Digital Commons Network^™

Genetics Of Substance Use Disorders: A Review, Joseph D Deak, Emma C Johnson

Open Access Publications

Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They are influenced by genetic factors (h2 = ~50%). Recent years have brought substantial progress in our understanding of the genetic etiology of SUDs and related traits. The present review covers the current state of the field for SUD genetics, including the epidemiology and genetic epidemiology of SUDs, findings from the first-generation of SUD genome-wide association studies (GWAS), cautions about translating GWAS findings to clinical settings, and suggested prioritizations for the next wave of SUD genetics efforts. Recent advances in SUD genetics have been facilitated by …

Canonical And Interior Circular Rnas Function As Competing Endogenous Rnas In Psoriatic Skin, Xiaoxin Liu, Jacqueline Frost, Anne Bowcock, Weixiong Zhang

Open Access Publications

(1) Background: Understanding the function of circular RNAs (circRNAs), a class of noncoding RNA, in psoriatic skin can provide important insights into the complex regulation of genes contributing to the pathogenesis of psoriasis. (2) Methods: A novel method was applied to RNA-seq datasets from 93 skin biopsy samples to comprehensively identify circRNAs of all types, i.e., canonical circRNAs from the intron-exon junctions of mRNAs and interior circRNAs (i-circRNAs) from the interior regions of exons, introns, and intergenic regions. Selected circRNAs were experimentally validated by qRT-PCR and Sanger sequencing. CircRNAs with abundant and differential expression were identified and their putative function …

Lysophospholipid Acylation Modulates Plasma Membrane Lipid Organization And Insulin Sensitivity In Skeletal Muscle, Patrick J Ferrara, Haowei Song, John Turk, Et Al

Open Access Publications

Aberrant lipid metabolism promotes the development of skeletal muscle insulin resistance, but the exact identity of lipid-mediated mechanisms relevant to human obesity remains unclear. A comprehensive lipidomic analysis of primary myocytes from individuals who were insulin-sensitive and lean (LN) or insulin-resistant with obesity (OB) revealed several species of lysophospholipids (lyso-PLs) that were differentially abundant. These changes coincided with greater expression of lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme involved in phospholipid transacylation (Lands cycle). Strikingly, mice with skeletal muscle-specific knockout of LPCAT3 (LPCAT3-MKO) exhibited greater muscle lysophosphatidylcholine/phosphatidylcholine, concomitant with improved skeletal muscle insulin sensitivity. Conversely, skeletal muscle-specific overexpression of LPCAT3 (LPCAT3-MKI) …

Phase Ii Study Of Pazopanib With Oral Topotecan In Patients With Metastatic And Non-Resectable Soft Tissue And Bone Sarcomas, Brian Schulte, Nisha Mohindra, Mohammed Milhem, Steven Attia, Steven Robinson, Varun Monga, Angela C Hirbe, Peter Oppelt, John Charlson, Irene Helenowski, Susan Abbinanti, Rasima Cehic, Scott Okuno, Brian A Van Tine, Mark Agulnik

Open Access Publications

BACKGROUND: Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma.

METHODS: This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort.

RESULTS: 57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet …

Long-Term Intake Of Gluten And Cognitive Function Among Us Women, Yiqing Wang, Benjamin Lebwohl, Raaj Mehta, Yin Cao, Peter H.R. Green, Francine Grodstein, Manol Jovani, Paul Lochhead, Olivia I. Okereke, Laura Sampson, Walter C. Willett, Qi Sun, Andrew T. Chan

Open Access Publications

Importance: Gluten avoidance has been suggested as having a benefit to cognitive health among the general population, given the link between gluten and cognitive impairment in patients with celiac disease. However, data are lacking in individuals without celiac disease.

Objective: To examine whether gluten intake is associated with cognitive function in women without celiac disease.

Design, Setting, and Participants: This cohort study included US women who participated in the longitudinal, population-based Nurses' Health Study II and had not previously or subsequently been diagnosed with celiac disease. Dietary data were collected from 1991 to 2015, and data on cognitive function were …

Computerized Tumor Multinucleation Index (Muni) Is Prognostic In P16+ Oropharyngeal Carcinoma, Can F Koyuncu, Wade L Thorstad, R D Chernock, Jingqin Luo, Et Al

Open Access Publications

BACKGROUNDPatients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure for p16+ OPSCC. Pathologist-based visual assessment of tumor cell multinucleation (MN) has been shown to be independently prognostic of disease-free survival (DFS) in p16+ OPSCC. However, its quantification is time intensive, subjective, and at risk of interobserver variability.METHODSWe present a deep-learning-based metric, the multinucleation index (MuNI), for prognostication in p16+ OPSCC. This approach quantifies tumor MN from digitally scanned H&E-stained slides. Representative H&E-stained whole-slide images from 1094 patients with previously untreated p16+ OPSCC were acquired from …

Molecular, Cellular And Functional Changes In The Retinas Of Young Adult Mice Lacking The Voltage-Gated K+ Channel Subunits Kv8.2 And K2.1, Xiaotian Jiang, Rabab Rashwan, Valentina Voigt, Jeanne Nerbonne, David M Hunt, Livia S Carvalho

Open Access Publications

Cone Dystrophy with Supernormal Rod Response (CDSRR) is a rare autosomal recessive disorder leading to severe visual impairment in humans, but little is known about its unique pathophysiology. We have previously shown that CDSRR is caused by mutations in the

Evaluation Of Perirenal Anatomic Landmarks On Computed Tomography To Reduce The Risk Of Thoracic Complications During Supracostal Percutaneous Nephrolithotomy, Alexander K. Chow, Shellee Ogawa, Cary Seigel, Kenneth G. Sands, Joel Vetter, Alana Desai, Ramakrishna Venkatesh

Open Access Publications

No abstract provided.

Longitudinal Growth Differentiation Factor 15 (Gdf15) And Long-Term Intraocular Pressure Fluctuation In Glaucoma: A Pilot Study, Jonathan B. Lin, Arsham Sheybani, Andrea Santeford, Rajendra S. Apte

Open Access Publications

No abstract provided.

Beam Energy Metrics For The Acceptance And Quality Assurance Of Halcyon Linear Accelerator, Song Gao, Mikhail A Chetvertkov, Bin Cai, Abhishek Dwivedi, Dimitris Mihailidis, Xenia Ray, Tucker Netherton, Laurence E Court, William E Simon, Peter A Balter

Open Access Publications

PURPOSE: Establish and compare two metrics for monitoring beam energy changes in the Halcyon platform and evaluate the accuracy of these metrics across multiple Halcyon linacs.

METHOD: The first energy metric is derived from the diagonal normalized flatness (F

RESULTS: Five Halcyon linacs from five institutions were used to evaluate the accuracy of the D

CONCLUSION: The F

Pathogenesis And Current Treatment Of Osteosarcoma: Perspectives For Future Therapies, Richa Rathore, Brian A Van Tine

Open Access Publications

Osteosarcoma is the most common primary malignant bone tumor in children and young adults. The standard-of-care curative treatment for osteosarcoma utilizes doxorubicin, cisplatin, and high-dose methotrexate, a standard that has not changed in more than 40 years. The development of patient-specific therapies requires an in-depth understanding of the unique genetics and biology of the tumor. Here, we discuss the role of normal bone biology in osteosarcomagenesis, highlighting the factors that drive normal osteoblast production, as well as abnormal osteosarcoma development. We then describe the pathology and current standard of care of osteosarcoma. Given the complex heterogeneity of osteosarcoma tumors, we …

Identification Of A Novel Genetic Marker For Risk Of Degenerative Rotator Cuff Disease Surgery In The Uk Biobank, Elizabeth L Yanik, Jay D Keener, Shiow J Lin, Graham A Colditz, Rick W Wright, Bradley A Evanoff, Nitin B Jain, Nancy L Saccone

Open Access Publications

BACKGROUND: While evidence indicates that familial predisposition influences the risk of developing degenerative rotator cuff disease (RCD), knowledge of specific genetic markers is limited. We conducted a genome-wide association study of RCD surgery using the UK Biobank, a prospective cohort of 500,000 people (40 to 69 years of age at enrollment) with genotype data.

METHODS: Cases with surgery for degenerative RCD were identified using linked hospital records. The cases were defined as an International Classification of Diseases, Tenth Revision (ICD-10) code of M75.1 determined by a trauma/orthopaedic specialist and surgery consistent with RCD treatment. Cases were excluded if a diagnosis …

Telomere Erosion In Human Pluripotent Stem Cells Leads To Atr-Mediated Mitotic Catastrophe, Alexandre T. Vessoni, Tianpeng Zhang, Annabel Quinet, Ho-Chang Jeong, Michael Munroe, Matthew Wood, Enzo Tedone, Alessandro Vindigni, Jerry W. Shay, Roger A. Greenberg, Luis F.Z. Batista

Open Access Publications

It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic …

All Epidural Needle Bevels Are Not The Same, Amber C. Benhardt, Bhavani Shankar Kodali

Open Access Publications

No abstract provided.

Effects Of Dietary Fatty Acid Composition On Lipid Metabolism And Body Fat Accumulation In Ovariectomized Rats, Jhih-Han Yeh, Yu-Tang Tung, Yu-Sheng Yeh, Yi-Wen Chien

Open Access Publications

BACKGROUND: Obesity is a state of excess energy storage resulting in body fat accumulation, and postmenopausal obesity is a rising issue. In this study using ovariectomized (OVX) rats, we mimicked low estrogen levels in a postmenopausal state in order to investigate the effects of different amounts and types of dietary fatty acids on body fat accumulation and body lipid metabolism.

METHODS: At 9 weeks of age, rats (

RESULTS: After OVX, compared to the S group, the C group showed significantly higher body weight, and insulin and leptin levels. Compared to the C group, the H group had lower hepatic …

Informative Regions In Viral Genomes, Jaime Leonardo Moreno-Gallego, Alejandro Reyes

Open Access Publications

Viruses, far from being just parasites affecting hosts' fitness, are major players in any microbial ecosystem. In spite of their broad abundance, viruses, in particular bacteriophages, remain largely unknown since only about 20% of sequences obtained from viral community DNA surveys could be annotated by comparison with public databases. In order to shed some light into this genetic dark matter we expanded the search of orthologous groups as potential markers to viral taxonomy from bacteriophages and included eukaryotic viruses, establishing a set of 31,150 ViPhOGs (Eukaryotic Viruses and Phages Orthologous Groups). To do this, we examine the non-redundant viral diversity …

Acceleration Of Small Intestine Development And Remodeling Of The Microbiome Following Hyaluronan 35 Kda Treatment In Neonatal Mice, Hala Chaaban, Kathryn Burge, Jeffrey Eckert, Majoi Trammell, David Dyer, Ravi S Keshari, Robert Silasi, Girija Regmi, Cristina Lupu, Misty Good, Steven J Mcelroy, Florea Lupu

Open Access Publications

The beneficial effects of human milk suppressing the development of intestinal pathologies such as necrotizing enterocolitis in preterm infants are widely known. Human milk (HM) is rich in a multitude of bioactive factors that play major roles in promoting postnatal maturation, differentiation, and the development of the microbiome. Previous studies showed that HM is rich in hyaluronan (HA) especially in colostrum and early milk. This study aims to determine the role of HA 35 KDa, a HM HA mimic, on intestinal proliferation, differentiation, and the development of the intestinal microbiome. We show that oral HA 35 KDa supplementation for 7 …

Prospective Spect-Ct Organ Dosimetry-Driven Radiation-Absorbed Dose Escalation Using The In-111 (111in)/Yttrium 90 (90y) Ibritumomab Tiuxetan (Zevalin ®) Theranostic Pair In Patients With Lymphoma At Myeloablative Dose Levels, Richard L Wahl, Eric C Frey, Heather A Jacene, Brad S Kahl, Steven Piantadosi, Jesus A Bianco, Richard J Hammes, Miah Jung, Wayne Kasecamp, Bin He, George Sgouros, Ian W Flinn, Lode J Swinnen

Open Access Publications

PURPOSE: We prospectively evaluated the feasibility of SPECT-CT/planar organ dosimetry-based radiation dose escalation radioimmunotherapy in patients with recurrent non-Hodgkin's lymphoma using the theranostic pair of

METHODS: 24 patients with CD20-positive relapsed or refractory rituximab-sensitive, low-grade, mantle cell, or diffuse large-cell NHL, with normal organ function, platelet counts > 75,000/mm

RESULTS: Patient-specific hybrid SPECT/CT + planar organ dosimetry was feasible in all 18 cases and used to determine the patient-specific therapeutic dose and guide dose escalation (26.8 ± 7.3 MBq/kg (mean), 26.3 MBq/kg (median) of

CONCLUSIONS: Patient-specific outpatient

Spatially Interacting Phosphorylation Sites And Mutations In Cancer, Kuan-Lin Huang, Adam D. Scott, Daniel Cui Zhou, Liang-Bo Wang, Amila Weerasinghe, Ruiyang Liu, Yige Wu, Michael C. Wendl, Matthew A. Wyczalkowski, Jessika Baral, Sohini Sengupta, Chin-Wen Lai, Li Ding, Et Al.

Open Access Publications

No abstract provided.

Adolescent Animal Product Intake In Relation To Later Prostate Cancer Risk And Mortality In The Nih-Aarp Diet And Health Study, Tuo Lan, Yikyung Park, Graham A Colditz, Jingxia Liu, Rashmi Sinha, Molin Wang, Kana Wu, Edward Giovannucci, Siobhan Sutcliffe

Open Access Publications

BACKGROUND: Adolescent intake of animal products has been proposed to contribute to prostate cancer (PCa) development because of its potentially carcinogenic constituents and influence on hormone levels during adolescence.

METHODS: We used data from 159,482 participants in the NIH-AARP Diet and Health Study to investigate associations for recalled adolescent intake of red meat (unprocessed beef and processed red meat), poultry, egg, canned tuna, animal fat and animal protein at ages 12-13 years with subsequent PCa risk and mortality over 14 years of follow-up. Cox proportional hazard regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of …

Bnp Facilitates Nmb-Encoded Histaminergic Itch Via Nprc-Nmbr Crosstalk, Qing-Tao Meng, Xian-Yu Liu, Xue-Ting Liu, Juan Liu, Admire Munanairi, Devin M. Barry, Benlong Liu, Hua Jin, Yu Sun, Qianyi Yang, Fang Gao, Li Wan, Jiahang Peng, Jin-Hua Jin, Kai-Feng Shen, Ray Kim, Jun Yin, Ailin Tao, Zhou-Feng Chen

Open Access Publications

Histamine-dependent and -independent itch is conveyed by parallel peripheral neural pathways that express gastrin-releasing peptide (GRP) and neuromedin B (NMB), respectively, to the spinal cord of mice. B-type natriuretic peptide (BNP) has been proposed to transmit both types of itch via its receptor NPRA encoded by

Despite Increasing Aldosterone, Elevated Potassium Is Not Necessary For Activating Aldosterone-Sensitive Hsd2 Neurons Or Sodium Appetite, Frederico S Fazan, Eduardo Colombari, Arthur D Loewy, Joel C Geerling

Open Access Publications

Restricting dietary sodium promotes sodium appetite in rats. Prolonged sodium restriction increases plasma potassium (pK), and elevated pK is largely responsible for a concurrent increase in aldosterone, which helps promote sodium appetite. In addition to increasing aldosterone, we hypothesized that elevated potassium directly influences the brain to promote sodium appetite. To test this, we restricted dietary potassium in sodium-deprived rats. Potassium restriction reduced pK and blunted the increase in aldosterone caused by sodium deprivation, but did not prevent sodium appetite or the activation of aldosterone-sensitive HSD2 neurons. Conversely, supplementing potassium in sodium-deprived rats increased pK and aldosterone, but did not …

Rna-Seq Identifies Genes Whose Proteins Are Upregulated During Syncytia Development In Murine C2c12 Myoblasts And Human Bewo Trophoblasts, Christopher Azar, Mark C Valentine, Julie Trausch-Azar, Lisa Rois, Moe Mahjoub, D Michael Nelson, Alan L Schwartz

Open Access Publications

The fusion of villous cytotrophoblasts into the multinucleated syncytiotrophoblast is critical for the essential functions of the mammalian placenta. Using RNA-Seq gene expression, quantitative protein expression, and siRNA knockdown we identified genes and their cognate proteins which are similarly upregulated in two cellular models of mammalian syncytia development (human BeWo cytotrophoblast to syncytiotrophoblast and murine C2C12 myoblast to myotube). These include DYSF, PDE4DIP, SPIRE2, NDRG1, PLEC, GPR146, HSPB8, DHCR7, and HDAC5. These findings provide avenues for further understanding of the mechanisms underlying mammalian placental syncytiotrophoblast development.

Lack Of Association Between Acute Stroke, Post-Stroke Dementia, Race, And Β-Amyloid Status, Lauren N Koenig, Lena M Mccue, Elizabeth Grant, Parinaz Massoumzadeh, Catherine M Roe, Chengjie Xiong, Krista L Moulder, Liang Wang, Allyson R Zazulia, Peggy Kelly, Aylin Dincer, Aiad Zaza, Joshua S Shimony, Tammie L S Benzinger, John C Morris

Open Access Publications

INTRODUCTION: Stroke and Alzheimer disease share risk factors and often co-occur, and both have been reported to have a higher prevalence in African Americans as compared to non-Hispanic whites. However, their interaction has not been established. The objective of this study was to determine if preclinical Alzheimer disease is a risk factor for stroke and post-stroke dementia and whether racial differences moderate this relationship.

METHODS: This case-control study was analyzed in 2019 using retrospective data from 2007 to 2013. Participants were adults age 65 and older with and without acute ischemic stroke. Recruitment included word of mouth and referrals in …

Test-Retest Reliability Of Neural Correlates Of Response Inhibition And Error Monitoring: An Fmri Study Of A Stop-Signal Task, Ozlem Korucuoglu, Michael P Harms, Serguei V Astafiev, Semyon Golosheykin, James T Kennedy, Deanna M Barch, Andrey P Anokhin

Open Access Publications

Response inhibition (RI) and error monitoring (EM) are important processes of adaptive goal-directed behavior, and neural correlates of these processes are being increasingly used as transdiagnostic biomarkers of risk for a range of neuropsychiatric disorders. Potential utility of these purported biomarkers relies on the assumption that individual differences in brain activation are reproducible over time; however, available data on test-retest reliability (TRR) of task-fMRI are very mixed. This study examined TRR of RI and EM-related activations using a stop signal task in young adults (

Video Feedback Intervention For Cognitively Impaired Older Drivers: A Randomized Clinical Trial, Brian R Ott, George D Papandonatos, Erin M Burke, Donna Erdman, David B Carr, Jennifer D Davis

Open Access Publications

Introduction: This clinical trial aimed to determine whether in-car video feedback about unsafe driving events (UDE) to cognitively impaired older drivers and family members leads to a reduction in such driving behaviors.

Methods: We randomized 51 cognitively impaired older drivers to receive either (1) a weekly progress report with recommendations and access to their videos, or (2) video monitoring alone without feedback over 3 months.

Results: UDE frequency/1000 miles was reduced by 12% in feedback (rate ratio [RR] = 0.88, 95% confidence interval [CI] = .58-1.34), while remaining constant with only monitoring (RR = 1.01, 95% CI = .68-1.51). UDE …

Substance Use Disorders And Behavioral Addictions During The Covid-19 Pandemic And Covid-19-Related Restrictions, Nicole M Avena, Julia Simkus, Anne Lewandowski, Mark S Gold, Marc N Potenza

Open Access Publications

COVID-19 was first identified in Wuhan, China in December of 2019 and appeared in the United States 1 month later. Between the onset of the pandemic and January 13, 2021, over 92 million people have tested positive for the virus and over 1.9 million people have died globally. Virtually every country in the world has been impacted by this virus. Beginning in March 2020, many U.S. state governments enforced a "quarantine" to respond to the growing health crisis. Citizens were required to remain at home; schools, restaurants, and non-essential businesses were forced to close, and large gatherings were prohibited. Americans' …

The Kinase Specificity Of Protein Kinase Inhibitor Peptide, Yao Chen, Bernardo L Sabatini

Open Access Publications

G-protein-coupled-receptor (GPCR) signaling is exquisitely controlled to achieve spatial and temporal specificity. The endogenous protein kinase inhibitor peptide (PKI) confines the spatial and temporal spread of the activity of protein kinase A (PKA), which integrates inputs from three major types of GPCRs. Despite its wide usage as a pharmaceutical inhibitor of PKA, it was unclear whether PKI only inhibits PKA activity. Here, the effects of PKI on 55 mouse kinases were tested in

Immunological Findings And Clinical Outcomes Of Infants With Positive Newborn Screening For Severe Combined Immunodeficiency From A Tertiary Care Center In The U.S., Vasudha Mantravadi, Jeffrey J Bednarski, Michelle A Ritter, Hongjie Gu, Ana L Kolicheski, Caroline Horner, Megan A Cooper, Maleewan Kitcharoensakkul

Open Access Publications

The implementation of severe combined immunodeficiency (SCID) newborn screening has played a pivotal role in identifying these patients early in life as well as detecting various milder forms of T cell lymphopenia (TCL). In this study we reviewed the diagnostic and clinical outcomes, and interesting immunology findings of term infants referred to a tertiary care center with abnormal newborn SCID screens over a 6-year period. Key findings included a 33% incidence of non-SCID TCL including infants with novel variants in

Frontotemporal Dementias In Latin America: History, Epidemiology, Genetics, And Clinical Research, Jorge J Llibre-Guerra, Angela Hardi, Et Al

Open Access Publications

No abstract provided.