Medicine and Health Sciences Commons^™

A Next Generation Sequencing-Based Protocol For Screening Of Variants Of Concern In Autism Spectrum Disorder, Jie Huang, Jun Liu, Ruiyi Tian, Kevin Liu, Patrick Zhuang, Hannah Tayla Sherman, Christoph Budjan, Michelle Fong, Min-Seo Jeong, Xue-Jun Kong

2020-Current year OA Pubs

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic influences. There is an increasing demand for ASD genetic testing beyond the traditionally recommended microarray and syndromic autism testing; however, the current whole genome sequencing (WGS) and whole exome sequencing (WES) methods are lacking an academic standard for WGS variant annotation, reporting, and interpretation, tailored towards patients with ASD and offer very limited interpretation for clinical significance. Using WGS data from six family trios, we demonstrate the clinical feasibility and technical implementation of an evidence-based, fully transparent bioinformatics pipeline and report framework for an ASD-focused WGS genetic report. We …

Transcriptional Reprogramming Differentiates Active From Inactive Esr1 Fusions In Endocrine Therapy-Refractory Metastatic Breast Cancer, Xuxu Gou, Shunqiang Li, Et Al.

2020-Current year OA Pubs

Genomic analysis has recently identified multiple

Spatial Concordance Of Dna Methylation Classification In Diffuse Glioma., Niels Verburg, Floris P Barthel, Kevin J Anderson, Kevin C Johnson, Thomas Koopman, Maqsood M Yaqub, Otto S Hoekstra, Adriaan A Lammertsma, Frederik Barkhof, Petra J W Pouwels, Jaap C Reijneveld, Annemieke J M Rozemuller, Jeroen A M Beliën, Ronald Boellaard, Michael D Taylor, Sunit Das, Joseph F Costello, William Peter Vandertop, Pieter Wesseling, Philip C De Witt Hamer, Roel G W Verhaak

Faculty Research 2021

BACKGROUND: Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence.

METHODS: We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion …

Patient-Derived Ipscs Link Elevated Mitochondrial Respiratory Complex I Function To Osteosarcoma In Rothmund-Thomson Syndrome, Brittany E Jewell, An Xu, Dandan Zhu, Mo-Fan Huang, Linchao Lu, Mo Liu, Erica L Underwood, Jun Hyoung Park, Huihui Fan, Julian A Gingold, Ruoji Zhou, Jian Tu, Zijun Huo, Ying Liu, Weidong Jin, Yi-Hung Chen, Yitian Xu, Shu-Hsia Chen, Nino Rainusso, Nathaniel K Berg, Danielle A Bazer, Christopher Vellano, Philip Jones, Holger K Eltzschig, Zhongming Zhao, Benny Abraham Kaipparettu, Ruiying Zhao, Lisa L Wang, Dung-Fang Lee

Journal Articles

Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays …

Risk Factors For Progression Or Death After First-Line Platinum-Based Chemotherapy In Real-World Patients In The Usa With Ovarian Cancer From 2011 To 2018, Shannon N Westin, Melinda Louie-Gao, Divya Gupta, Premal H Thaker

2020-Current year OA Pubs

No abstract provided.

Analysis Of Sars-Cov-2 Genomes Of Samples From Peru, Johnny Leandro Saavedra-Camacho, Sebastian Iglesias-Osores, Miguel Alcántara-Mimbela, Lizbeth M. Córdova-Rojas

Revista de la Facultad de Medicina Humana

Introduction: Genomic analysis of samples from documented COVID-19 cases can be used successfully to help track sources of Sars-Cov-2 infection, which can be quarantined to prevent the recurrent spread of the disease around the world. Objective: To describe the SARS-CoV-2 sequences isolated from Peruvian patients. Methods: All genomes published up to March 2021, uploaded in the GISAID and Nextstrain repository, were selected. All data is on the web in a public way; In addition, the information was filtered by continent, country, region, clade, lineage, and sex from March 2020 to February 2021. Results: It was evidenced that the region with …

Somatic Pik3r1 Variation As A Cause Of Vascular Malformations And Overgrowth, Catherine E Cottrell, Jonathan W Heusel, Meagan Corliss, Michael J Evenson, Carrie C Coughlin, Et Al.

2020-Current year OA Pubs

PURPOSE: Somatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1.

METHODS: Affected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity.

RESULTS: The …

Comprehensive Characterization Of 536 Patient-Derived Xenograft Models Prioritizes Candidatesfor Targeted Treatment., Hua Sun, Song Cao, R Jay Mashl, Chia-Kuei Mo, Simone Zaccaria, Michael C Wendl, Sherri R Davies, Matthew H Bailey, Tina M Primeau, Jeremy Hoog, Jacqueline L Mudd, Dennis A Dean, Rajesh Patidar, Li Chen, Matthew A Wyczalkowski, Reyka G Jayasinghe, Fernanda Martins Rodrigues, Nadezhda V Terekhanova, Yize Li, Kian-Huat Lim, Andrea Wang-Gillam, Brian A Van Tine, Cynthia X Ma, Rebecca Aft, Katherine C Fuh, Julie K Schwarz, Jose P Zevallos, Sidharth V Puram, John F Dipersio, Nci Pdxnet Consortium, Brandi Davis-Dusenbery, Matthew J Ellis, Michael T Lewis, Michael A Davies, Meenhard Herlyn, Bingliang Fang, Jack A Roth, Alana L Welm, Bryan E Welm, Funda Meric-Bernstam, Feng Chen, Ryan C Fields, Shunqiang Li, Ramaswamy Govindan, James H Doroshow, Jeffrey A Moscow, Yvonne A Evrard, Jeffrey Chuang, Benjamin J Raphael, Li Ding, Carol J Bult, Peter N Robinson

Faculty Research 2021

Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications …

Hypertrophic Cardiomyopathy Associated E22k Mutation In Myosin Regulatory Light Chain Decreases Calcium-Activated Tension And Stiffness And Reduces Myofilament Ca, Jiajia Zhang, Li Wang, Katarzyna Kazmierczak, Hang Yun, Danuta Szczesna-Cordary, Masataka Kawai

Journal Articles

UNLABELLED: We investigated the mechanisms associated with E22K mutation in myosin regulatory light chain (RLC), found to cause hypertrophic cardiomyopathy (HCM) in humans and mice. Specifically, we characterized the mechanical profiles of papillary muscle fibers from transgenic mice expressing human ventricular RLC wild-type (Tg-WT) or E22K mutation (Tg-E22K). Because the two mouse models expressed different amounts of transgene, the B6SJL mouse line (NTg) was used as an additional control. Mechanical experiments were carried out on Ca

SUB-DISCIPLINE: Bioenergetics.

DATABASE: The data that support the findings of this study are available from the corresponding authors upon reasonable request.

ANIMAL PROTOCOL: BK20150353 …

Rnase Κ Promotes Robust Pirna Production By Generating 2',3'-Cyclic Phosphate-Containing Precursors, Megumi Shigematsu, Takuya Kawamura, Keisuke Morichika, Natsuko Izumi, Takashi Kiuchi, Shozo Honda, Venetia Pliatsika, Ryuma Matsubara, Isidore Rigoutsos, Susumu Katsuma, Yukihide Tomari, Yohei Kirino

Computational Medicine Center Faculty Papers

In animal germlines, PIWI proteins and the associated PIWI-interacting RNAs (piRNAs) protect genome integrity by silencing transposons. Here we report the extensive sequence and quantitative correlations between 2′,3′-cyclic phosphate-containing RNAs (cP-RNAs), identified using cP-RNA-seq, and piRNAs in the Bombyx germ cell line and mouse testes. The cP-RNAs containing 5′-phosphate (P-cP-RNAs) identified by P-cP-RNA-seq harbor highly consistent 5′-end positions as the piRNAs and are loaded onto PIWI protein, suggesting their direct utilization as piRNA precursors. We identified Bombyx RNase Kappa (BmRNase κ) as a mitochondria-associated endoribonuclease which produces cP-RNAs during piRNA biogenesis. BmRNase κ-depletion elevated transposon levels and disrupted a piRNA-mediated …

Coding And Noncoding Variants In Ebf3 Are Involved In Hadds And Simplex Autism, Evin M Padhi, Jeffrey K Ng, Elvisa Mehinovic, Tychele N Turner, Et Al.

2020-Current year OA Pubs

BACKGROUND: Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737. …

Balanced Impacts Of Fitness And Drug Pressure On The Evolution Of Pfmdr1 Polymorphisms In Plasmodium Falciparum., Marvin Duvalsaint, Melissa D. Conrad, Stephen Tukwasibwe, Patrick K. Tumwebaze, Jennifer Legac, Roland A. Cooper, Philip J. Rosenthal

Natural Sciences and Mathematics | Faculty Scholarship

BACKGROUND: Anti-malarial drug resistance may be limited by decreased fitness in resistant parasites. Important contributors to resistance are mutations in the Plasmodium falciparum putative drug transporter PfMDR1.

METHODS: Impacts on in vitro fitness of two common PfMDR1 polymorphisms, N86Y, which is associated with sensitivity to multiple drugs, and Y184F, which has no clear impact on drug sensitivity, were evaluated to study associations between resistance mediators and parasite fitness, measured as relative growth in competitive culture experiments. NF10 P. falciparum lines engineered to represent all PfMDR1 N86Y and Y184F haplotypes were co-cultured for 40 days, and the genetic make-up of the …

The Rare C9 P167s Risk Variant For Age-Related Macular Degeneration Increases Polymerization Of The Terminal Component Of The Complement Cascade, O Mcmahon, A Java, J P Atkinson, Et Al.

2020-Current year OA Pubs

Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma …

An Investigation On The Irish Population’S Attitudes And Knowledge Towards Genetic Screening For Cancer, Emer Mccarthy, Ada Fleming, Dawn Hannah Cronin

International Undergraduate Journal of Health Sciences

Genetic mutations are alterations in DNA that may result in the development of a disease later in life. A BRCA gene is a tumour suppressor gene that helps to prevent the development of some cancers, particularly breast cancer. If a mutation occurs, this gene no longer functions at preventing these cancers. Genetic screening is when a population is tested for a mutation in an attempt to identify a group of people that are positive for the mutation. This can help identify cancer in different populations as well as track their inheritance. This study was conducted online, questioning the Irish populations …

Full Issue: The International Undergraduate Journal Of Health Sciences, Volume 1, Issue 1, June 2021

International Undergraduate Journal of Health Sciences

The full June 2021 issue (Volume 1, Issue 1) of the International Undergraduate Journal of Health Sciences

Cancer-Associated Mutations Reveal A Novel Role For Epcam As An Inhibitor Of Cathepsin-L And Tumor Cell Invasion, Narendra V Sankpal, Taylor C Brown, Timothy P Fleming, John M Herndon, Anusha A Amaravati, Allison N Loynd, William E Gillanders

2020-Current year OA Pubs

BACKGROUND: EpCAM (Epithelial cell adhesion molecule) is often dysregulated in epithelial cancers. Prior studies implicate EpCAM in the regulation of oncogenic signaling pathways and epithelial-to-mesenchymal transition. It was recently demonstrated that EpCAM contains a thyroglobulin type-1 (TY-1) domain. Multiple proteins with TY-1 domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor cell invasion and metastasis. Analysis of human cancer sequencing studies reveals that somatic EpCAM mutations are present in up to 5.1% of tested tumors.

METHODS: The Catalogue of Somatic Mutations in Cancer (COSMIC) database was queried to tabulate the position and amino acid changes of …

Replication Protein A (Rpa) Targeting Of Uracil Dna Glycosylase (Ung2), Derek Chen, Brian P Weiser

Rowan-Virtua Research Day

Replication Protein A (RPA) is a single stranded DNA binding protein which stabilizes ssDNA for replication and repair. One function of RPA is to bind the DNA repair enzyme uracil DNA glycosylase (UNG2) and direct its activity towards ssDNA dsDNA junctions.

UNG2 removes uracil bases from DNA which can appear through dUMP misincorporation or through cytosine deamination. If uracil is present instead of a cytosine, then the original GC pair becomes a GU pair. The uracil will then base pair to adenine in the replicated daughter strand. This results in a GC → AT mutation that could contribute to cancer …

Covid-19: The Vaccine Race Continues, L. Hayley Burgess, Carley Castelein, Andrew Rubio, Mandelin K. Cooper

HCA Healthcare Journal of Medicine

Over a year has passed since the discovery of SARS-CoV-2 and the subsequent COVID-19 pandemic. As mitigation efforts continue, COVID-19 has claimed over half a million lives in the United States and 3.1 million lives globally. The development and availability of vaccines delivering immunity to prevent COVID-19 offers hope to end the pandemic.

Emergency use authorizations from the Food and Drug Administration have been issued in the United States for three vaccines, one each from Pfizer-BioNTech, Moderna and Janssen/J&J. Pfizer-BioNTech and Moderna are both mRNA vaccines with efficacy of 95% and 94.1% respectively, while the vector-based vaccine from Janssen/J&J has …

Pfmfr3: A Multidrug-Resistant Modulator In Plasmodium Falciparum, Frances Rocamora, Purva Gupta, Eva S Istvan, Madeline R Luth, Emma F Carpenter, Krittikorn Kümpornsin, Erika Sasaki, Jaeson Calla, Nimisha Mittal, Krypton Carolino, Edward Owen, Manuel Llinás, Sabine Ottilie, Daniel E Goldberg, Marcus C S Lee, Elizabeth A Winzeler

2020-Current year OA Pubs

In malaria, chemical genetics is a powerful method for assigning function to uncharacterized genes. MMV085203 and GNF-Pf-3600 are two structurally related napthoquinone phenotypic screening hits that kill both blood- and sexual-stage

The Distribution In Native Populations From Mexico And Central America Of The C677t Variant In The Mthfr Gene, Lucio A. Reyes

USF Tampa Graduate Theses and Dissertations

Objectives: To explore evolutionary hypotheses for the high frequencies of a substitution in the methylenetetrahydrofolate reductase (MTHFR) gene, in Mexican and Central American Indigenous populations.

Materials and methods: We obtained allele frequencies for the C677T variant in the MTHFR gene and ecological information for 37 indigenous samples from Mexico and Central America. We calculated Hardy–Weinberg equilibrium and computed Fst statistics. We computed correlations between the samples' allele frequencies and ecological and geochemical variables.

Results: Many of the samples have extremely high frequencies of the T allele (q̄ = 0.62, median = 0.66). In this region, the frequency of the T …

Phenotype Expression Variability In Children With Gabrb3 Heterozygous Mutations., Abdulhafeez M. Khair, Alana E. Salvucci

Department of Pediatrics Faculty Papers

GABRB3 gene is a recently identified gene located in 15q12 chromosome and encodes for gamma-aminobutyric acid (GABA) receptor subunit beta-3 protein, which is linked to the GABAA receptor. The gene is believed to share a role in inhibitory GABAergic synapses, GABA iron-gated channel function, and possible cellular response to histamine. The β3 subunit is expressed in cerebral grey matter, thalami, hippocampi, and cerebellum, among other structures. Faulty GABRB3 function is linked to several neurological disorders and clinical syndromes. However, the spectrum of such disorders is not yet well known. We present three case reports highlighting the potentially expanding clinical phenotype …

Relationship Between Clinicopathologic Factors And Fdg Avidity In Radioiodine-Negative Recurrent Or Metastatic Differentiated Thyroid Carcinoma, Le Ngoc Ha, Amir Iravani, Nguyen Thi Nhung, Ngo Thi Minh Hanh, Febby Hutomo, Mai Hong Son

2020-Current year OA Pubs

BACKGROUND: In this study, we investigated the relationship between clinicopathologic factors, BRAF

METHODS: From 2015 to 2018 all patients with suspected recurrent or metastatic radioiodine-negative DTC patients who underwent FDG positron emission tomography/computed tomography (PET/CT) were retrospectively reviewed. Suspected lesions on FDG PET/CT were biopsied and underwent BRAF

RESULTS: Sixty-three consecutive patients, 55 (87.3%) female, with median age of 48 (range 17-81) were included. The majority of patients had BRAF

CONCLUSION: The majority of recurrent or metastatic RAI-negative DTC have BRAF

Multiplex Qpcr Discriminates Variants Of Concern To Enhance Global Surveillance Of Sars-Cov-2, Chantal B. F. Vogels, Mallery I. Breban, Isabel M. Ott, Tara Alpert, Mary E. Petrone, Anne E. Watkins, Chaney C. Kalinich, Rebecca Earnest, Jessica E. Rothman, Jaqueline Goes De Jesus, Ingra Morales Claro, Giulia Magalhães Ferreira, Myuki A. E. Crispim, Brazil-Uk Cadde Genomic Network, Lavanya Singh, Houriiyah Tegally, Ugochukwu J. Anyaneji, Network For Genomic Surveillance In South Africa, Emma B. Hodcroft, Christopher E. Mason, Gaurav Khullar, Jessica Metti, Joel T. Dudley, Matthew J. Mackay, Megan Nash, Jianhui Wang, Chen Liu, Pei Hui, Steven Murphy, Caleb Neal, Eva Laszlo, Marie L. Landry, Anthony Muyombwe, Randy Downing, Jafar Razeq, Tulio De Oliveira, Nuno R. Faria, Ester C. Sabino, Richard A. Neher, Joseph R. Fauver, Nathan D. Grubaugh

Journal Articles: Epidemiology

With the emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants that may increase transmissibility and/or cause escape from immune responses, there is an urgent need for the targeted surveillance of circulating lineages. It was found that the B.1.1.7 (also 501Y.V1) variant, first detected in the United Kingdom, could be serendipitously detected by the Thermo Fisher TaqPath COVID-19 PCR assay because a key deletion in these viruses, spike Δ69-70, would cause a "spike gene target failure" (SGTF) result. However, a SGTF result is not definitive for B.1.1.7, and this assay cannot detect other variants of concern (VOC) that lack …

Questions Concerning The Proximal Origin Of Sars-Cov-2, Murat Seyran, Damiano Pizzol, Parise Adadi, Tarek M. El-Aziz, Sk. Sarif Hassan, Antonio Soares, Ramesh Kandimalla, Kenneth Lundstrom, Murtaza Tambuwala, Alaa A. Aljabali, Amos Lal, Gajendra K. Azad, Pabitra P. Choudhury, Vladimir N. Uversky, Samendra P. Sherchan, Bruce D. Uhal, Nima Rezaei, Adam M. Brufsky

Molecular Medicine Faculty Publications

No abstract provided.