Digital Commons Network^™

A Novel, Brief, Fully Automated Intervention To Extend The Antidepressant Effect Of A Single Ketamine Infusion: A Randomized Clinical Trial, Rebecca B Price, Crystal Spotts, Benjamin Panny, Angela Griffo, Michelle Degutis, Nicolas Cruz, Elizabeth Bell, Kevin Do-Nguyen, Meredith L Wallace, Sanjay J Mathew, Robert H Howland

Staff and Researcher Publications

Objective: Intravenous ketamine, which displays rapid antidepressant properties, is posited to reverse depression by rapidly enhancing neuroplasticity. The authors tested whether an automated, computer-based approach could efficiently leverage enhanced neuroplasticity to extend the durability of rapid clinical response.

Methods: A total of 154 adults (ages 18-60) with treatment-resistant unipolar depression were randomized in a double-blind, parallel-arm design to receive an active/active treatment combination (ketamine plus active "automated self-association training" [ASAT]; N=53) or one of two control arms that lacked either the active drug component (saline plus active ASAT; N=51) or the active behavioral component (ketamine plus sham ASAT; N=50). One …

A Phase I/Ii Trial Of Nivolumab Plus Ipilimumab In Children And Young Adults With Relapsed/Refractory Solid Tumors: A Children's Oncology Group Study Advl1412, Kara L Davis, Elizabeth Fox, Emasenyie Isikwei, Joel M Reid, Xiaowei Liu, Charles G Minard, Stephan Voss, Stacey L Berg, Brenda J Weigel, Crystal L Mackall

Faculty, Staff and Students Publications

PURPOSE: In many cancers, nivolumab in combination with ipilimumab improves response rates compared with either agent alone, but the combination has not been evaluated in childhood cancer. We conducted a phase I/II trial of nivolumab plus ipilimumab in children and young adults with recurrent/refractory solid tumors.

PATIENTS AND METHODS: ADVL1412, Part C assessed safety of nivolumab plus ipilimumab at two dose levels (DL): DL1 1 mg/kg of each drug and DL2 3 mg/kg nivolumab plus 1 mg/kg ipilimumab. Part D evaluated response at the recommended phase II dose (RP2D) in Ewing sarcoma, rhabdomyosarcoma, and osteosarcoma. Part E tested DL3 (1 …

Progress In Gastroparesis - A Narrative Review Of The Work Of The Gastroparesis Clinical Research Consortium, Pankaj J Pasricha, Madhusudan Grover, Katherine P Yates, Thomas L Abell, Kenneth L Koch, Richard W Mccallum, Irene Sarosiek, Cheryl E Bernard, Braden Kuo, Robert Bulat, Robert J Shulman, Bruno P Chumpitazi, James Tonascia, Laura A Miriel, Laura A Wilson, Mark L Van Natta, Emily Mitchell, Frank Hamilton, Gianrico Farrugia, Henry P Parkman, Niddk/Nih Gpcrc Consortium

Faculty, Staff and Students Publications

The Gastroparesis Clinical Research Consortium is a multicenter coalition created and funded by the National Institutes of Diabetes and Digestive and Kidney Disorders, with a mission to advance understanding of the pathophysiology of gastroparesis and develop an effective treatment for patients with symptomatic gastroparesis. In this review, we summarize the results of the published Gastroparesis Clinical Research Consortium studies as a ready and convenient resource for gastroenterologists and others to provide a clear understanding of the consortium's experience and perspective on gastroparesis and related disorders.

A Framework For Detecting Noncoding Rare-Variant Associations Of Large-Scale Whole-Genome Sequencing Studies, Zilin Li, Xihao Li, Hufeng Zhou, Sheila M Gaynor, Margaret Sunitha Selvaraj, Theodore Arapoglou, Corbin Quick, Yaowu Liu, Han Chen, Ryan Sun, Rounak Dey, Donna K Arnett, Paul L Auer, Lawrence F Bielak, Joshua C Bis, Thomas W Blackwell, John Blangero, Eric Boerwinkle, Donald W Bowden, Jennifer A Brody, Brian E Cade, Matthew P Conomos, Adolfo Correa, L Adrienne Cupples, Joanne E Curran, Paul S De Vries, Ravindranath Duggirala, Nora Franceschini, Barry I Freedman, Harald H H Göring, Xiuqing Guo, Rita R Kalyani, Charles Kooperberg, Brian G Kral, Leslie A Lange, Bridget M Lin, Ani Manichaikul, Alisa K Manning, Lisa W Martin, Rasika A Mathias, James B Meigs, Braxton D Mitchell, May E Montasser, Alanna C Morrison, Take Naseri, Jeffrey R O'Connell, Nicholette D Palmer, Patricia A Peyser, Bruce M Psaty, Laura M Raffield, Susan Redline, Alexander P Reiner, Muagututi'a Sefuiva Reupena, Kenneth M Rice, Stephen S Rich, Jennifer A Smith, Kent D Taylor, Margaret A Taub, Ramachandran S Vasan, Daniel E Weeks, James G Wilson, Lisa R Yanek, Wei Zhao, Jerome I Rotter, Cristen J Willer, Pradeep Natarajan, Gina M Peloso, Xihong Lin

Faculty, Staff and Student Publications

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare-variant (RV) associations with complex human diseases and traits. Variant-set analysis is a powerful approach to study RV association. However, existing methods have limited ability in analyzing the noncoding genome. We propose a computationally efficient and robust noncoding RV association detection framework, STAARpipeline, to automatically annotate a whole-genome sequencing study and perform flexible noncoding RV association analysis, including gene-centric analysis and fixed window-based and dynamic window-based non-gene-centric analysis by incorporating variant functional annotations. In gene-centric analysis, STAARpipeline uses STAAR to group noncoding variants based on functional categories of genes and incorporate …

Human Loss-Of-Function Variants In The Serotonin 2c Receptor Associated With Obesity And Maladaptive Behavior, Yang He, Bas Brouwers, Hesong Liu, Hailan Liu, Katherine Lawler, Edson Mendes De Oliveira, Dong-Kee Lee, Yongjie Yang, Aaron R Cox, Julia M Keogh, Elana Henning, Rebecca Bounds, Aliki Perdikari, Vikram Ayinampudi, Chunmei Wang, Meng Yu, Longlong Tu, Nan Zhang, Na Yin, Junying Han, Nikolas A Scarcelli, Zili Yan, Kristine M Conde, Camille Potts, Jonathan C Bean, Mengjie Wang, Sean M Hartig, Lan Liao, Jianming Xu, Inês Barroso, Jacek Mokrosinski, Yong Xu, I Sadaf Farooqi

Children’s Nutrition Research Center Staff Publications

Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression. Here we studied the role of the serotonin 2C receptor (5-HT2CR) in weight regulation and behavior. Using exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed …

Development Of Myelinating Glia: An Overview, Carlo D Cristobal, Hyun Kyoung Lee

Duncan NRI Faculty and Staff Publications

Myelin is essential to nervous system function, playing roles in saltatory conduction and trophic support. Oligodendrocytes (OLs) and Schwann cells (SCs) form myelin in the central and peripheral nervous systems respectively and follow different developmental paths. OLs are neural stem-cell derived and follow an intrinsic developmental program resulting in a largely irreversible differentiation state. During embryonic development, OL precursor cells (OPCs) are produced in distinct waves originating from different locations in the central nervous system, with a subset developing into myelinating OLs. OPCs remain evenly distributed throughout life, providing a population of responsive, multifunctional cells with the capacity to remyelinate …

Clinical And Demographic Factors Contributing To Asparaginase-Associated Toxicities In Children With Acute Lymphoblastic Leukemia, Priyadarshani Dharia, Michael D Swartz, M Brooke Bernhardt, Han Chen, M Monica Gramatges, Philip J Lupo, Austin L Brown, Michael E Scheurer

Center for Medical Ethics and Health Policy Staff Publications

A total of 548 patients (age range: 1-22 years, 60.4% Hispanic, 55.8% male) diagnosed with acute lymphoblastic leukemia were reviewed for pegaspargase-associated hypersensitivity (14.8%), hyperbilirubinemia (9.7%), venous thromboembolism (VTE, 9.7%), and pancreatitis (5.3%). Odds ratios (OR) and 95% confidence intervals (CI) evaluated associations between clinical factors and each toxicity, cumulative number of toxicities, and toxicity clusters identified using k-mode analysis. Most (68.9%) did not experience any toxicity, 24.6% experienced one toxicity, and 6.3% two or more. Age >10 years was associated with hyperbilirubinemia (OR = 3.83; 95% CI: 1.64-8.95), pancreatitis (OR = 3.72; 95% CI: 1.29-10.68), VTE (OR = 4.65; …

Phase I Car-T Clinical Trials Review, Shaun Bulsara, Mengfen Wu, Tao Wang

Center for Medical Ethics and Health Policy Staff Publications

Background/aim: Chimeric antigen receptor (CAR) T cells with tumor specificity are being increasingly investigated. Phase I trials are the first step of testing for safety of novel CAR-T therapy to determine the maximum tolerated dose (MTD). Several dose escalation methods have been developed over time including rule-based, model-based, and model-assisted designs. The goal of this project is to overview the phase I designs used in current CAR-T trials.

Materials and methods: We searched PubMed for peer-reviewed literature published between January 1, 2015 and December 31, 2021. The search was limited to human studies in the English language using the keywords …

Incidence Of An Insulin-Requiring Hyperglycemic Syndrome In Sars-Cov-2-Infected Young Individuals: Is It Type 1 Diabetes?, Massimo Pietropaolo, Peter Hotez, Nick Giannoukakis

Center for Medical Ethics and Health Policy Staff Publications

Pancreatic ACE2 receptor expression, together with increased prevalence of insulin-requiring hyperglycemia in patients with coronavirus disease 2019 (COVID-19), suggested that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pancreatic infection might trigger a β-cell-selective inflammation precipitating autoimmune type 1 diabetes (T1D). We examined T1D incidence in patients with COVID-19 inside a large, global population using a "big data" approach. The incidence in 0-30-year-old patients with confirmed COVID-19 over an ∼15-month period from the beginning of the COVID-19 pandemic was compared with an age-matched population without COVID-19 inside the TriNetX COVID-19 Research Network (>80 million deidentified patient electronic medical records globally). …

Factors Affecting Need For Blood Transfusion In Paediatric Patients Undergoing Open Surgery For Hip Dysplasia, Adam C Adler, Lisa A H Hensch, Brittany E Bryant, Arvind Chandrakantan, Hai-Yen Nguyen, Brian H Nathanson, Scott B Rosenfeld

Faculty, Staff and Students Publications

BACKGROUND AND OBJECTIVES: The management of intraoperative blood loss in the surgical treatment of paediatric hip dysplasia is resource intensive. There are numerous clinical factors that impact the need for intraoperative transfusion. Identification of patient and surgical factors associated with increased blood loss may reduce the unnecessary use of resources. This study aimed to identify factors predictive of intraoperative transfusion in children undergoing hip dysplasia surgery.

MATERIALS AND METHODS: This is a single-centre retrospective review of patients undergoing surgery for hip dysplasia from 1 January 2012 to 15 April 2021. Patient demographic factors, anaesthetic, surgical and transfusion histories were reviewed. …

Wide Range Of Phenotypic Severity In Individuals With Late Truncations Unique To The Predominant Cdkl5 Transcript In The Brain, Laura Keehan, Isabel Haviland, Yoel Gofin, Lindsay C Swanson, Christelle Moufawad El Achkar, John Schreiber, Grace E Vannoy, Emily O'Heir, Anne O'Donnell-Luria, Richard Alan Lewis, Pilar Magoulas, Alyssa Tran, Mahshid S Azamian, Hsiao-Tuan Chao, Lisa Pham, Rodney C Samaco, Sarah Elsea, Erin Thorpe, Akanchha Kesari, Denise Perry, Brendan Lee, Seema R Lalani, Jill A Rosenfeld, Heather E Olson, Lindsay C Burrage

Faculty, Staff and Students Publications

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is caused by heterozygous or hemizygous variants in CDKL5 and is characterized by refractory epilepsy, cognitive and motor impairments, and cerebral visual impairment. CDKL5 has multiple transcripts, of which the longest transcripts, NM_003159 and NM_001037343, have been used historically in clinical laboratory testing. However, the transcript NM_001323289 is the most highly expressed in brain and contains 170 nucleotides at the 3' end of its last exon that are noncoding in other transcripts. Two truncating variants in this region have been reported in association with a CDD phenotype. To clarify the significance and range …

Early Systemic Glycolytic Shift After Aneurysmal Subarachnoid Hemorrhage Is Associated With Functional Outcomes, Aaron M Gusdon, Chenlian Fu, Vasanta Putluri, Atzhiry S Paz, Hua Chen, Xuefang Ren, Mohammed Khurshidul Hassan, Pramod Dash, Cristian Coarfa, Nagireddy Putluri, Huimahn A Choi, Jude P J Savarraj

Faculty, Staff and Student Publications

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) leads to a robust systemic inflammatory response. We hypothesized that an early systemic glycolytic shift occurs after aSAH, resulting in a unique metabolic signature and affecting systemic inflammation.

METHODS: Control patients and patients with aSAH were analyzed. Samples from patients with aSAH were collected within 24 h of aneurysmal rupture. Mass spectrometry-based metabolomics was performed to assess relative abundance of 16 metabolites involved in the tricarboxylic acid cycle, glycolysis, and pentose phosphate pathway. Principal component analysis was used to segregate control patients from patients with aSAH. Dendrograms were developed to depict correlations between metabolites and …

Cic Missense Variants Contribute To Susceptibility For Spina Bifida, Xiao Han, Xuanye Cao, Vanessa Aguiar-Pulido, Wei Yang, Menuka Karki, Paula Andrea Pimienta Ramirez, Robert M Cabrera, Ying Linda Lin, Bogdan J Wlodarczyk, Gary M Shaw, M Elizabeth Ross, Cuilian Zhang, Richard H Finnell, Yunping Lei

Faculty, Staff and Students Publications

Neural tube defects (NTDs) are congenital malformations resulting from abnormal embryonic development of the brain, spine, or spinal column. The genetic etiology of human NTDs remains poorly understood despite intensive investigation. CIC, homolog of the Capicua transcription repressor, has been reported to interact with ataxin-1 (ATXN1) and participate in the pathogenesis of spinocerebellar ataxia type 1. Our previous study demonstrated that CIC loss of function (LoF) variants contributed to the cerebral folate deficiency syndrome by downregulating folate receptor 1 (FOLR1) expression. Given the importance of folate transport in neural tube formation, we hypothesized that CIC variants could contribute to increased …

Mild Hypoxic-Ischemic Encephalopathy (Hie): Timing And Pattern Of Mri Brain Injury, Yi Li, Jessica L Wisnowski, Lina Chalak, Amit M Mathur, Robert C Mckinstry, Genesis Licona, Dennis E Mayock, Taeun Chang, Krisa P Van Meurs, Tai-Wei Wu, Kaashif A Ahmad, Marie-Coralie Cornet, Rakesh Rao, Aaron Scheffler, Yvonne W Wu

2020-Current year OA Pubs

BACKGROUND: Mild hypoxic-ischemic encephalopathy (HIE) is increasingly recognized as a risk factor for neonatal brain injury. We examined the timing and pattern of brain injury in mild HIE.

METHODS: This retrospective cohort study includes infants with mild HIE treated at 9 hospitals. Neonatal brain MRIs were scored by 2 reviewers using a validated classification system, with discrepancies resolved by consensus. Severity and timing of MRI brain injury (i.e., acute, subacute, chronic) was scored on the subset of MRIs that were performed at or before 8 days of age.

RESULTS: Of 142 infants with mild HIE, 87 (61%) had injury on …

Differential Roles Of Aβ42/40, P-Tau231 And P-Tau217 For Alzheimer's Trial Selection And Disease Monitoring, Nicholas J Ashton, Yan Li, Randall J Bateman, Et Al.

2020-Current year OA Pubs

Blood biomarkers indicative of Alzheimer's disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio …

The Clinical Landscape Of Cell-Free Dna Alterations In 1671 Patients With Advanced Biliary Tract Cancer, J E Berchuck, B Tan, Et Al.

2020-Current year OA Pubs

BACKGROUND: Targeted therapies have transformed clinical management of advanced biliary tract cancer (BTC). Cell-free DNA (cfDNA) analysis is an attractive approach for cancer genomic profiling that overcomes many limitations of traditional tissue-based analysis. We examined cfDNA as a tool to inform clinical management of patients with advanced BTC and generate novel insights into BTC tumor biology.

PATIENTS AND METHODS: We analyzed next-generation sequencing data of 2068 cfDNA samples from 1671 patients with advanced BTC generated with Guardant360. We carried out clinical annotation on a multi-institutional subset (n = 225) to assess intra-patient cfDNA-tumor concordance and the association of cfDNA variant …

Transferability Of Alzheimer Disease Polygenic Risk Score Across Populations And Its Association With Alzheimer Disease-Related Phenotypes, Sang-Hyuk Jung, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Polygenic risk scores (PRSs), which aggregate the genetic effects of single-nucleotide variants identified in genome-wide association studies (GWASs), can help distinguish individuals at a high genetic risk for Alzheimer disease (AD). However, genetic studies have predominantly focused on populations of European ancestry.

OBJECTIVE: To evaluate the transferability of a PRS for AD in the Korean population using summary statistics from a prior GWAS of European populations.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study developed a PRS based on the summary statistics of a large-scale GWAS of a European population (the International Genomics of Alzheimer Project; 21 982 AD cases …

Racial And Ethnic Disparities In Access To Minimally Invasive Mitral Valve Surgery, Laurent G Glance, Karen E Joynt Maddox, Michael Mazzefi, Peter W Knight, Michael P Eaton, Changyong Feng, Miklos D Kertai, James Albernathy, Isaac Y Wu, Julie A Wyrobek, Marisa Cevasco, Nimesh Desai, Andrew W Dick

2020-Current year OA Pubs

IMPORTANCE: Whether people from racial and ethnic minority groups experience disparities in access to minimally invasive mitral valve surgery (MIMVS) is not known.

OBJECTIVE: To investigate racial and ethnic disparities in the utilization of MIMVS.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from the Society of Thoracic Surgeons Database for patients who underwent mitral valve surgery between 2014 and 2019. Statistical analysis was performed from January 24 to August 11, 2022.

EXPOSURES: Patients were categorized as non-Hispanic White, non-Hispanic Black, and Hispanic individuals.

MAIN OUTCOMES AND MEASURES: The association between MIMVS (vs full sternotomy) and race and ethnicity …

Pilot Study: Parp1 Imaging In Advanced Prostate Cancer, Farrokh Dehdashti, Melissa A. Reimers, Kooresh I. Shoghi, Delphine L. Chen, Jingqin Luo, Buck Rogers, Russell K. Pachynski, Sreeja Sreekumar, Cody Weimholt, Dong Zhou

2020-Current year OA Pubs

PURPOSE: PARP inhibitor (PARPi) therapy is approved for patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) genomic aberrations. However, only a fraction of patients with BRCA1/2 mutations respond to PARPi therapy. In this pilot study, we assess PARP-1 expression in prostate cancer patients with and without HRR genomic alternations using a novel PARP-based imaging agent.

PROCEDURES: Nine advanced prostate cancer patients were studied with PET/CT and [

RESULTS: We found great variability in FTT uptake (SUV

CONCLUSIONS: FTT-PET/CT may serve as an alternate biomarker for PARP1 expression and a potential method for PARPi treatment selection.

A Sarm1-Mitochondrial Feedback Loop Drives Neuropathogenesis In A Charcot-Marie-Tooth Disease Type 2a Rat Model, Yurie Sato-Yamada, Amy Strickland, Yo Sasaki, Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt

2020-Current year OA Pubs

Charcot-Marie-Tooth disease type 2A (CMT2A) is an axonal neuropathy caused by mutations in the mitofusin 2 (MFN2) gene. MFN2 mutations result in profound mitochondrial abnormalities, but the mechanism underlying the axonal pathology is unknown. Sterile α and Toll/IL-1 receptor motif-containing 1 (SARM1), the central executioner of axon degeneration, can induce neuropathy and is activated by dysfunctional mitochondria. We tested the role of SARM1 in a rat model carrying a dominant CMT2A mutation (Mfn2H361Y) that exhibits progressive dying-back axonal degeneration, neuromuscular junction (NMJ) abnormalities, muscle atrophy, and mitochondrial abnormalities - all hallmarks of the human disease. We generated Sarm1-KO (Sarm1-/-) and …

Listeria Motility Increases The Efficiency Of Epithelial Invasion During Intestinal Infection, Inge M. N. Wortel, Seonyoung Kim, Annie Y. Liu, Enid C. Ibarra, Mark J. Miller

2020-Current year OA Pubs

Listeria monocytogenes (Lm) is a food-borne pathogen that causes severe bacterial gastroenteritis, with high rates of hospitalization and mortality. Lm is ubiquitous in soil, water and livestock, and can survive and proliferate at low temperatures. Following oral ingestion of contaminated food, Lm crosses the epithelium through intestinal goblet cells in a mechanism mediated by Lm InlA binding host E-cadherin. Importantly, human infections typically occur with Lm growing at or below room temperature, which is flagellated and motile. Even though many important human bacterial pathogens are flagellated, little is known regarding the effect of Lm motility on invasion and immune evasion. …

Identification Of Patients With Ovarian Cancer Experiencing The Highest Benefit From Bevacizumab In The First-Line Setting On The Basis Of Their Tumor-Intrinsic Chemosensitivity (Kelim): The Gog-0218 Validation Study, Benoit You, David Mutch, Et Al.

2020-Current year OA Pubs

PURPOSE: In patients with high-grade ovarian cancer, predictors of bevacizumab efficacy in first-line setting are needed. In the ICON-7 trial, a poor tumor intrinsic chemosensitivity (defined by unfavorable modeled cancer antigen-125 [CA-125] ELIMination rate constant K [KELIM] score) was a predictive biomarker. Only the patients with high-risk disease (suboptimally resected stage III, or stage IV) exhibiting unfavorable KELIM score < 1.0 had overall survival (OS) benefit from bevacizumab (median: 29.7

METHODS: In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel ± concurrent-maintenance bevacizumab/placebo. Patient KELIM values were calculated with CA-125 kinetics during the first 100 chemotherapy days by the Lyon University team. The association between KELIM score (favorable ≥ 1.0, or unfavorable …

Spectrum Of Ddc Variants Causing Aromatic L-Amino Acid Decarboxylase (Aadc) Deficiency And Pathogenicity Interpretation Using Acmg-Amp/Acgs Recommendations, Nastassja Himmelreich, Riccardo Montioli, Sven F Garbade, Jeffrey Kopesky, Sarah H Elsea, Carla Carducci, Carla B Voltattorni, Nenad Blau

Faculty, Staff and Students Publications

Pathogenic variants in dopa decarboxylase (DDC), the gene encoding the aromatic l-amino acid decarboxylase (AADC) enzyme, lead to a severe deficiency of neurotransmitters, resulting in neurological, neuromuscular, and behavioral manifestations clinically characterized by developmental delays, oculogyric crises, dystonia, and severe neurologic dysfunction in infancy. Historically, therapy has been aimed at compensating for neurotransmitter abnormalities, but response to pharmacologic therapy varies, and in most cases, the therapy shows little or no benefit. A novel human DDC gene therapy was recently approved in the European Union that targets the underlying genetic cause of the disorder, providing a new treatment option for patients …

G Protein Gamma Subunit, A Hidden Master Regulator Of Gpcr Signaling, Dinesh Kankanamge, Mithila Tennakoon, Ajith Karunarathne, N Gautam

2020-Current year OA Pubs

Heterotrimeric G proteins (αβγ subunits) that are activated by G protein-coupled receptors (GPCRs) mediate the biological responses of eukaryotic cells to extracellular signals. The α subunits and the tightly bound βγ subunit complex of G proteins have been extensively studied and shown to control the activity of effector molecules. In contrast, the potential roles of the large family of γ subunits have been less studied. In this review, we focus on present knowledge about these proteins. Induced loss of individual γ subunit types in animal and plant models result in strikingly distinct phenotypes indicating that γ subtypes play important and …

Guidelines For Assessment Of Cardiac Electrophysiology And Arrhythmias In Small Animals, Crystal M Ripplinger, Stacey L Rentschler, Et Al.

2020-Current year OA Pubs

Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. Although recent advances in cell-based models, including human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM), are contributing to our understanding of electrophysiology and arrhythmia mechanisms, preclinical animal studies of cardiovascular disease remain a mainstay. Over the past several decades, animal models of cardiovascular disease have advanced our understanding of pathological remodeling, arrhythmia mechanisms, and drug effects and have led to major improvements in pacing and defibrillation therapies. There exist a variety of methodological approaches for the assessment of cardiac electrophysiology and a plethora of parameters may be assessed with each approach. …

Loss Of Wnt4 In The Gubernaculum Causes Unilateral Cryptorchidism And Fertility Defects, Abhishek Seth, Juan C Bournat, Olga Medina-Martinez, Armando Rivera, Joshua Moore, Hunter Flores, Jill A Rosenfeld, Liya Hu, Carolina J Jorgez

Faculty, Staff and Students Publications

Undescended testis (UDT) affects 6% of male births. Despite surgical correction, some men with unilateral UDT may experience infertility with the contralateral descended testis (CDT) showing no A-dark spermatogonia. To improve our understanding of the etiology of infertility in UDT, we generated a novel murine model of left unilateral UDT. Gubernaculum-specific Wnt4 knockout (KO) mice (Wnt4-cKO) were generated using retinoic acid receptor β2-cre mice and were found to have a smaller left-unilateral UDT. Wnt4-cKO mice with abdominal UDT had an increase in serum follicle-stimulating hormone and luteinizing hormone and an absence of germ cells in the undescended testicle. Wnt4-cKO mice …

Human Islet Amyloid Polypeptide (Hiapp) Protofibril-Specific Antibodies For Detection And Treatment Of Type 2 Diabetes, Angelina S Bortoletto, W Vallen Graham, Gabriella Trout, Alessandra Bonito-Oliva, Manija A Kazmi, Jing Gong, Emily Weyburne, Brandy L Houser, Thomas P Sakmar, Ronald J Parchem

Faculty, Staff and Students Publications

Type 2 diabetes mellitus (T2D) is a major public health concern and is characterized by sustained hyperglycemia due to insulin resistance and destruction of insulin-producing β cells. One pathological hallmark of T2D is the toxic accumulation of human islet amyloid polypeptide (hIAPP) aggregates. Monomeric hIAPP is a hormone normally co-secreted with insulin. However, increased levels of hIAPP in prediabetic and diabetic patients can lead to the formation of hIAPP protofibrils, which are toxic to β cells. Current therapies fail to address hIAPP aggregation and current screening modalities do not detect it. Using a stabilizing capping protein, monoclonal antibodies (mAbs) can …

The Clinical Spectrum Of Sma-Pme And In Vitro Normalization Of Its Cellular Ceramide Profile, Michelle M Lee, Toni S Pearson, Et Al.

2020-Current year OA Pubs

OBJECTIVE: The objectives of this study were to define the clinical and biochemical spectrum of spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and to determine if aberrant cellular ceramide accumulation could be normalized by enzyme replacement.

METHODS: Clinical features of 6 patients with SMA-PME were assessed by retrospective chart review, and a literature review of 24 previously published cases was performed. Leukocyte enzyme activity of acid ceramidase was assessed with a fluorescence-based assay. Skin fibroblast ceramide content and was assessed by high performance liquid chromatography, electrospray ionization tandem mass spectroscopy. Enzyme replacement was assessed using recombinant human acid ceramidase …

Vascular Endothelial-Cadherin As A Marker Of Endothelial Injury In Preclinical Alzheimer Disease, Rawan Tarawneh, Rachel S Kasper, Jessie Sanford, Chia-Ling Phuah, Jason Hassenstab, Carlos Cruchaga

2020-Current year OA Pubs

OBJECTIVE: Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD.

METHODS: Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n = 700). Preclinical Alzheimer's Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Aβ42/Aβ40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) …

Diptoindonesin G Is A Middle Domain Hsp90 Modulator For Cancer Treatment, Kristine Donahue, Haibo Xie, Miyang Li, Ang Gao, Min Ma, Yidan Wang, Rose Tipton, Nicole Semanik, Tina Primeau, Shunqiang Li, Lingjun Li, Weiping Tang, Wei Xu

2020-Current year OA Pubs

HSP90 inhibitors can target many oncoproteins simultaneously, but none have made it through clinical trials due to dose-limiting toxicity and induction of heat shock response, leading to clinical resistance. We identified diptoindonesin G (dip G) as an HSP90 modulator that can promote degradation of HSP90 clients by binding to the middle domain of HSP90 (K