Digital Commons Network^™

Genome-Wide Analysis Of The Interplay Between Chromatin-Associated Rna And 3d Genome Organization In Human Cells, Riccardo Calandrelli, Xingzhao Wen, John Lalith Charles Richard, Zhifei Luo, Tri C Nguyen, Chien-Ju Chen, Zhijie Qi, Shuanghong Xue, Weizhong Chen, Zhangming Yan, Weixin Wu, Kathia Zaleta-Rivera, Rong Hu, Miao Yu, Yuchuan Wang, Wenbo Li, Jian Ma, Bing Ren, Sheng Zhong

Faculty, Staff and Student Publications

The interphase genome is dynamically organized in the nucleus and decorated with chromatin-associated RNA (caRNA). It remains unclear whether the genome architecture modulates the spatial distribution of caRNA and vice versa. Here, we generate a resource of genome-wide RNA-DNA and DNA-DNA contact maps in human cells. These maps reveal the chromosomal domains demarcated by locally transcribed RNA, hereafter termed RNA-defined chromosomal domains. Further, the spreading of caRNA is constrained by the boundaries of topologically associating domains (TADs), demonstrating the role of the 3D genome structure in modulating the spatial distribution of RNA. Conversely, stopping transcription or acute depletion of RNA …

Investigating Associations Of Omega-3 Fatty Acids, Lung Function Decline, And Airway Obstruction, Bonnie K Patchen, Pallavi Balte, Traci M Bartz, R Graham Barr, Myriam Fornage, Mariaelisa Graff, David R Jacobs, Ravi Kalhan, Rozenn N Lemaitre, George O'Connor, Bruce Psaty, Jungkyun Seo, Michael Y Tsai, Alexis C Wood, Hanfei Xu, Jingwen Zhang, Sina A Gharib, Ani Manichaikul, Kari North, Lyn M Steffen, Josée Dupuis, Elizabeth Oelsner, Dana B Hancock, Patricia A Cassano

Faculty, Staff and Student Publications

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and may benefit lung health.

Objectives: To investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in a diverse sample of adults from general-population cohorts.

Methods: Complementary study designs: 1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV1 and FVC measures in the NHLBI Pooled Cohorts Study and 2) two-sample Mendelian randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters.

Measurements and Main Results: The …

Possible Delayed Foreign Body Reactions Against Titanium Clips And Coating Materials After Unruptured Cerebral Aneurysm Surgery, Ryota Tatezawa, Taku Sugiyama, Shuho Gotoh, Takafumi Shindo, Hiroshi Ikeda, Masaaki Hokari, Katsumi Takizawa, Naoki Nakayama, Miki Fujimura

Faculty, Staff and Student Publications

Delayed foreign body reactions to either or both clipping and coating materials have been reported in several small series; however, studies in the titanium clip era are scarce. This study aims to survey the contemporary status of such reactions to titanium clips and coating materials. Among patients who received a total of 2327 unruptured cerebral aneurysmal surgeries, 12 developed delayed intraparenchymal reactions during outpatient magnetic resonance imaging (MRI) follow-up. A retrospective investigation was conducted. The patients' average age was 58.6 (45-73) years, and 11 were women. The aneurysms were located in the middle cerebral artery (n = 7), internal carotid …

Stroke Recovery Is A Journey: Prediction And Potentials Of Motor Recovery After A Stroke From A Practical Perspective, Sheng Li

Faculty, Staff and Student Publications

Stroke recovery is a journey. Stroke survivors can face many consequences that may last the rest of their lives. Assessment of initial impairments allows reasonable prediction of biological spontaneous recovery at 3 to 6 months for a majority of survivors. In real-world clinical practice, stroke survivors continue to improve their motor function beyond the spontaneous recovery period, but management plans for maximal recovery are not well understood. A model within the international classification of functioning (ICF) theoretical framework is proposed to systematically identify opportunities and potential barriers to maximize and realize the potentials of functional recovery from the acute to …

Us Adolescent Rest-Activity Patterns: Insights From Functional Principal Component Analysis (Nhanes 2011-2014), Chris Ho Ching Yeung, Jiachen Lu, Erica G Soltero, Cici Bauer, Qian Xiao

Faculty, Staff and Student Publications

BACKGROUND: Suboptimal rest-activity patterns in adolescence are associated with worse health outcomes in adulthood. Understanding sociodemographic factors associated with rest-activity rhythms may help identify subgroups who may benefit from interventions. This study aimed to investigate the association of rest-activity rhythm with demographic and socioeconomic characteristics in adolescents.

METHODS: Using cross-sectional data from the nationally representative National Health and Nutrition Examination Survey (NHANES) 2011-2014 adolescents (N = 1814), this study derived rest-activity profiles from 7-day 24-hour accelerometer data using functional principal component analysis. Multiple linear regression was used to assess the association between participant characteristics and rest-activity profiles. Weekday and weekend …

Tuberculosis Presentation And Outcomes In Older Hispanic Adults From Tamaulipas, Mexico, Belinda A Medrano, Miryoung Lee, Gretchen Gemeinhardt, Javier E Rodríguez-Herrera, Moncerrato García-Viveros, Blanca I Restrepo

Faculty, Staff and Student Publications

Older people are at high risk of developing and dying from pulmonary infections like tuberculosis (TB), but there are few studies among them, particularly in Hispanics. To address these gaps, we sought to identify host factors associated with TB and adverse treatment outcomes in older Hispanics by conducting a cross-sectional study of TB surveillance data from Tamaulipas, Mexico (2006-2013; n = 8381). Multivariable logistic regressions were assessed for older adults (OA ≥65 years) when compared to young (YA, 18-39 years) and middle-aged adults (40-64 years). We found that the OA had features associated with a less complicated TB (e.g., lower …

Effect Of Abutment Tooth Location On The Accuracy Of Digital Impressions Obtained Using An Intraoral Scanner For Removable Partial Dentures, Kazuki Sakamoto, Junichiro Wada, Yuki Arai, Hironari Hayama, Yurika Ishioka, Eung-Yeol Kim, Ryunosuke Kazama, Yusuke Toyoshima, Noriyuki Wakabayashi

Faculty, Staff and Student Publications

Purpose: To verify the effect of abutment tooth location on the accuracy of digital impressions obtained using an intraoral scanner (IOS) for removable partial dentures (RPDs).

Methods: The target abutment teeth included the left first premolar (#34), second molar (#37), and right second premolar (#45) in a mandibular Kennedy class II model and the left and right second molars (#37, #47) in a class III model. Only #37 was isolated from the remaining teeth by the mucosal area in both models. Digital impressions were obtained using a desktop scanner (reference data) and an IOS (IOS data; scanning origin #37; n=10). …

Efficacy And Safety Of Mas825 (Anti-Il-1Β/Il-18) In Covid-19 Patients With Pneumonia And Impaired Respiratory Function, Alex D Hakim, Mustafa Awili, Hollis R O'Neal, Omar Siddiqi, Naseem Jaffrani, Richard Lee, Jeffrey S Overcash, Ann Chauffe, Terese C Hammond, Bela Patel, Michael Waters, Gerard J Criner, Alok Pachori, Guido Junge, Rafael Levitch, Jen Watts, Philip Koo, Tirtha Sengupta, Lili Yu, Michael Kiffe, Anne Pinck, Richard R Stein, Jamie Bendrick-Peart, Janet Jenkins, Marianna Rowlands, Frank Waldron-Lynch, Jesse Matthews

Faculty, Staff and Student Publications

MAS825, a bispecific IL-1β/IL-18 monoclonal antibody, could improve clinical outcomes in COVID-19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized non-ventilated patients with COVID-19 pneumonia (n = 138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on the day of discharge (whichever was earlier) with worst-case imputation for death. Other study endpoints included safety, C-reactive protein (CRP), SARS-CoV-2 presence, and inflammatory markers. On Day 15, the APACHE II score was 14.5 …

Guide-Specific Loss Of Efficiency And Off-Target Reduction With Cas9 Variants, Liang Zhang, Wei He, Rongjie Fu, Shuyue Wang, Yiwen Chen, Han Xu

Faculty, Staff and Student Publications

High-fidelity clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) variants have been developed to reduce the off-target effects of CRISPR systems at a cost of efficiency loss. To systematically evaluate the efficiency and off-target tolerance of Cas9 variants in complex with different single guide RNAs (sgRNAs), we applied high-throughput viability screens and a synthetic paired sgRNA-target system to assess thousands of sgRNAs in combination with two high-fidelity Cas9 variants HiFi and LZ3. Comparing these variants against wild-type SpCas9, we found that ∼20% of sgRNAs are associated with a significant loss of efficiency when complexed with either HiFi or LZ3. …

Novobiocin Blocks Nucleic Acid Binding To Polθ And Inhibits Stimulation Of Its Atpase Activity, Aleem Syed, Frantisek Filandr, Jeffrey Patterson-Fortin, Albino Bacolla, Ramya Ravindranathan, Jia Zhou, Drew T Mcdonald, Mohammed E Albuhluli, Amy Verway-Cohen, Joseph A Newman, Miaw-Sheue Tsai, Darin E Jones, David C Schriemer, Alan D D'Andrea, John A Tainer

Faculty, Staff and Student Publications

Polymerase theta (Polθ) acts in DNA replication and repair, and its inhibition is synthetic lethal in BRCA1 and BRCA2-deficient tumor cells. Novobiocin (NVB) is a first-in-class inhibitor of the Polθ ATPase activity, and it is currently being tested in clinical trials as an anti-cancer drug. Here, we investigated the molecular mechanism of NVB-mediated Polθ inhibition. Using hydrogen deuterium exchange-mass spectrometry (HX-MS), biophysical, biochemical, computational and cellular assays, we found NVB is a non-competitive inhibitor of ATP hydrolysis. NVB sugar group deletion resulted in decreased potency and reduced HX-MS interactions, supporting a specific NVB binding orientation. Collective results revealed that NVB …

Reap-2: An Interactive Quantitative Tool For Robust And Efficient Dose-Response Curve Estimation, Xinying Fang, Xinyi Liu, Vernon M Chinchilli, Michael Wang, Hong-Gang Wang, Nikolay V Dokholyan, Chan Shen, J Jack Lee, Shouhao Zhou

Faculty, Staff and Student Publications

REAP-2 is an interactive dose-response curve estimation tool for Robust and Efficient Assessment of drug Potency. It provides user-friendly dose-response curve estimation for in vitro studies and conducts statistical testing for model comparisons with a redesigned user interface. We also make a major update of the underlying estimation method with penalized beta regression, which demonstrates great reliability and accuracy in dose estimation and uncertainty quantification. In this note, we describe the method and implementation of REAP-2 with a highlight on potency estimation and drug comparison.

Bacterial And Fungal Characterization Of Pancreatic Adenocarcinoma From Endoscopic Ultrasound-Guided Biopsies, Robin D Wright, Thais F Bartelli, Seyda Baydogan, James Robert White, Michael P Kim, Manoop S Bhutani, Florencia Mcallister

Faculty, Staff and Student Publications

INTRODUCTION: The tumor microbiome (TM) has been linked to pancreatic cancer prognosis. Specific microbes can confer tumor resistance to therapies. Early knowledge of the TM at time of diagnosis would be clinically relevant for precision therapy based on microbial composition. However, it is difficult to define the TM prior to surgical resection.

METHODS: In this pilot feasibility study, patients underwent Endoscopic Ultrasound-Fine Needle Aspiration (EUS-FNA) biopsy of pancreatic adenocarcinoma. These samples were analyzed using 16S rRNA and internal transcribed spacer (ITS) sequencing for characterization of the tumor bacteria and fungi.

RESULT: After in silico decontamination and comparison to non-matched tumor, …

Cancer Origin Tracing And Timing In Two High-Risk Prostate Cancers Using Multisample Whole Genome Analysis: Prospects For Personalized Medicine, Anssi Nurminen, Serafiina Jaatinen, Sinja Taavitsainen, Gunilla Högnäs, Tom Lesluyes, Naser Ansari-Pour, Teemu Tolonen, Kerstin Haase, Antti Koskenalho, Matti Kankainen, Juho Jasu, Hanna Rauhala, Jenni Kesäniemi, Tiia Nikupaavola, Paula Kujala, Irina Rinta-Kiikka, Jarno Riikonen, Antti Kaipia, Teemu Murtola, Teuvo L Tammela, Tapio Visakorpi, Matti Nykter, David C Wedge, Peter Van Loo, G Steven Bova

Faculty, Staff and Student Publications

BACKGROUND: Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as androgen deprivation. Such heterogeneity can be deciphered in the context of evolutionary principles, but current clinical trials do not include evolution as an essential feature. Whether or not analysis of genomic data in an evolutionary context in primary prostate cancer can provide unique added value in the research and clinical domains remains an open question.

METHODS: We used novel processing techniques to obtain whole genome data together with 3D anatomic and histomorphologic analysis in two men (GP5 and GP12) with high-risk PrCa undergoing radical prostatectomy. A total of …

Immune-Depleted Tumor Microenvironment Is Associated With Poor Outcomes And Btk Inhibitor Resistance In Mantle Cell Lymphoma, Preetesh Jain, Krystle Nomie, Nikita Kotlov, Vitaiy Segodin, Holly Hill, Chi Young Ok, Ahmed Fetooh, Rashmi Kanagal-Shamanna, Francisco Vega, Alexander Bagaev, Nathan Fowler, Christopher R Flowers, Michael Wang

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is a generally aggressive B cell non-Hodgkin lymphoma (B-NHL). Outcomes of patients have improved in the era of Bruton’s tyrosine kinase inhibitors (BTKi). However, MCL patients can develop resistance to BTKi over time and can progress [1]. Ibrutinib resistance in MCL is correlated with an overexpression of OXPHOS, MYC and PI3K/AKT/m-TOR pathways. Somatic mutations in TP53, KMT2D, NSD2, SMARCA4, CCND1, TRAF2, NFKBIE genes are reported with ibrutinib resistance [2]. A few reports have also demonstrated that a decrease in T cell numbers [3, 4] or a downregulation of effector/cytotoxic …

Next-Generation Crispr Gene-Drive Systems Using Cas12a Nuclease, Sara Sanz Juste, Emily M Okamoto, Christina Nguyen, Xuechun Feng, Víctor López Del Amo

Faculty, Staff and Student Publications

One method for reducing the impact of vector-borne diseases is through the use of CRISPR-based gene drives, which manipulate insect populations due to their ability to rapidly propagate desired genetic traits into a target population. However, all current gene drives employ a Cas9 nuclease that is constitutively active, impeding our control over their propagation abilities and limiting the generation of alternative gene drive arrangements. Yet, other nucleases such as the temperature sensitive Cas12a have not been explored for gene drive designs in insects. to address this, we herein present a proof-of-concept gene-drive system driven by Cas12a that can be regulated …

Complete Loss Of Tp53 And Rb1 Is Associated With Complex Genome And Low Immune Infiltrate In Pleomorphic Rhabdomyosarcoma, Hannah C Beird, Chia-Chin Wu, Michael Nakazawa, Davis Ingram, Joseph R Daniele, Rossana Lazcano, Latasha Little, Christopher Davies, Najat C Daw, Khalida Wani, Wei-Lien Wang, Xingzhi Song, Curtis Gumbs, Jianhua Zhang, Brian Rubin, Anthony Conley, Adrienne M Flanagan, Alexander J Lazar, P Andrew Futreal

Faculty, Staff and Student Publications

Rhabdomyosarcoma accounts for roughly 1% of adult sarcomas, with pleomorphic rhabdomyosarcoma (PRMS) as the most common subtype. Survival outcomes remain poor for patients with PRMS, and little is known about the molecular drivers of this disease. To better characterize PRMS, we performed a broad array of genomic and immunostaining analyses on 25 patient samples. In terms of gene expression and methylation, PRMS clustered more closely with other complex karyotype sarcomas than with pediatric alveolar and embryonal rhabdomyosarcoma. Immune infiltrate levels in PRMS were among the highest observed in multiple sarcoma types and contrasted with low levels in other rhabdomyosarcoma subtypes. …

Unleashing The Potential Of 1,3-Diketone Analogues As Selective Lh2 Inhibitors, Juhoon Lee, Hou-Fu Guo, Shike Wang, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Zhifeng Jing, Rae M Sammons, Eun Jeong Cho, Pengyu Ren, G Andrés Cisneros, Jonathan M Kurie, Kevin N Dalby

Faculty, Staff and Student Publications

Lysyl hydroxylase 2 (LH2) catalyzes the formation of highly stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus promoting lung cancer metastasis through its capacity to modulate specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1-18, and identified 12 and 13 that inhibit LH2 with IC50's of approximately 300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of 12 and 13 …

Project Inclusive Genetics: Protecting Reproductive Autonomy From Bias Via Prenatal Patient-Centered Counseling, Apolline Jungels, Lindsay Demers, Eric Ford, Blair K Stevens, Maya Sabatello, Shoumita Dasgupta

Faculty, Staff and Student Publications

Clinician bias negatively impacts the healthcare received by marginalized communities. In this study, we explored factors that influence clinician and trainee bias against individuals with intellectual disabilities and its impact on clinical judgment in prenatal genetic testing settings. Specifically, we examined bias toward a fetus with a higher chance of developing a disability. We compared genetics specialists with their non-expert counterparts. This web-based study included clinical vignettes, implicit association tests (IATs), and an educational module. 595 participants were recruited via their institution or professional society. We conducted statistical analyses, including regression models controlling for key demographic characteristics, to analyze recommendation …

Trio-Based Gwas Identifies Novel Associations And Subtype-Specific Risk Factors For Cleft Palate, Kelsey Robinson, Trenell J Mosley, Kenneth S Rivera-González, Christopher R Jabbarpour, Sarah W Curtis, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, David J Cutler, Michael P Epstein, Lord J J Gowans, Jacqueline T Hecht, Jeffrey C Murray, Gary M Shaw, Lina Moreno Uribe, Seth M Weinberg, Harrison Brand, Mary L Marazita, Robert J Lipinski, Elizabeth J Leslie

Faculty, Staff and Student Publications

Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n = 435), and subtype-specific risks for any cleft soft palate (CSP), (n = 259) and any cleft hard palate (CHP) (n = 125). We identified …

Usp1 Promotes Cholangiocarcinoma Progression By Deubiquitinating Parp1 To Prevent Its Proteasomal Degradation, Deng Yong Zhang, Yan Zhu, Qiong Wu, Shuoshuo Ma, Yang Ma, Zheng Chao Shen, Zhonglin Wang, Wanliang Sun, Yong Chun Zhou, Dongdong Wang, Shuo Zhou, Zhong Liu, Lawrence N Kwong, Zheng Lu

Faculty, Staff and Student Publications

Despite its involvement in various cancers, the function of the deubiquitinase USP1 (ubiquitin-specific protease 1) is unexplored in cholangiocarcinoma (CCA). In this study, we provide evidence that USP1 promotes CCA progression through the stabilization of Poly (ADP-ribose) polymerase 1 (PARP1), consistent with the observation that both USP1 and PARP1 are upregulated in human CCA. Proteomics and ubiquitylome analysis of USP1-overexpressing CCA cells nominated PARP1 as a top USP1 substrate. Indeed, their direct interaction was validated by a series of immunofluorescence, co-immunoprecipitation (CO-IP), and GST pull-down assays, and their interaction regions were identified using deletion mutants. Mechanistically, USP1 removes the ubiquitin …

Vaccination With A Replication-Defective Cytomegalovirus Vaccine Elicits A Glycoprotein B-Specific Monoclonal Antibody Repertoire Distinct From Natural Infection, Sarah M Valencia, Eric Rochat, Melissa J Harnois, Maria Dennis, Helen S Webster, Bhavna Hora, Amit Kumar, Hsuan-Yuan Sherry Wang, Leike Li, Daniel Freed, Ningyan Zhang, Zhiqiang An, Dai Wang, Sallie R Permar

Faculty, Staff and Student Publications

Human Cytomegalovirus (HCMV) is the leading infectious congenital infection globally and the most common viral infection in transplant recipients, therefore identifying a vaccine for HCMV is a top priority. Humoral immunity is a correlate of protection for HCMV infection. The most effective vaccine tested to date, which achieved 50% reduction in acquisition of HCMV, was comprised of the glycoprotein B protein given with an oil-in-water emulsion adjuvant MF59. We characterize gB-specific monoclonal antibodies isolated from individuals vaccinated with a disabled infectious single cycle (DISC) CMV vaccine, V160, and compare these to the gB-specific monoclonal antibody repertoire isolated from naturally-infected individuals. …

Integrated Molecular Characterization Of Intraductal Papillary Mucinous Neoplasms: An Nci Cancer Moonshot Precancer Atlas Pilot Project, Alexander Semaan, Vincent Bernard, Justin Wong, Yuki Makino, Daniel B Swartzlander, Kimal I Rajapakshe, Jaewon J Lee, Adam Officer, Christian Max Schmidt, Howard H Wu, Courtney L Scaife, Kajsa E Affolter, Daniela Nachmanson, Matthew A Firpo, Michele Yip-Schneider, Andrew M Lowy, Olivier Harismendy, Subrata Sen, Anirban Maitra, Yasminka A Jakubek, Paola A Guerrero

Faculty, Staff and Student Publications

Intraductal papillary mucinous neoplasms (IPMN) are cystic precursor lesions to pancreatic ductal adenocarcinoma (PDAC). IPMNs undergo multistep progression from low-grade (LG) to high-grade (HG) dysplasia, culminating in invasive neoplasia. While patterns of IPMN progression have been analyzed using multiregion sequencing for somatic mutations, there is no integrated assessment of molecular events, including copy-number alterations (CNA) and transcriptional changes that accompany IPMN progression. We performed laser capture microdissection on surgically resected IPMNs of varying grades of histologic dysplasia obtained from 23 patients, followed by whole-exome and whole-transcriptome sequencing. Overall, HG IPMNs displayed a significantly greater aneuploidy score than LG lesions, with …

First-In-Human, Phase I Dose-Escalation And Dose-Expansion Study Of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan In Non-Small-Cell Lung Cancer: Tropion-Pantumor01, Toshio Shimizu, Jacob Sands, Kiyotaka Yoh, Alexander Spira, Edward B Garon, Satoru Kitazono, Melissa L Johnson, Funda Meric-Bernstam, Anthony W Tolcher, Noboru Yamamoto, Jon Greenberg, Yui Kawasaki, Hong Zebger-Gong, Fumiaki Kobayashi, Penny Phillips, Aaron E Lisberg, Rebecca S Heist

Faculty, Staff and Student Publications

PURPOSE: This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate in solid tumors, including advanced non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics.

RESULTS: Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. …

Outcomes Of Breakthrough Covid-19 Infections In Patients With Hematologic Malignancies, Kelly S Chien, Christine B Peterson, Elliana Young, Dai Chihara, Elizabet E Manasanch, Jeremy L Ramdial, Philip A Thompson

Faculty, Staff and Student Publications

Patients with hematologic malignancies have both an increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and higher morbidity/mortality. They have lower seroconversion rates after vaccination, potentially leading to inferior coronavirus disease 2019 (COVID-19) outcomes, despite vaccination. We consequently evaluated the clinical outcomes of COVID-19 infections in 243 vaccinated and 175 unvaccinated patients with hematologic malignancies. Hospitalization rates were lower in the vaccinated group when compared with the unvaccinated group (31.3% vs 52.6%). However, the rates of COVID-19-associated death were similar at 7.0% and 8.6% in vaccinated and unvaccinated patients, respectively. By univariate logistic regression, females, older patients, …

Impact Of Preparing Nursing Students To Deliver A Parent-Based Sexual Health Intervention On Attitudes And Intentions For Sexual Health Education And Parent Communication Counseling: A Mixed Methods Study, Deidra Carroll Coleman, Anitra Frederick, Stanley Cron, Christine Markham, Vincent Guilamo-Ramos, Diane Santa Maria

Faculty, Staff and Student Publications

BACKGROUND: Nurses are well positioned to promote sexual health but are not adequately prepared in their nursing programs to engage families on this topic and often lack the knowledge and confidence necessary to counsel families about sexual health communication. The purpose of this study was to determine how facilitating a parent-based sexual health intervention would impact nursing students' attitudes and intentions about sexual health education and parent communication counseling.

METHODS: Using an embedded mixed-methods design, which integrated a quasi-experimental framework, we examined the impact of participation in a parent-based sexual health intervention among 126 baccalaureate nursing students enrolled in a …

Collective Motion In Hcp-Fe At Earth's Inner Core Conditions, Youjun Zhang, Yong Wang, Yuqian Huang, Junjie Wang, Zhixin Liang, Long Hao, Zhipeng Gao, Jun Li, Qiang Wu, Hong Zhang, Yun Liu, Jian Sun, Jung-Fu Lin

Faculty, Staff and Student Publications

Earth's inner core is predominantly composed of solid iron (Fe) and displays intriguing properties such as strong shear softening and an ultrahigh Poisson's ratio. Insofar, physical mechanisms to explain these features coherently remain highly debated. Here, we have studied longitudinal and shear wave velocities of hcp-Fe (hexagonal close-packed iron) at relevant pressure-temperature conditions of the inner core using in situ shock experiments and machine learning molecular dynamics (MLMD) simulations. Our results demonstrate that the shear wave velocity of hcp-Fe along the Hugoniot in the premelting condition, defined as

Cd13 Facilitates Immune Cell Migration And Aggravates Acute Injury But Promotes Chronic Post-Stroke Recovery, Justin N Nguyen, Eric C Mohan, Gargee Pandya, Uzma Ali, Chunfeng Tan, Julia K Kofler, Linda Shapiro, Sean P Marrelli, Anjali Chauhan

Faculty, Staff and Student Publications

Introduction

Acute stroke leads to the activation of myeloid cells. These cells express adhesion molecules and transmigrate to the brain, thereby aggravating injury. Chronically after stroke, repair processes, including angiogenesis, are activated and enhance post-stroke recovery. Activated myeloid cells express CD13, which facilitates their migration into the site of injury. However, angiogenic blood vessels which play a role in recovery also express CD13. Overall, the specific contribution of CD13 to acute and chronic stroke outcomes is unknown.

Methods

CD13 expression was estimated in both mice and humans after the ischemic stroke. Young (8–12 weeks) male wild-type and global CD13 knockout …

Bronchial Epithelial Gene Expression And Interstitial Lung Abnormalities, Aravind A Menon, Minyi Lee, Xu Ke, Rachel K Putman, Takuya Hino, Jonathan A Rose, Fenghai Duan, Samuel Y Ash, Michael H Cho, George T O'Connor, Josée Dupuis, Hiroto Hatabu, Marc E Lenburg, Ehab S Billatos, Gary M Hunninghake, Decamp Investigators

Faculty, Staff and Student Publications

INTRODUCTION: Interstitial lung abnormalities (ILA) often represent early fibrotic changes that can portend a progressive fibrotic phenotype. In particular, the fibrotic subtype of ILA is associated with increased mortality and rapid decline in lung function. Understanding the differential gene expression that occurs in the lungs of participants with fibrotic ILA may provide insight into development of a useful biomarker for early detection and therapeutic targets for progressive pulmonary fibrosis.

METHODS: Measures of ILA and gene expression data were available in 213 participants in the Detection of Early Lung Cancer Among Military Personnel (DECAMP1 and DECAMP2) cohorts. ILA was defined using …

The Significant Impacts Of Interleukin-8 Genotypes On The Risk Of Colorectal Cancer In Taiwan, Chia-Wen Tsai, Wen-Shin Chang, Te-Cheng Yueh, Yun-Chi Wang, Yu-Ting Chin, Mei-Due Yang, Yi-Chih Hung, Mei-Chin Mong, Ya-Chen Yang, Jian Gu, Da-Tian Bau

Faculty, Staff and Student Publications

Interleukin-8 (IL-8), a pro-inflammatory cytokine, is upregulated in CRC and plays an important role in its development and progression. Genetic variants in the IL-8 gene may impact the risk of CRC by modulating IL-8 levels. Our primary objective was to investigate the role of IL-8 genotypes in the development of CRC. To accomplish this, we employed the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze the genotypes of IL-8 rs4017, rs2227306, rs2227543, and rs1126647 in 362 CRC patients and 362 controls. Additionally, we evaluated the interactions between these genotypes and factors such as age, gender, smoking, alcohol consumption, …

Nasal Iodophor Antiseptic Vs Nasal Mupirocin Antibiotic In The Setting Of Chlorhexidine Bathing To Prevent Infections In Adult Icus: A Randomized Clinical Trial, Susan S Huang, Edward J Septimus, Ken Kleinman, Lauren T Heim, Julia A Moody, Taliser R Avery, Laura Mclean, Syma Rashid, Katherine Haffenreffer, Lauren Shimelman, Whitney Staub-Juergens, Caren Spencer-Smith, Selsebil Sljivo, Ed Rosen, Russell E Poland, Micaela H Coady, Chi Hyun Lee, Eunice J Blanchard, Kimberly Reddish, Mary K Hayden, Robert A Weinstein, Brandon Carver, Kimberly Smith, Jason Hickok, Karen Lolans, Nadia Khan, S Gwynn Sturdevant, Sujan C Reddy, John A Jernigan, Kenneth E Sands, Jonathan B Perlin, Richard Platt

Faculty, Staff and Student Publications

IMPORTANCE: Universal nasal mupirocin plus chlorhexidine gluconate (CHG) bathing in intensive care units (ICUs) prevents methicillin-resistant Staphylococcus aureus (MRSA) infections and all-cause bloodstream infections. Antibiotic resistance to mupirocin has raised questions about whether an antiseptic could be advantageous for ICU decolonization.

OBJECTIVE: To compare the effectiveness of iodophor vs mupirocin for universal ICU nasal decolonization in combination with CHG bathing.

DESIGN, SETTING, AND PARTICIPANTS: Two-group noninferiority, pragmatic, cluster-randomized trial conducted in US community hospitals, all of which used mupirocin-CHG for universal decolonization in ICUs at baseline. Adult ICU patients in 137 randomized hospitals during baseline (May 1, 2015-April 30, 2017) …