Digital Commons Network^™

The Effect Of Thermal Therapy On The Blood-Brain Barrier And Blood-Tumor Barrier, Bhuvic Patel, Peter H Yang, Albert H Kim

Open Access Publications

The blood-brain and blood-tumor barriers represent highly specialized structures responsible for tight regulation of molecular transit into the central nervous system. Under normal circumstances, the relative impermeability of the blood-brain barrier (BBB) protects the brain from circulating toxins and contributes to a brain microenvironment necessary for optimal neuronal function. However, in the context of tumors and other diseases of central nervous system, the BBB and the more recently appreciated blood-tumor barrier (BTB) represent barriers that prevent effective drug delivery. Overcoming both barriers to optimize treatment of central nervous system diseases remains the subject of intense scientific investigation. Although many newer …

Mechanism Of Ligand Activation Of A Eukaryotic Cyclic Nucleotide-Gated Channel, Xiangdong Zheng, Ziao Fu, Deyuan Su, Yuebin Zhang, Minghui Li, Yaping Pan, Huan Li, Shufang Li, Robert A Grassucci, Zhenning Ren, Zhengshan Hu, Xueming Li, Ming Zhou, Guohui Li, Joachim Frank, Jian Yang

Faculty, Staff and Students Publications

Cyclic nucleotide-gated (CNG) channels convert cyclic nucleotide (CN) binding and unbinding into electrical signals in sensory receptors and neurons. The molecular conformational changes underpinning ligand activation are largely undefined. We report both closed- and open-state atomic cryo-EM structures of a full-length Caenorhabditis elegans cyclic GMP-activated channel TAX-4, reconstituted in lipid nanodiscs. These structures, together with computational and functional analyses and a mutant channel structure, reveal a double-barrier hydrophobic gate formed by two S6 amino acids in the central cavity. cGMP binding produces global conformational changes that open the cavity gate located ~52 Å away but do not alter the structure …

Combined Lenvatinib And Pembrolizumab As Salvage Therapy In Advanced Adrenal Cortical Carcinoma, Sara Bedrose, Kevin Charles Miller, Lina Altameemi, Mohamed S Ali, Sameh Nassar, Naveen Garg, Marilyne Daher, Keith D Eaton, Jeffrey Thomas Yorio, Davey B Daniel, Matthew Campbell, Keith C Bible, Mabel Ryder, Ashish V Chintakuntlawar, Mouhammed Amir Habra

Faculty, Staff and Students Publications

BACKGROUND: There is no effective systemic therapy for metastatic adrenal cortical carcinoma (ACC) after failure of platinum-based chemotherapy. The efficacies of single-agent oral multikinase inhibitors (MKIs) or salvage immune checkpoint inhibitors (CPIs) have been very limited. It is unknown whether combining CPIs, such as pembrolizumab (PEM), with other therapies, such as MKIs, could yield higher response rates in ACC, yet this combination has shown promise in other cancers. Herein, we describe the first case series using PEM in combination with the MKI lenvatinib (LEN) in patients with progressive, metastatic ACC.

METHODS: A retrospective case series describing the use of LEN/PEM …

Systematic Review With Meta-Analysis: Prevalence Of Prior And Concurrent Barrett’S Oesophagus In Oesophageal Adenocarcinoma Patients, Mimi C Tan, Nabil Mansour, Donna L White, Amy Sisson, Hashem B El-Serag, Aaron P Thrift

Library Staff Publications

BACKGROUND: The proportions of patients with oesophageal adenocarcinoma (OAC) diagnosed by Barrett's oesophagus surveillance or with pre-existing Barrett's oesophagus are unclear.

AIM: To estimate the prevalence of prior and concurrent Barrett's oesophagus diagnosis among patients with OAC or oesophagogastric junction adenocarcinomas (OGJAC).

METHODS: We searched PubMed and Embase to identify studies published 1966-1/8/2020 that examined the prevalence of prior (≥6 months) or concurrent Barrett's diagnosis (at cancer diagnosis) among OAC and OGJAC patients. Random effects models estimated overall and stratified pooled prevalence rates.

RESULTS: A total of 69 studies, including 33 002 OAC patients (53 studies) and 2712 patients with …

Rna-Gps Predicts High-Resolution Rna Subcellular Localization And Highlights The Role Of Splicing, Kevin E Wu, Kevin R Parker, Furqan M Fazal, Howard Y Chang, James Zou

Faculty, Staff and Students Publications

Subcellular localization is essential to RNA biogenesis, processing, and function across the gene expression life cycle. However, the specific nucleotide sequence motifs that direct RNA localization are incompletely understood. Fortunately, new sequencing technologies have provided transcriptome-wide atlases of RNA localization, creating an opportunity to leverage computational modeling. Here we present RNA-GPS, a new machine learning model that uses nucleotide-level features to predict RNA localization across eight different subcellular locations-the first to provide such a wide range of predictions. RNA-GPS's design enables high-throughput sequence ablation and feature importance analyses to probe the sequence motifs that drive localization prediction. We find localization …

Association Analysis Of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci With 20,871 Lung Cancer Cases And 15,971 Controls, Yuzhuo Wang, Olga Y Gorlova, Ivan P Gorlov, Meng Zhu, Juncheng Dai, Demetrius Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Gary E Goodman, Stig E Bojesen, Maria Teresa Landi, Mattias Johansson, Angela Risch, Heunz-Erich Wichmann, Heike Bickeboller, David C Christiani, Gad Rennert, Susanne M Arnold, Paul Brennan, John K Field, Sanjay Shete, Loïc Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Rayjean J Hung, Angeline S Andrew, Lambertus A Kiemeney, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E Caporaso, Penella J Woll, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Victoria L Stevens, Hongxia Ma, Guangfu Jin, Zhibin Hu, Christopher I Amos, Hongbing Shen

Faculty, Staff and Students Publications

BACKGROUND: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.

METHODS: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data …

Prevalence, Incidence, And Clearance Of Human Papillomavirus Types Covered By Current Vaccines In Men With Human Immunodeficiency Virus In The Sun Study, Pragna Patel, Tim Bush, Lois Conley, Elizabeth R Unger, Teresa M Darragh, Keith Henry, Gerome Escota, John T Brooks, Erna Milunka Kojic

2020-Current year OA Pubs

BACKGROUND: High-risk anal human papillomavirus (HPV) infection is prevalent among men living with human immunodeficiency virus (HIV); the association between 9-valent (9v) high-risk HPV (HR-HPV) vaccine types and abnormal cytology has not been well characterized.

METHODS: We followed a prospective cohort study of persons with HIV at 7 HIV clinics in 4 US cities from March 2004 through June 2012. Annually, providers collected separate anal swabs for HPV detection and cytopathologic examination. Among men, we examined prevalence, incidence, and clearance of 9v HR-HPV vaccine types, compared with other HR types, and associations with abnormal cytology to assess potential vaccine impact. …

Nuclear Localization Of A Novel Calpain-2 Mediated Junctophilin-2 C-Terminal Cleavage Peptide Promotes Cardiomyocyte Remodeling, Satadru K Lahiri, Ann P Quick, Benoit Samson-Couterie, Mohit Hulsurkar, Ies Elzenaar, Ralph J Van Oort, Xander H T Wehrens

Faculty, Staff and Students Publications

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Patients with HF exhibit a loss of junctophilin-2 (JPH2), a structural protein critical in forming junctional membrane complexes in which excitation-contraction takes place. Several mechanisms have been proposed to mediate the loss of JPH2, one being cleavage by the calcium-dependent protease calpain. The downstream mechanisms underlying HF progression after JPH2 cleavage are presently poorly understood. In this study, we used Labcas to bioinformatically predict putative calpain cleavage sites on JPH2. We identified a cleavage site that produces a novel C-terminal JPH2 peptide (JPH2-CTP) using several domain-specific antibodies. Western …

Pathogenesis Of Preeclampsia And Therapeutic Approaches Targeting The Placenta., Manoj Kumar Jena, Neeta Raj Sharma, Matthew Petitt, Devika Maulik, Nihar Ranjan Nayak

Manuscripts, Articles, Book Chapters and Other Papers

Preeclampsia (PE) is a serious pregnancy complication, affecting about 5-7% of pregnancies worldwide and is characterized by hypertension and damage to multiple maternal organs, primarily the liver and kidneys. PE usually begins after 20 weeks' gestation and, if left untreated, can lead to serious complications and lifelong disabilities-even death-in both the mother and the infant. As delivery is the only cure for the disease, treatment is primarily focused on the management of blood pressure and other clinical symptoms. The pathogenesis of PE is still not clear. Abnormal spiral artery remodeling, placental ischemia and a resulting increase in the circulating levels …

Nuclear Morphology And The Biology Of Cancer Cells, Edgar G. Fischer

Pathology Research and Scholarship

BACKGROUND: For more than a century, diagnostic pathologists have used morphologic abnormalities of the nucleus as essential diagnostic features to distinguish benign from malignant cells. These features include nuclear enlargement and increased nuclear-to-cytoplasmic ratio, nuclear membrane irregularities, hyperchromasia, and abnormal chromatin distribution. As our knowledge about the genetic and epigenetic abnormalities of cancer cells has increased in recent decades, the pathophysiologic mechanisms that underlie these morphologic abnormalities remain incompletely understood.

SUMMARY: This review attempts to summarize biologic abnormalities in malignant cells related to these morphologic changes. The molecular anatomy of the nuclear envelope in normal and malignant cells is discussed …

Pet Radiopharmaceuticals For Imaging Chemotherapy-Induced Cardiotoxicity, Jothilingam Sivapackiam, Monica Sharma, Thomas H Schindler, Vijay Sharma

Open Access Publications

PURPOSE OF REVIEW: Currently, cardiotoxicity is monitored through echocardiography or multigated acquisition scanning and is defined as 10% or higher LVEF reduction. The latter stage may represent irreversible myocardium injury and limits modification of therapeutic paradigms at earliest stages. To stratify patients for anthracycline-related heart failure, highly sensitive and molecularly specific probes capable of interrogating cardiac damage at the subcellular levels have been sought.

RECENT FINDINGS: PET tracers may provide noninvasive assessment of earliest changes within myocardium. These tracers are at nascent stages of development and belong primarily to (a) mitochondrial potential-targeted and (b) general ROS (reactive oxygen species)-targeted radiotracers. …

25-Hydroxycholesterol Amplifies Microglial Il-1Β Production In An Apoe Isoform-Dependent Manner, Man Ying Wong, Michael Lewis, James J Doherty, Yang Shi, Anil G Cashikar, Anna Amelianchik, Svitlana Tymchuk, Patrick M Sullivan, Mingxing Qian, Douglas F Covey, Gregory A Petsko, David M Holtzman, Steven M Paul, Wenjie Luo

2020-Current year OA Pubs

BACKGROUND: Genome-wide association studies of Alzheimer's disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models.

METHODS: We used real-time PCR and immunoblotting to examine …

Linking Activity, Nutrition, And Child Health (Launch): Protocol For A Longitudinal Cohort Study Of Children As They Develop From Infancy To Preschool Age, Russell R. Pate, Edward A. Frongillo Jr., Kerry Cordan, Marsha Dowda, Alexander C. Mclain, Myriam E. Torres, William H. Brown, Agnes Bucko, Emily R. Shull

Faculty Publications

Background

Physical activity is known to provide important health benefits in children ages 3 years and above, but little is known about the effects of physical activity on health in very young children under age 3. LAUNCH (Linking Activity, Nutrition, and Child Health) is a study designed to expand the body of knowledge on development of physical activity behavior and associations between physical activity and other health characteristics as children transition from infancy to preschool age.

Methods

Physical activity and sedentary behavior will be measured objectively in young children over a period of 30 months. Each child will complete a …

Covid-19 Medical Papers Have Fewer Women First Authors Than Expected., Jens Peter Andersen, Mathias Wullum Nielsen, Nicole L Simone, Resa E Lewiss, Reshma Jagsi

Department of Radiation Oncology Faculty Papers

The COVID-19 pandemic has resulted in school closures and distancing requirements that have disrupted both work and family life for many. Concerns exist that these disruptions caused by the pandemic may not have influenced men and women researchers equally. Many medical journals have published papers on the pandemic, which were generated by researchers facing the challenges of these disruptions. Here we report the results of an analysis that compared the gender distribution of authors on 1893 medical papers related to the pandemic with that on papers published in the same journals in 2019, for papers with first authors and last …

A Genome-Wide Association Study Identifies Two Novel Susceptible Regions For Squamous Cell Carcinoma Of The Head And Neck, Sanjay Shete, Hongliang Liu, Jian Wang, Robert Yu, Erich M Sturgis, Guojun Li, Kristina R Dahlstrom, Zhensheng Liu, Christopher I Amos, Qingyi Wei

Faculty, Staff and Students Publications

To identify genetic variants for risk of squamous cell carcinoma of the head and neck (SCCHN), we conducted a two-phase genome-wide association study consisting of 7,858,089 SNPs in 2,171 cases and 4,493 controls of non-Hispanic white, of which 434,839 typed and 7,423,250 imputed SNPs as the discovery. SNPs with P <1×10–3 were further validated in the OncoArray study of oral and pharynx cancer (5,205 cases and 3,232 controls of European ancestry) from dbGaP. Meta-analysis of the discovery and replication studies identified one novel locus 6p22.1 (P = 2.96×10–9 for the leading rs259919) and two cancer susceptibility loci 6p21.32 (rs3135001, HLA-DQB1) and 6p21.33 (rs1265081, CCHCR1) associated with SCCHN risk. Further stratification by tumor site revealed four known cancer loci (5p15.33, 6p21.32, 6p21.33, and 2p23.1) associated with oral cavity cancer risk and oropharyngeal cancer risk, respectively. In addition, one novel locus 18q22.2 (P = 2.54×10–9 for the leading SNP rs142021700) was identified for hypo-pharynx and larynx cancer risk. For SNPs in those reported or novel loci, we also performed functional annotations by bioinformatics prediction and eQTL analysis. Collectively, our identification of four reported loci (2p23.1, 5p15.33, 6p21.32, and 6p21.33) and two novel loci (6p22.1 and 18q22.2) for SCCHN risk highlight the importance of HLA loci for oropharyngeal cancer risk, suggesting that immunologic mechanisms are implicated in the etiology of this subset of SCCHN.

Implications Of New Understandings Of Gliomas In Children And Adults With Nf1: Report Of A Consensus Conference, Roger J Packer, David H Gutmann, Et Al.

2020-Current year OA Pubs

Gliomas are the most common primary central nervous system tumors occurring in children and adults with neurofibromatosis type 1 (NF1). Over the past decade, discoveries of the molecular basis of low-grade gliomas (LGGs) have led to new approaches for diagnosis and treatments. However, these new understandings have not been fully applied to the management of NF1-associated gliomas. A consensus panel consisting of experts in NF1 and gliomas was convened to review the current molecular knowledge of NF1-associated low-grade "transformed" and high-grade gliomas; insights gained from mouse models of NF1-LGGs; challenges in diagnosing and treating older patients with NF1-associated gliomas; and …

Covid-19 Preclinical Models: Human Angiotensin-Converting Enzyme 2 Transgenic Mice., Cathleen Lutz, Leigh Maher, Charles Lee, Wonyoung Kang

Faculty Research 2020

Coronavirus disease 2019 (COVID-19) is a declared pandemic that is spreading all over the world at a dreadfully fast rate. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the pathogen of COVID-19, infects the human body using angiotensin-converting enzyme 2 (ACE2) as a receptor identical to the severe acute respiratory syndrome (SARS) pandemic that occurred in 2002-2003. SARS-CoV-2 has a higher binding affinity to human ACE2 than to that of other species. Animal models that mimic the human disease are highly essential to develop therapeutics and vaccines against COVID-19. Here, we review transgenic mice that express human ACE2 in the airway and …

Aav-Crispr Gene Editing Is Negated By Pre-Existing Immunity To Cas9, Ang Li, Mark R Tanner, Ciaran M Lee, Ayrea E Hurley, Marco De Giorgi, Kelsey E Jarrett, Timothy H Davis, Alexandria M Doerfler, Gang Bao, Christine Beeton, William R Lagor

Faculty, Staff and Students Publications

Adeno-associated viral (AAV) vectors are a leading candidate for the delivery of CRISPR-Cas9 for therapeutic genome editing in vivo. However, AAV-based delivery involves persistent expression of the Cas9 nuclease, a bacterial protein. Recent studies indicate a high prevalence of neutralizing antibodies and T cells specific to the commonly used Cas9 orthologs from Streptococcus pyogenes (SpCas9) and Staphylococcus aureus (SaCas9) in humans. We tested in a mouse model whether pre-existing immunity to SaCas9 would pose a barrier to liver genome editing with AAV packaging CRISPR-Cas9. Although efficient genome editing occurred in mouse liver with pre-existing SaCas9 immunity, this was accompanied by …

Ccdc61/Vfl3 Is A Paralog Of Sas6 And Promotes Ciliary Functions, Takashi Ochi, Huawen Lin, Susan K Dutcher, Et Al.

2020-Current year OA Pubs

Centrioles are cylindrical assemblies whose peripheral microtubule array displays a 9-fold rotational symmetry that is established by the scaffolding protein SAS6. Centriole symmetry can be broken by centriole-associated structures, such as the striated fibers in Chlamydomonas that are important for ciliary function. The conserved protein CCDC61/VFL3 is involved in this process, but its exact role is unclear. Here, we show that CCDC61 is a paralog of SAS6. Crystal structures of CCDC61 demonstrate that it contains two homodimerization interfaces that are similar to those found in SAS6, but result in the formation of linear filaments rather than rings. Furthermore, we show …

Prevalence And Clinical Features Of Inflammatory Bowel Diseases Associated With Monogenic Variants, Identified By Whole-Exome Sequencing In 1000 Children At A Single Center, Eileen Crowley, Neil Warner, Jie Pan, Sam Khalouei, Abdul Elkadri, Karoline Fiedler, Justin Foong, Andrei L Turinsky, Dana Bronte-Tinkew, Shiqi Zhang

Paediatrics Publications

BACKGROUND & AIMS: A proportion of infants and young children with inflammatory bowel diseases (IBDs) have subtypes associated with a single gene variant (monogenic IBD). We aimed to determine the prevalence of monogenic disease in a cohort of pediatric patients with IBD.

METHODS: We performed whole-exome sequencing analyses of blood samples from an unselected cohort of 1005 children with IBD, aged 0-18 years (median age at diagnosis, 11.96 years) at a single center in Canada and their family members (2305 samples total). Variants believed to cause IBD were validated using Sanger sequencing. Biopsies from patients were analyzed by immunofluorescence and …

Traumatic Injury Results In Prolonged Circulation Of Ultralarge Von Willebrand Factor And A Reduction In Adamts13 Activity, Mitchell R. Dyer, William E. Plautz, Margaret V. Ragni, Wyeth Alexander, Shannon Haldeman, Jason L. Sperry, Francis X. Guyette, Brian S. Zuckerbraun, Marian A. Rollins-Raval, Jay S. Raval, Matthew D. Neal

Pathology Research and Scholarship

BACKGROUND: Increases in plasma von Willebrand Factor (VWF) levels, accompanied by decreases in the metalloprotease ADAMTS13, have been demonstrated soon after traumatic injury while downstream effects remain unclear.

STUDY DESIGN AND METHODS: A cohort of 37 injured trauma patients from a randomized control trial investigating the use of prehospital plasma transfusion were analyzed for activity and antigen levels of ADAMTS13 and VWF at 0 and 24 hours after admission. Relevant clinical data were abstracted from the medical records. Trauma patient plasma was analyzed via agarose gel electrophoresis to evaluate the effects of injury on VWF multimer composition compared to healthy …

Relationships Of P16 Immunohistochemistry And Other Biomarkers With Diagnoses Of Cervical Abnormalities: Implications For Last Terminology, Philip E. Castle, Rachael Adcock, Jack Cuzick, Nicolas Wentzensen, Norah E. Torrez-Martinez, Salina M. Torres, Mark H. Stoler, Brigitte M. Ronnett, Nancy E. Joste, Teresa M. Darragh, Patti E. Gravitt, Mark Schiffman, William C. Hunt, Walter K. Kinney, Cosette M. Wheeler

Pathology Research and Scholarship

CONTEXT.—: Lower Anogenital Squamous Terminology (LAST) standardization recommended p16

OBJECTIVE.—: To describe the relationships of p16 IHC and other biomarkers associated with cervical cancer risk with biopsy diagnoses.

DESIGN.—: A statewide, stratified sample of cervical biopsies diagnosed by community pathologists (CPs), including 1512 CIN2, underwent a consensus, expert pathologist panel (EP) review (without p16 IHC results), p16 IHC interpretation by a third pathology group, and human papillomavirus (HPV) genotyping, results of which were grouped hierarchically according to cancer risk. Antecedent cytologic interpretations were also available.

RESULTS.—: Biopsies were more likely to test p16 IHC positive with increasing severity of CP …

Secukinumab Provides Sustained Low Rates Of Radiographic Progression In Psoriatic Arthritis: 52-Week Results From A Phase 3 Study, Future 5., Désirée Van Der Heijde, Philip Mease, Robert B M Landewé, Proton Rahman, Hasan Tahir, Atul Singhal, Elke Boettcher, Sandra Navarra, Xuan Zhu, Gregory Ligozio, Aimee Readie, Shephard Mpofu, Luminita Pricop

Articles, Abstracts, and Reports

OBJECTIVE: To evaluate the effect of secukinumab on radiographic progression through 52 weeks in patients with PsA from the FUTURE 5 study.

METHODS: Patients with active PsA, stratified by prior anti-TNF use (naïve or inadequate response), were randomized to s.c. secukinumab 300 mg load (300 mg), 150 mg load (150 mg), 150 mg no load regimens or placebo at baseline, at weeks 1, 2 and 3 and every 4 weeks starting at week 4. Radiographic progression was assessed by change in van der Heijde-modified total Sharp score (vdH-mTSS; mean of two readers). Statistical analysis used a linear mixed-effects model (random …

Von Willebrand Factor As A Thrombotic And Inflammatory Mediator In Critical Illness, William E. Plautz, Zachary A. Matthay, Marian A. Rollins-Raval, Jay S. Raval, Lucy Z. Kornblith, Matthew D. Neal

Pathology Research and Scholarship

The endothelial exocytosis of high-molecular-weight multimeric von Willebrand factor (vWF) may occur in critical illness states, including trauma and sepsis, leading to the sustained elevation and altered composition of plasma vWF. These critical illnesses involve the common process of sympathoadrenal activation and loss of the endothelial glycocalyx. As a prothrombotic and proinflammatory molecule that interacts with the endothelium, the alterations exhibited by vWF in critical illness have been implicated in the development and damaging effects of downstream pathologies, such as disseminated intravascular coagulation and systemic inflammatory response syndrome. Given the role of vWF in these pathologies, there has been a …

Growth Velocity In Children With Environmental Enteric Dysfunction Is Associated With Specific Bacterial And Viral Taxa Of The Gastrointestinal Tract In Malawian Children, Chandni Desai, Scott A. Handley, Rachel Rodgers, Cynthia Rodriguez, Maria I. Ordiz, Mark J. Manary, Lori R. Holtz

Open Access Publications

Environmental enteric dysfunction (EED) is characterized by diffuse villous atrophy of the small bowel. EED is strongly associated with stunting, a major public health problem linked to increased childhood morbidity and mortality. EED and subsequent stunting of linear growth are surmised to have microbial origins. To interrogate this relationship, we defined the comprehensive virome (eukaryotic virus and bacteriophage) and bacterial microbiome of a longitudinal cohort of rural Malawian children with extensive metadata and intestinal permeability testing at each time point. We found thirty bacterial taxa differentially associated with linear growth. We detected many eukaryotic viruses. Neither the total number of …

Potent, Specific Mepicides For Treatment Of Zoonotic Staphylococci, Rachel L. Edwards, Isabel Heueck, Soon Goo Lee, Ishaan T. Shah, Justin J. Miller, Andrew J. Jezewski, Marwa O. Mikati, Xu Wang, Robert C. Brothers, Kenneth M. Heidel, Damon M. Osbourn, Carey-Ann D. Burnham, Sophie Alvarez, Stephanie A. Fritz, Cynthia S. Dowd, Joseph M. Jez, Audrey R. Odom John

Open Access Publications

Coagulase-positive staphylococci, which frequently colonize the mucosal surfaces of animals, also cause a spectrum of opportunistic infections including skin and soft tissue infections, urinary tract infections, pneumonia, and bacteremia. However, recent advances in bacterial identification have revealed that these common veterinary pathogens are in fact zoonoses that cause serious infections in human patients. The global spread of multidrug-resistant zoonotic staphylococci, in particular the emergence of methicillin-resistant organisms, is now a serious threat to both animal and human welfare. Accordingly, new therapeutic targets that can be exploited to combat staphylococcal infections are urgently needed. Enzymes of the methylerythritol phosphate pathway (MEP) …

Role Of Micro-Rna For Pain After Surgery: Narrative Review Of Animal And Human Studies, Juan P Cata, Aysegul Gorur, Xiaoyi Yuan, Nathaniel K Berg, Anil K Sood, Holger K Eltzschig

Faculty, Staff and Student Publications

One of the most prevalent symptoms after major surgery is pain. When postoperative pain treatment is unsatisfactory, it can lead to poor surgical recovery, decreased quality of life, and increased health care costs. Current analgesics, single or in combination, have limited efficacy due to low potency, limited duration of action, toxicities, and risk of addiction. The lack of nonaddictive strong analgesics along with the over prescription of opioids has led to an opioid epidemic in the United States. Therefore, there is an urgent need for the development of newer analgesics. Microribonucleic acids (miRNAs) are small noncoding RNA molecules that modulate …

Beyond An Updated Graded Prognostic Assessment (Breast Gpa): A Prognostic Index And Trends In Treatment And Survival In Breast Cancer Brain Metastases From 1985 To Today, Paul W Sperduto, Shane Mesko, Jing Li, Daniel Cagney, Ayal Aizer, Nancy U Lin, Eric Nesbit, Tim J Kruser, Jason Chan, Steve Braunstein, Jessica Lee, John P Kirkpatrick, Will Breen, Paul D Brown, Diana Shi, Helen A Shih, Hany Soliman, Arjun Sahgal, Ryan Shanley, William Sperduto, Emil Lou, Ashlyn Everett, Drexell Hunter Boggs, Laura Masucci, David Roberge, Jill Remick, Kristin Plichta, John M Buatti, Supriya Jain, Laurie E Gaspar, Cheng-Chia Wu, Tony J C Wang, John Bryant, Michael Chuong, James Yu, Veronica Chiang, Toshimichi Nakano, Hidefumi Aoyama, Minesh P Mehta

Faculty, Staff and Student Publications

PURPOSE: Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts.

METHODS AND MATERIALS: A multi-institutional (19), multinational (3), retrospective database of 2473 …

Pooled Crispr Screens With Imaging On Microraft Arrays Reveals Stress Granule-Regulatory Factors, Emily C Wheeler, Anthony Q Vu, Jaclyn M Einstein, Matthew Disalvo, Noorsher Ahmed, Eric L Van Nostrand, Alexander A Shishkin, Wenhao Jin, Nancy L Allbritton, Gene W Yeo

Faculty, Staff and Students Publications

Genetic screens using pooled CRISPR-based approaches are scalable and inexpensive, but restricted to standard readouts, including survival, proliferation and sortable markers. However, many biologically relevant cell states involve cellular and subcellular changes that are only accessible by microscopic visualization, and are currently impossible to screen with pooled methods. Here we combine pooled CRISPR-Cas9 screening with microraft array technology and high-content imaging to screen image-based phenotypes (CRaft-ID; CRISPR-based microRaft followed by guide RNA identification). By isolating microrafts that contain genetic clones harboring individual guide RNAs (gRNA), we identify RNA-binding proteins (RBPs) that influence the formation of stress granules, the punctate protein-RNA …

Simultaneous Examination Of Cellular Pathways Using Multiplex Hextuple Luciferase Assaying, Alejandro Sarrion-Perdigones, Lyra Chang, Yezabel Gonzalez, Tatiana Gallego-Flores, Damian W Young, Koen J T Venken

Faculty, Staff and Students Publications

Multiplex experimentation that can assay multiple cellular signaling pathways in the same cells requires orthogonal genetically encoded reporters that report over large dynamic ranges. Luciferases are cost-effective, versatile candidates whose output signals can be sensitively detected in a multiplex fashion. Commonly used dual luciferase reporter assays detect one luciferase that is coupled to a single cellular pathway, and a second that is coupled to a control pathway for normalization purposes. We expanded this approach to multiplex hextuple luciferase assaying that can report on five cellular signaling pathways and one control, each of which is encoded by a unique luciferase. Light …