendations for recording and reporting epidemiological data on injuries and illness in sports in 2020, but with little, if any, focus on female athletes. Therefore, the aims of this supplement to the IOC consensus statement are to (i) propose a taxonomy for categorisation of female athlete health problems across the lifespan; (ii) make recommendations for data capture to inform consistent recording and reporting of symptoms, injuries, illnesses and other health outcomes in sports injury epidemiology and (iii) make recommendations for specifications when applying the Strengthening the Reporting of Observational Studies in Epidemiology-Sport Injury and Illness Surveillance (STROBE-SIIS) …

Heterogeneity In The Effect Of Marked Weight Loss On Metabolic Function In Women With Obesity, Bettina Mittendorfer, Brandon D. Kayser, Mihoko Yoshino, Jun Yoshino, Jeramie D. Watrous, Mohit Jain, J. Christopher Eagon, Bruce W. Patterson, Samuel Klein

2020-Current year OA Pubs

BACKGROUNDThere is considerable heterogeneity in the effect of weight loss on metabolic function in people with obesity.METHODSWe evaluated muscle and liver insulin sensitivity, body composition, and circulating factors associated with insulin action before and after approximately 20% weight loss in women identified as "Responders" (n = 11) or "Non-responders" (n = 11), defined as the top (>75% increase) and bottom (<5% increase) quartiles of the weight loss-induced increase in glucose disposal rate (GDR) during a hyperinsulinemic-euglycemic clamp procedure, among 43 women with obesity (BMI: 44.1 ± 7.9 kg/m2).RESULTSAt baseline, GDR, which provides an index of muscle insulin sensitivity, and the hepatic insulin sensitivity index were more than 50% lower in Responders than Non-responders, but both increased much more after weight loss in Responders than Non-responders, which eliminated the differences between groups. Weight loss also caused greater decreases in intrahepatic triglyceride content and plasma adiponectin and PAI-1 concentrations in Responders than Non-responders and greater insulin-mediated suppression of plasma free fatty acids, branched-chain amino acids, and C3/C5 acylcarnitines in Non-responders than Responders, so that differences between groups at baseline were no longer present after weight loss. The effect of weight loss on total body fat mass, intra-abdominal adipose tissue volume, adipocyte size, and circulating inflammatory markers were not different between groups.CONCLUSIONThe results from our study demonstrate that the heterogeneity in the effects of marked weight loss on muscle and hepatic insulin sensitivity in people with obesity is determined by baseline insulin action, and reaches a ceiling when "normal" insulin action is achieved.TRIAL REGISTRATIONNCT00981500, NCT01299519, NCT02207777.FUNDINGNIH grants P30 DK056341, P30 DK020579, P30 DK052574, UL1 TR002345, and T32 HL13035, the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation (2019-011), and the Atkins Philanthropic Trust.

Β Cell Function After Roux-En-Y Gastric Bypass Surgery Or Reduced Energy Intake Alone In People With Obesity, Bettina Mittendorfer, Bruce W. Patterson, Faidon Magkos, Mihoko Yoshino, David P. Bradley, J. Christopher Eagon, Samuel Klein

2020-Current year OA Pubs

BackgroundThe effects of diet-induced weight loss (WL) and WL after Roux-en-Y gastric bypass (RYGB) surgery on β cell function (BCF) are unclear because of conflicting results from different studies, presumably because of differences in the methods used to measure BCF, the amount of WL between treatment groups, and baseline BCF. We evaluated the effect of WL after RYGB surgery or reduced energy intake alone on BCF in people with obesity with and without type 2 diabetes.MethodsBCF (insulin secretion in relationship to plasma glucose) was assessed before and after glucose or mixed-meal ingestion before and after (a) progressive amounts (6%, 11%, …

Blm Overexpression As A Predictive Biomarker For Chk1 Inhibitor Response In Parp Inhibitor-Resistant Brca-Mutant Ovarian Cancer, Nitasha Gupta, Tzu-Ting Huang, Jayakumar R Nair, Daniel An, Grant Zurcher, Erika J Lampert, Ann Mccoy, Ashley Cimino-Mathews, Elizabeth M Swisher, Marc R Radke, Christina M Lockwood, Jonathan B Reichel, Chih-Yuan Chiang, Kelli M Wilson, Ken Chih-Chien Cheng, Darryl Nousome, Jung-Min Lee

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene (BRCA)–mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib …

An Improved Reporter Identifies Ruxolitinib As A Potent And Cardioprotective Camkii Inhibitor, Oscar E Reyes Gaido, Nikoleta Pavlaki, Jonathan M Granger, Olurotimi O Mesubi, Bian Liu, Brian L Lin, Alan Long, David Walker, Joshua Mayourian, Kate L Schole, Chantelle E Terrillion, Lubika J Nkashama, Mohit M Hulsurkar, Lauren E Dorn, Kimberly M Ferrero, Richard L Huganir, Frank U Müller, Xander H T Wehrens, Jun O Liu, Elizabeth D Luczak, Vassilios J Bezzerides, Mark E Anderson

Faculty, Staff and Students Publications

Ca2+/calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits of CaMKII inhibition in numerous preclinical models of heart disease, translation of CaMKII antagonists into humans has been stymied by low potency, toxicity, and an enduring concern for adverse effects on cognition due to an established role of CaMKII in learning and memory. To address these challenges, we asked whether any clinically approved drugs, developed for other purposes, were potent CaMKII inhibitors. For this, we engineered an improved fluorescent reporter, CaMKAR (CaMKII activity reporter), which features superior sensitivity, kinetics, and …

Impact Of Food Environments On Obesity Rates: A State-Level Analysis., Elizabeth Cerceo, Elena Sharma, Anne Boguslavsky, Jean-Sebastian Rachoin

Cooper Medical School of Rowan University Departmental Research

INTRODUCTION: Limited access to healthy food in areas that are predominantly food deserts or food swamps may be associated with obesity. Other unhealthy behaviors may also be associated with obesity and poor food environments.

METHODS: We calculated Modified Retail Food Environment Index (mRFEI) to assess food retailers. Using data collected from the Behavioral Risk Factor Surveillance System (BRFSS) survey, the NJ Department of Health (NJDOH), and the US Census Bureau, we conducted a cross-sectional analysis of the interaction of obesity with the food environment and assessed smoking, leisure-time physical activity (LPA), and poor sleep.

RESULTS: There were 17.9% food deserts …

Using Ai-Generated Suggestions From Chatgpt To Optimize Clinical Decision Support, Siru Liu, Aileen P Wright, Barron L Patterson, Jonathan P Wanderer, Robert W Turer, Scott D Nelson, Allison B Mccoy, Dean F Sittig, Adam Wright

Faculty, Staff and Student Publications

OBJECTIVE: To determine if ChatGPT can generate useful suggestions for improving clinical decision support (CDS) logic and to assess noninferiority compared to human-generated suggestions.

METHODS: We supplied summaries of CDS logic to ChatGPT, an artificial intelligence (AI) tool for question answering that uses a large language model, and asked it to generate suggestions. We asked human clinician reviewers to review the AI-generated suggestions as well as human-generated suggestions for improving the same CDS alerts, and rate the suggestions for their usefulness, acceptance, relevance, understanding, workflow, bias, inversion, and redundancy.

RESULTS: Five clinicians analyzed 36 AI-generated suggestions and 29 human-generated suggestions …

Tumor Biology And Immune Infiltration Define Primary Liver Cancer Subsets Linked To Overall Survival After Immunotherapy, Anuradha Budhu, Erica C Pehrsson, Aiwu He, Lipika Goyal, Robin Kate Kelley, Hien Dang, Changqing Xie, Cecilia Monge, Mayank Tandon, Lichun Ma, Mahler Revsine, Laura Kuhlman, Karen Zhang, Islam Baiev, Ryan Lamm, Keyur Patel, David E Kleiner, Stephen M Hewitt, Bao Tran, Jyoti Shetty, Xiaolin Wu, Yongmei Zhao, Tsai-Wei Shen, Sulbha Choudhari, Yuliya Kriga, Kris Ylaya, Andrew C Warner, Elijah F Edmondson, Marshonna Forgues, Tim F Greten, Xin Wei Wang

Kimmel Cancer Center Faculty Papers

Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond to immune checkpoint inhibitors is of great interest in the field. In a retrospective arm of the National Cancer Institute Cancers of the Liver: Accelerating Research of Immunotherapy by a Transdisciplinary Network (NCI-CLARITY) study, we use archived formalin-fixed, paraffin-embedded samples to profile the transcriptome and genomic alterations among 86 hepatocellular carcinoma and cholangiocarcinoma patients prior to and following immune checkpoint inhibitor treatment. …

Arginine Depletion Attenuates Renal Cystogenesis In Tuberous Sclerosis Complex Model, Athar Amleh, Hadass Pri Chen, Lana Watad, Ifat Abramovich, Bella Agranovich, Eyal Gottlieb, Iddo Z Ben-Dov, Morris Nechama, Oded Volovelsky

Faculty, Staff and Student Publications

Cystic kidney disease is a leading cause of morbidity in patients with tuberous sclerosis complex (TSC). We characterize the misregulated metabolic pathways using cell lines, a TSC mouse model, and human kidney sections. Our study reveals a substantial perturbation in the arginine biosynthesis pathway in TSC models with overexpression of argininosuccinate synthetase 1 (ASS1). The rise in ASS1 expression is dependent on the mechanistic target of rapamycin complex 1 (mTORC1) activity. Arginine depletion prevents mTORC1 hyperactivation and cell cycle progression and averts cystogenic signaling overexpression of c-Myc and P65. Accordingly, an arginine-depleted diet substantially reduces the TSC cystic load in …

Long-Term Outcomes And Molecular Correlates Of Sotorasib Efficacy In Patients With Pretreated Kras G12c-Mutated Non–Small-Cell Lung Cancer: 2-Year Analysis Of Codebreak 100, Grace K Dy, Ramaswamy Govindan, Vamsidhar Velcheti, Gerald S Falchook, Antoine Italiano, Jürgen Wolf, Adrian G Sacher, Toshiaki Takahashi, Suresh S Ramalingam, Christophe Dooms, Dong-Wan Kim, Alfredo Addeo, Jayesh Desai, Martin Schuler, Pascale Tomasini, David S Hong, Piro Lito, Qui Tran, Simon Jones, Abraham Anderson, Antreas Hindoyan, Wendy Snyder, Ferdinandos Skoulidis, Bob T Li

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

In the longest follow-up, to our knowledge, for a KRAS^G12C inhibitor, we assessed the long-term efficacy, safety, and biomarkers of sotorasib in patients with KRAS G12C-mutated advanced non–small-cell lung cancer (NSCLC) from the CodeBreaK 100 clinical …