Medical Specialties Commons^™

Successful Brace Treatment Of Pectus Carinatum In Osteogenesis Imperfecta Using The Dynamic Compression System., Beth A. Orrick, Amy L. Pierce, Charles L. Snyder, Uri S. Alon

Manuscripts, Articles, Book Chapters and Other Papers

Osteogenesis imperfecta (OI) is a genetic disorder of collagen resulting in a "fragile" skeleton with increased fracture risk and other complications, dependent on the specific variant. Pectus deformities of the chest wall, while not common, can be associated with OI. The use of a pectus carinatum brace in a patient with OI poses unknown risks for fractures and adverse treatment outcomes. We successfully applied external compression bracing using the dynamic compression system to one such patient. This case illustrates the ability to treat an OI patient with pectus carinatum using a nonsurgical brace, without complications, resulting in an excellent cosmetic …

Genomic Prediction Of Relapse In Recipients Of Allogeneic Haematopoietic Stem Cell Transplantation., J Ritari, K Hyvärinen, S Koskela, M Itälä-Remes, R Niittyvuopio, A Nihtinen, U Salmenniemi, M Putkonen, L Volin, T Kwan, T Pastinen, J Partanen

Manuscripts, Articles, Book Chapters and Other Papers

Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the …

Melatonin Enhances Sorafenib-Induced Cytotoxicity In Flt3-Itd Acute Myeloid Leukemia Cells By Redox Modification, Tian Tian, Jiajun Li, Yizhuo Li, Yun-Xin Lu, Yan-Lai Tang, Hua Wang, Fufu Zheng, Dingbo Shi, Qian Long, Miao Chen, Guillermo Garcia-Manero, Yumin Hu, Lijun Qin, Wuguo Deng

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with an internal tandem duplication in Fms-related tyrosine kinase 3 (FLT3-ITD) is identified as a subgroup with poor outcome and intrinsic resistance to chemotherapy and therefore urgent need for development of novel therapeutic strategies.

Methods: The antitumor effects of melatonin alone or combined with sorafenib were evaluated via flow cytometry and immunoblotting assays in FLT-ITD AML cells. Also, the ex vivo and in vivo models were used to test the synergistic effects of melatonin and sorafenib against leukemia with FLT3/ITD mutation.

Results: Our study shows for the first time that melatonin inhibits proliferation and induces apoptosis …

Ribonucleotide Reductase Inhibitor 3-Ap Induces Oncogenic Virus Infected Cell Death And Represses Tumor Growth, Lu Dai, Jungang Chen, Yueyu Cao, Luis Del Valle, Zhiqiang Qin

School of Medicine Faculty Publications

Kaposi's Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human malignancies, particularly Kaposi's Sarcoma (KS), which preferentially arise in immunocompromised patients such as HIV+ subpopulation while still lacking of effective therapeutic options. We recently found that the ribonucleotide reductase (RR) subunit M2 is potentially regulated by the key oncogenic HGF/c-MET pathway in KSHV-related lymphoma cells. One of RR inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) effectively induced apoptosis of KSHV+ lymphomas and suppressed tumor progression . In the current study, we found that 3-AP treatment selectively inhibited the proliferation of KSHV-infected endothelial cells, the major cellular components of KS, through inducing DNA …

Regulators Of Oncogenic Mutant Tp53 Gain Of Function., Satomi Yamamoto, Tomoo Iwakuma

Manuscripts, Articles, Book Chapters and Other Papers

The tumor suppressor p53 (TP53) is the most frequently mutated human gene. Mutations in TP53 not only disrupt its tumor suppressor function, but also endow oncogenic gain-of-function (GOF) activities in a manner independent of wild-type TP53 (wtp53). Mutant TP53 (mutp53) GOF is mainly mediated by its binding with other tumor suppressive or oncogenic proteins. Increasing evidence indicates that stabilization of mutp53 is crucial for its GOF activity. However, little is known about factors that alter mutp53 stability and its oncogenic GOF activities. In this review article, we primarily summarize key regulators of mutp53 stability/activities, including genotoxic stress, post-translational modifications, ubiquitin …

Precision Medicine In Pediatric Cancer: Current Applications And Future Prospects., Atif Ahmed, Divya S. Vundamati, Midhat S. Farooqi, Erin M. Guest

Manuscripts, Articles, Book Chapters and Other Papers

Precision oncologic medicine is an emerging approach for cancer treatment that has recently taken giant steps in solid clinical practice. Recent advances in molecular diagnostics that can analyze the individual tumor's variability in genes have provided greater understanding and additional strategies to treat cancers. Although tumors can be tested by several molecular methods, the use of next-generation sequencing (NGS) has greatly facilitated our understanding of pediatric cancer and identified additional therapeutic opportunities. Pediatric tumors have a different genetic make-up, with a fewer number of actionable targets than adult tumors. Nevertheless, precision oncology in the pediatric population has greatly improved the …

Notch Signaling Regulates Mitochondrial Metabolism And Nf-Κb Activity In Triple-Negative Breast Cancer Cells Via Ikkα-Dependent Non-Canonical Pathways, Fokhrul Hossain, Claudia Sorrentino, Deniz A. Ucar, Yin Peng, Margarite Matossian, Dorota Wyczechowska, Judy Crabtree, Jovanny Zabaleta, Silvana Morello, Luis Del Valle, Matthew Burow, Bridgette Collins-Burow, Antonio Pannuti, Lisa M. Minter, Todd E. Golde, Barbara A. Osborne, Lucio Miele

School of Medicine Faculty Publications

Triple negative breast cancer (TNBC) patients have high risk of recurrence and metastasis, and current treatment options remain limited. Cancer stem-like cells (CSCs) have been linked to cancer initiation, progression and chemotherapy resistance. Notch signaling is a key pathway regulating TNBC CSC survival. Treatment of TNBC with PI3K or mTORC1/2 inhibitors results in drug-resistant, Notch-dependent CSC. However, downstream mechanisms and potentially druggable Notch effectors in TNBC CSCs are largely unknown. We studied the role of the AKT pathway and mitochondrial metabolism downstream of Notch signaling in TNBC CSC from cell lines representative of different TNBC molecular subtypes as well as …

Autoimmune Hyperphosphatemic Tumoral Calcinosis In A Patient With Fgf23 Autoantibodies., Mary Scott Roberts, Peter D. Burbelo, Daniela Egli-Spichtig, Farzana Perwad, Christopher J. Romero, Shoji Ichikawa, Emily G. Farrow, Michael J. Econs, Lori C. Guthrie, Michael T. Collins, Rachel I. Gafni

Manuscripts, Articles, Book Chapters and Other Papers

Hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder of ectopic calcification due to deficiency of or resistance to intact fibroblast growth factor 23 (iFGF23). Inactivating mutations in FGF23, N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO (KL) have been reported as causing HFTC/HHS. We present what we believe is the first identified case of autoimmune hyperphosphatemic tumoral calcinosis in an 8-year-old boy. In addition to the classical clinical and biochemical features of hyperphosphatemic tumoral calcinosis, the patient exhibited markedly elevated intact and C-terminal FGF23 levels, suggestive of FGF23 resistance. However, no mutations in FGF23, KL, or FGF receptor 1 …

Genetic Predisposition To Necrotizing Enterocolitis In Premature Infants: Current Knowledge, Challenges, And Future Directions., Alain Cuna, Lovya George, Venkatesh Sampath

Manuscripts, Articles, Book Chapters and Other Papers

The role of genetics in the pathogenesis of necrotizing enterocolitis (NEC) was initially informed by epidemiological data indicating differences in prevalence among different ethnic groups as well as concordance in twins. These early observations, together with major advances in genomic research, paved the way for studies that begin to reveal the contribution of genetics to NEC. Using the candidate gene or pathway approach, several potential pathogenic variants for NEC in premature infants have already been identified. More recently, genome-wide association studies and exome-sequencing based studies for NEC have been reported. These advances, however, are tempered by the lack of adequately …

Proteomics Of Human Liver Membrane Transporters: A Focus On Fetuses And Newborn Infants., Bianca D. Van Groen, Evita Van De Steeg, Miriam G. Mooij, Marola M H Van Lipzig, Barbara A E De Koning, Robert M. Verdijk, Heleen M. Wortelboer, R Gaedigk, Chengpeng Bi, J Steven Leeder, Ron H N Van Schaik, Joost Van Rosmalen, Dick Tibboel, Wouter H. Vaes, Saskia N. De Wildt

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples.

METHODS: Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples. mRNA expression was quantified using RNA sequencing, and genetic variants with TaqMan assays. We explored relationships between protein expression and age …

Distinct Neuropsychological Profile And Associated Neurochemical Changes In Individuals With Mitochondrial Encephalomyopathy, Lactic Acidosis, And Stroke-Like Episodes (Melas), Emily B. Leaffer

Dissertations, Theses, and Capstone Projects

Background: Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS) is a maternally inherited progressive multisystemic disorder. Occurrence of seizure and/or stroke-like episode, as well as classic biomarkers (i.e., cerebral lactic acidosis, depleted N-acetylaspartate (NAA)), have been linked to neuropsychological deficit and trigger the developmental cascade of neurodegeneration affecting posterior prior to anterior brain regions. While a pattern of global deterioration has been reported, systematic examination in a large MELAS cohort has not been conducted.

Objective: First, we examined verbal and visual memory function and its relationship to brain metabolites (lactate, NAA) in individuals with MELAS. Second, we hypothesized that MELAS …

Lafora Disease Masquerading As Hepatic Dysfunction, Faisal Inayat, Waqas Ullah, Hanan T. Lodhi, Zarak H. Khan, Ghulam Ilyas, Nouman Safdar Ali, Hafez Mohammad A. Abdullah

Abington Jefferson Health Papers

Lafora disease is fatal intractable progressive myoclonic epilepsy. It is frequently characterized by epileptic seizures, difficulty walking, muscle spasms, and dementia in late childhood or adolescence. We chronicle here an unusual case of an asymptomatic young male soccer player who presented with elevated liver enzymes. Neurological examination was unremarkable. The diagnostic workup for hepatitis, infectious etiologies, autoimmune disorders, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, and other related diseases was inconclusive. He subsequently underwent an uneventful percutaneous liver biopsy. Based on the pathognomonic histopathological findings, Lafora disease was considered the likely etiology. The present study is a unique illustration of this …

An Eqtl Landscape Of Kidney Tissue In Human Nephrotic Syndrome., Christopher E. Gillies, Rosemary Putler, Rajasree Menon, Edgar Otto, Kalyn Yasutake, Viji Nair, Paul Hoover, David Lieb, Shuqiang Li, Sean Eddy, Damian Fermin, Michelle T. Mcnulty, Nephrotic Syndrome Study Network (Neptune), Nir Hacohen, Krzysztof Kiryluk, Matthias Kretzler, Xiaoquan Wen, Matthew G. Sampson, Tarak Srivastava

Manuscripts, Articles, Book Chapters and Other Papers

Expression quantitative trait loci (eQTL) studies illuminate the genetics of gene expression and, in disease research, can be particularly illuminating when using the tissues directly impacted by the condition. In nephrology, there is a paucity of eQTL studies of human kidney. Here, we used whole-genome sequencing (WGS) and microdissected glomerular (GLOM) and tubulointerstitial (TI) transcriptomes from 187 individuals with nephrotic syndrome (NS) to describe the eQTL landscape in these functionally distinct kidney structures. Using MatrixEQTL, we performed cis-eQTL analysis on GLOM (n = 136) and TI (n = 166). We used the Bayesian "Deterministic Approximation of Posteriors" (DAP) to fine-map …

Review Of Karyotypic Data From Low Grade Glial Brain Tumors, Specifically Pilocytic Astrocytomas, And Correlation Of Genetic Aberrations With Tumor Recurrence., Linda D. Cooley, Scott C. Smith, Lisa Warren, Melissa Gener, Kevin Ginn, John Herriges

Posters

Abstract: Brain tumors are the most common solid tumor of childhood. Approximately 50% of pediatric CNS tumors are low grade gliomas (WHO grade I or II) and Pilocytic astrocytoma (PA) is the most common accounting for 33% of all gliomas in children 0-14 years and ~18% of all childhood brain tumors. Prognosis with this slow-growing tumor is excellent; 10 year overall survival of ~95%. However, event free survival averages ~50%. Patient age and extent of tumor resection are key prognostic factors; tumor location and size impact resection and outcome. Histopathological features indicate PA is a benign tumor and rarely are …

Banning Abortion In Cases Of Down Syndrome: Important Lessons For Advances In Genetic Diagnosis, Rebecca Reingold, Lawrence O. Gostin

Georgetown Law Faculty Publications and Other Works

In December 2017, Ohio passed into law legislation that prohibited physicians from performing abortions if the pregnant woman’s decision was influenced by her belief that the fetus has Down syndrome. Physicians who perform abortions in these cases would face fourth-degree felony charges and revocation of their medical license. No other state bans abortion specifically for Down syndrome, but several ban abortions in cases of genetic diseases. Lower courts have struck down most such laws, holding they violate the constitutional rights of women. In February 2018, a federal district court judge blocked enforcement of Ohio’s law pending a final determination.

This …

Outcomes Of Genetic Testing In A Genitourinary Genetics Clinic, Annelise Pace

Dissertations and Theses (Open Access)

Several known hereditary cancer syndromes confer an increased risk for genitourinary (GU)related malignancies. Various guidelines indicate when to refer patients to genetic counseling for GU-related hereditary cancer syndromes but there is limited research on the clinical picture of these patients, including their cancerous and non-cancerous features, the genetic testing strategy for this population, and the probability of having a positive germline mutation if testing is performed. The purpose of this study is to determine the most common indications for ordering genetic testing in a GU Genetics Clinic and evaluate whether there is a relationship between the indication for genetic testing …

Hla-Dqa1 And Apol1 As Risk Loci For Childhood-Onset Steroid-Sensitive And Steroid-Resistant Nephrotic Syndrome., Adebowale Adeyemo, Christopher Esezobor, Adaobi Solarin, Asiri Abeyagunawardena, Jameela A. Kari, Sherif El Desoky, Larry A. Greenbaum, Margret Kamel, Mahmoud Kallash, Cynthia Silva, Alex Young, Tracey E. Hunley, Nilka De Jesus-Gonzalez, Tarak Srivastava, Rasheed Gbadegesin

Manuscripts, Articles, Book Chapters and Other Papers

Background: Few data exist for the genetic variants underlying the risk for steroid-sensitive nephrotic syndrome (SSNS) in children. The objectives of this study were to evaluate HLA-DQA1 and APOL1 variants as risk factors for SSNS in African American children and use classic HLA antigen types and amino acid inference to refine the HLA-DQA1 association.

Study design: Case-control study.

Setting & participants: African American children with SSNS or steroid-resistant nephrotic syndrome (SRNS) were enrolled from Duke University and centers participating in the Midwest Pediatric Nephrology Consortium.

Factor: Genetic variants in HLA-DQA1 (C34Y [rs1129740]; F41S [rs1071630]) and APOL1 high-risk alleles.

Outcomes: SSNS …

Novel Combination Bmp7 And Hgf Gene Therapy Instigates Selective Myofibroblast Apoptosis And Reduces Corneal Haze In Vivo, Suneel Gupta, Michael K. Fink, Arkasubhra Ghosh, Ratnakar Tripathi, Prashant R. Sinha, Ajay Sharma, Nathan P. Hesemann, Shyam S. Chaurasia, Elizabeth A. Giuliano, Rajiv R. Mohan

Pharmacy Faculty Articles and Research

PURPOSE. We tested the potential of bone morphogenic protein 7 (BMP7) and hepatocyte growth factor (HGF) combination gene therapy to treat preformed corneal fibrosis using established rabbit in vivo and human in vitro models.

METHODS. Eighteen New Zealand White rabbits were used. Corneal fibrosis was produced by alkali injury. Twenty-four hours after scar formation, cornea received topically either balanced salt solution (BSS; n ¼ 6), polyethylenimine-conjugated gold nanoparticle (PEI2-GNP)-naked plasmid (n ¼ 6) or PEI2-GNP plasmids expressing BMP7 and HGF genes (n ¼ 6). Donor human corneas were used to obtain primary human corneal fibroblasts and myofibroblasts for mechanistic studies. …

Microrna 1207-3p In Prostate Cancer, Dibash Das

Dissertations, Theses, and Capstone Projects

Prostate cancer (PCa) is the most commonly diagnosed male cancer and the second leading cause of cancer-related death for men in the United States. Understanding the molecular mechanisms involved in progression from the asymptomatic androgen-dependent PCa to the lethal castration resistant prostate cancer (CRPC) is a major challenge. MicroRNAs (miRNAs), are known to be dysregulated in PCa. MicroRNA-1207-3p (miR-1207-3p) is encoded by the non-protein coding gene locus PVT1 on the 8q24 human chromosomal region, an established PCa susceptibility locus. However, the role of miR-1207-3p in PCa is unclear. We have discovered that miR-1207-3p is significantly underexpressed in PCa cell lines …

A Plasma Telomeric Cell-Free Dna Level In Unaffected Women With Brca1 Or/And Brca2 Mutations: A Pilot Study, Shatovisha Dey, Natascia Marino, Kanokwan Bishop, Paige N. Dahlgren, Aditi Shendre, Anna Maria Storniolo, Chunyan He, Hiromi Tanaka

Internal Medicine Faculty Publications

Plasma cell-free DNA (cfDNA) is a small DNA fragment circulating in the bloodstream originating from both non-tumor- and tumor-derived cells. A previous study showed that a plasma telomeric cfDNA level decreases in sporadic breast cancer patients compared to controls. Tumor suppressor gene products including BRCA1 and BRCA2 (BRCA1&2) play an important role in telomere maintenance. In this study, we hypothesized that the plasma telomeric cfDNA level is associated with the mutation status of BRCA1&2 genes. To test this hypothesis, we performed plasma telomeric cfDNA quantitative PCR (qPCR)-based assays to compare 28 women carriers of the BRCA1&2 mutation with age-matched controls …

Fasudil In Combination With Bone Marrow Stromal Cells (Bmscs) Attenuates Alzheimer’S Disease-Related Changes Through The Regulation Of The Peripheral Immune System, Jiezhong Yu, Yuqing Yan, Qingfang Gu, Gajendra Kumar, Hongqiang Yu, Yijin Zhao, Chunyun Liu, Ye Gao, Zhi Chai, Jasleen Chumber, Bao-Guo Xiao, Guang-Xian Zhang, Han-Ting Zhang, Yuqiang Jiang, Cun-Gen Ma

Faculty & Staff Scholarship

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease. Its mechanism is still not clear. Majority of research focused on the central nervous system (CNS) changes, while few studies emphasize on peripheral immune system modulation. Our study aimed to investigate the regulation of the peripheral immune system and its relationship to the severity of the disease after treatment in an AD model of APPswe/PSEN1dE9 transgenic (APP/PS1 Tg) mice. APP/PS1 Tg mice (8 months old) were treated with the ROCK-II inhibitor 1-(5-isoquinolinesulfonyl)- homo-piperazine (Fasudil) (intraperitoneal (i.p.) injections, 25 mg/kg/day), bone marrow stromal cells (BMSCs; caudal vein injections, 1 × 106 BMSCs …

Mechanotransduction Signaling In Podocytes From Fluid Flow Shear Stress., Tarak Srivastava, Hongying Dai, Daniel P. Heruth, Uri S. Alon, Robert E. Garola, Jianping Zhou, R Scott Duncan, Ashraf El-Meanawy, Ellen T. Mccarthy, Ram Sharma, Mark L. Johnson, Virginia J. Savin, Mukut Sharma

Manuscripts, Articles, Book Chapters and Other Papers

Recently, we and others have found that hyperfiltration-associated increase in biomechanical forces, namely, tensile stress and fluid flow shear stress (FFSS), can directly and distinctly alter podocyte structure and function. The ultrafiltrate flow over the major processes and cell body generates FFSS to podocytes. Our previous work suggests that the cyclooxygenase-2 (COX-2)-PGE2-PGE2 receptor 2 (EP2) axis plays an important role in mechanoperception of FFSS in podocytes. To address mechanotransduction of the perceived stimulus through EP2, cultured podocytes were exposed to FFSS (2 dyn/cm2) for 2 h. Total RNA from cells at the end of FFSS treatment, 2-h post-FFSS, and 24-h …

Combinational Sirna Delivery Using Hyaluronic Acid Modified Amphiphilic Polyplexes Against Cell Cycle And Phosphatase Proteins To Inhibit Growth And Migration Of Triple-Negative Breast Cancer Cells, Manoj B. Parmar, Daniel Nisakar Meenakshi Sundaram, Remant Bahadur Kc, Robert Maranchuk, Hamidreza Montazeri Aliabadi, Judith C. Hugh, Raimar Löbenberg, Hasan Uludağ

Pharmacy Faculty Articles and Research

Triple-negative breast cancer is an aggressive form of breast cancer with few therapeutic options if it recurs after adjuvant chemotherapy. RNA interference could be an alternative therapy for metastatic breast cancer, where small interfering RNA (siRNA) can silence the expression of aberrant genes critical for growth and migration of malignant cells. Here, we formulated a siRNA delivery system using lipid-substituted polyethylenimine (PEI) and hyaluronic acid (HA), and characterized the size, ζ-potential and cellular uptake of the nanoparticulate delivery system. Higher cellular uptake of siRNA by the tailored PEI/HA formulation suggested better interaction of complexes with breast cancer cells due to …

The Influence Of A Kdt501, A Novel Isohumulone, On Adipocyte Function In Humans, Brian S. Finlin, Beibei Zhu, Bernard P. Kok, Cristina Godio, Philip M. Westgate, Neile Grayson, Robert Sims, Jeffrey S. Bland, Enrique Saez, Philip A. Kern

Internal Medicine Faculty Publications

Objective: In a phase II clinical trial in nine obese, insulin-resistant humans, we observed that treatment with KDT501, a novel isohumulone drug, increased total and high-molecular weight (HMW) adiponectin in plasma. The objective was to determine whether KDT501 increased adiponectin secretion from subcutaneous white adipose tissue (SC WAT) and the underlying mechanism(s).

Methods: Nine obese participants with either prediabetes or with normal glucose tolerance plus three features of metabolic syndrome were part of the study. SC WAT biopsies were performed before and after 28 days of KDT501 treatment in a clinical research setting. In addition, a cold stimulus was used …

Expression Of Placental Regulatory Genes Is Associated With Fetal Growth, Maya A. Deyssenroth, Qian Li, Marina Lacasaña, Yoko Nomura, Carmen Marsit, Jia Chen

Publications and Research

The placenta is the principal organ regulating respiratory, nutritional, endocrine and metabolic functions on behalf of the developing fetus. Changes in gene expression patterns of placenta-specific genes may influence fetal growth. We profiled the expression of 17 genes related to placenta functioning in term placentas (n=677) to identify genes differentially expressed across birth weight categories [small (SGA), appropriate (AGA) and large (LGA) for gestational age]. ABCG2, CEBPB, CRH, GCM1, GPC3, INSL4, PGF and PLAC1 were inversely associated with LGA status, with odds ratios (ORs) and 95% confidence intervals (CI) ranging from GCM1 (OR=0.44, 95% CI: 0.29, 0.70) to CRH (OR=0.73, …

Managing Variant Discrepancy In Hereditary Cancer: Clinical Practice, Barriers, And Desired Resources, Ellen Zirkelbach

Dissertations and Theses (Open Access)

Variants are changes in the DNA whose phenotypic effects may or may not be definitively understood. Because variant interpretation is a complex process, sources sometimes disagree on the classification of a variant, which is called a variant discrepancy. This study aimed to determine the practice of genetic counselors regarding variant discrepancies and to identify the barriers to counseling a variant discrepancy in hereditary cancer genetic testing. This investigation was unique because it was the first to address variant discrepancies from a clinical point of view. An electronic survey was sent to genetic counselors in the NSGC Cancer Special Interest Group. …

The Utilization Of Prenatal Microarray: A Survey Of Current Genetic Counseling Practices And Barriers, Leslie N. Durham, Leslie Durham

Dissertations and Theses (Open Access)

Chromosomal microarray (CMA) assesses chromosome copy number variants (CNVs) missed by standard karyotyping. The American College of Obstetricians and Gynecologists (ACOG) recommends CMA for all patients with fetuses with an ultrasound anomaly and suggests that it be made available to all women undergoing invasive testing. In order to assess prenatal genetic counselors’ (GCs) practices regarding the utilization of CMA we conducted a survey of their current practices, attitudes, and perceived barriers. Of the 192 respondents, 183 (95%) have incorporated CMA into clinical practice with the majority (64%) believing that the benefits of CMA outweigh the harms. However, only half (52%) …

Activity Of Distinct Growth Factor Receptor Network Components In Breast Tumors Uncovers Two Biologically Relevant Subtypes, Moom Roosan, Shelley M. Macneil, David F. Jenkins, Gajendra Shrestha, Sydney R. Wyatt, Jasmine A. Mcquerry, Stephen R. Piccolo, Laura M. Heiser, Joe W. Gray, W. Evan Johnson, Andrea H. Bild

Pharmacy Faculty Articles and Research

Background
The growth factor receptor network (GFRN) plays a significant role in driving key oncogenic processes. However, assessment of global GFRN activity is challenging due to complex crosstalk among GFRN components, or pathways, and the inability to study complex signaling networks in patient tumors. Here, pathway-specific genomic signatures were used to interrogate GFRN activity in breast tumors and the consequent phenotypic impact of GRFN activity patterns.

Methods
Novel pathway signatures were generated in human primary mammary epithelial cells by overexpressing key genes from GFRN pathways (HER2, IGF1R, AKT1, EGFR, KRAS (G12V), RAF1, BAD). The pathway analysis toolkit Adaptive Signature Selection …

Genomic Contraindications For Heart Transplantation., Danton S. Char, Gabriel Lázaro-Muñoz, Aliessa Barnes, David Magnus, Michael J. Deem, John Lantos

Manuscripts, Articles, Book Chapters and Other Papers

Genome sequencing raises new ethical challenges. Decoding the genome produces new forms of diagnostic and prognostic information; however, the information is often difficult to interpret. The connection between most genetic variants and their phenotypic manifestations is not understood. This scenario is particularly true for disorders that are not associated with an autosomal genetic variant. The analytic uncertainty is compounded by moral uncertainty about how, exactly, the results of genomic testing should influence clinical decisions. In this Ethics Rounds, we present a case in which genomic findings seemed to play a role in deciding whether a patient was to be listed …

Fine-Mapping The Mhc Locus In Juvenile Idiopathic Arthritis (Jia) Reveals Genetic Heterogeneity Corresponding To Distinct Adult Inflammatory Arthritic Diseases., A Hinks, J Bowes, J Cobb, H C. Ainsworth, M C. Marion, M E. Comeau, M Sudman, B Han, Juvenile Arthritis Consortium For Immunochip, Mara L. Becker, J F. Bohnsack, P I W De Bakker, J P. Haas, M Hazen, D J. Lovell, P A. Nigrovic, E Nordal, M Punnaro, A M. Rosenberg, M Rygg, S L. Smith, C A. Wise, V Videm, L R. Wedderburn, A Yarwood, R S M Yeung, S Prahalad, C D. Langefeld, S Raychaudhuri, S D. Thompson, W Thomson

Manuscripts, Articles, Book Chapters and Other Papers

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides.

METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. …