Medicine and Health Sciences Commons^™

A Pilot Phase Ib Study To Evaluate Tadalafil To Overcome Immunosuppression During Chemoradiotherapy For Idh-Wild-Type Glioblastoma, Subhajit Ghosh, Tanner M Johanns, Milan G Chheda, Eric Liu, Omar Butt, Christopher Abraham, Shahed Badiyan, Yi Huang, David Denardo, Albert H Kim, Dennis Hallahan, Dinesh Thotala, Jiayi Huang

2020-Current year OA Pubs

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are critical regulators of immunosuppression and radioresistance in glioblastoma (GBM). The primary objective of this pilot phase Ib study was to validate the on-target effect of tadalafil on inhibiting MDSCs in peripheral blood and its safety when combined with chemoradiotherapy in GBM patients.

METHODS: Patients with newly diagnosed IDH-wild-type GBM received radiation therapy (RT) and temozolomide (TMZ) combined with oral tadalafil for 2 months. A historical cohort of 12 GBM patients treated with RT and TMZ was used as the comparison group. The ratio of MDSCs, T cells, and cytokines at week 6 of RT …

The Vacc-Seqqc Project: Benchmarking Rna-Seq For Clinical Vaccine Studies, Johannes B Goll, Richard D Head, Et Al.

2020-Current year OA Pubs

[This corrects the article DOI: 10.3389/fimmu.2022.1093242.].

Objective Response To Immune Checkpoint Inhibitor Therapy In Nras-Mutant Melanoma: A Systematic Review And Meta-Analysis, Zachary J Jaeger, Neel S Raval, Natalia K A Maverakis, David Y Chen, George Ansstas, Angela Hardi, Lynn A Cornelius

2020-Current year OA Pubs

INTRODUCTION:

METHODS: We performed a comprehensive literature search across several large databases. Inclusion criteria were trials, cohorts, and large case series that analyzed the primary outcome of objective response rate by

RESULTS: Data on 1770 patients from ten articles were pooled for meta-analysis, and the objective response rate to ICIs was calculated to compare

DISCUSSION: In this meta-analysis evaluating the impact of

Simple And Complex Cells Revisited: Toward A Selectivity-Invariance Model Of Object Recognition, Xin Li, Shuo Wang

2020-Current year OA Pubs

This paper presents a theoretical perspective on modeling ventral stream processing by revisiting the computational abstraction of simple and complex cells. In parallel to David Marr's vision theory, we organize the new perspective into three levels. At the computational level, we abstract simple and complex cells into space partitioning and composition in a topological space based on the redundancy exploitation hypothesis of Horace Barlow. At the algorithmic level, we present a hierarchical extension of sparse coding by exploiting the manifold constraint in high-dimensional space (i.e., the blessing of dimensionality). The resulting over-parameterized models for object recognition differ from existing hierarchical …

The Immunology Of Takotsubo Syndrome, Kenji Rowel Q Lim, Douglas L Mann, Tsuneaki Kenzaka, Tomohiro Hayashi

2020-Current year OA Pubs

Takotsubo syndrome (TTS) is a disorder characterized by transient cardiac dysfunction with ventricular regional wall motion abnormalities, primarily thought to be caused by the effects of a sudden catecholamine surge on the heart. Although the majority of patients exhibit prompt recovery of their cardiac dysfunction, TTS remains associated with increased mortality rates acutely and at long-term, and there is currently no cure for TTS. Inflammation has been shown to play a key role in determining outcomes in TTS patients, as well as in the early pathogenesis of the disorder. There are also cases of TTS patients that have been successfully …

Factors Influencing Delayed Clearance Of High Dose Methotrexate (Hdmtx) In Pediatric, Adolescent, And Young Adult Oncology Patients, Ema Mosleh, Stacy Snyder, Ningying Wu, Daniel N Willis, Rema Malone, Robert J Hayashi

2020-Current year OA Pubs

PURPOSE: To identify modifiable risk factors associated with prolonged clearance of methotrexate in pediatric, adolescent, and young adult (AYA) oncology patients receiving high dose methotrexate (HDMTX).

DESIGN/METHOD: A single institution, retrospective chart review of patients receiving HDMTX between 2010-2017. Patients had a diagnosis of either leukemia or osteosarcoma. Data included demographics, concurrent intravenous (IV) medications, IV fluids (IVF) administered, urine output (UO), and rises in serum creatinine (RSC) reflective of renal toxicity (RT). Outcome measures included 1) delayed targeted MTX clearance (DC), 2) actual time to clearance (TTC) and 3) length of stay (LOS).

RESULTS: Data from 447 HDMTX administrations …

Glial Regulation Of Critical Period Plasticity, Jacob Starkey, Eric J Horstick, Sarah D Ackerman

2020-Current year OA Pubs

Animal behavior, from simple to complex, is dependent on the faithful wiring of neurons into functional neural circuits. Neural circuits undergo dramatic experience-dependent remodeling during brief developmental windows called critical periods. Environmental experience during critical periods of plasticity produces sustained changes to circuit function and behavior. Precocious critical period closure is linked to autism spectrum disorders, whereas extended synaptic remodeling is thought to underlie circuit dysfunction in schizophrenia. Thus, resolving the mechanisms that instruct critical period timing is important to our understanding of neurodevelopmental disorders. Control of critical period timing is modulated by neuron-intrinsic cues, yet recent data suggest that …

Rare Predicted Loss-Of-Function Variants Of Type I Ifn Immunity Genes Are Associated With Life-Threatening Covid-19, Daniela Matuozzo, Megan A. Cooper, Et Al.

2020-Current year OA Pubs

No abstract provided.

Allele-Specific Quantification Of Human Leukocyte Antigen Transcript Isoforms By Nanopore Sequencing, Andrew E O Hughes, Maureen C Montgomery, Chang Liu, Eric T Weimer

2020-Current year OA Pubs

INTRODUCTION: While tens of thousands of HLA alleles have been identified by DNA sequencing, the contribution of alternative splicing to HLA diversity is not well characterized. In this study, we sought to determine if long-read sequencing could be used to accurately quantify allele-specific HLA transcripts in primary human lymphocytes.

METHODS: cDNA libraries were prepared from peripheral blood lymphocytes from 12 donors and sequenced by nanopore long-read sequencing. HLA reads were aligned to donor-specific reference sequences based on the known type of each donor. Allele-specific exon utilization was calculated as the proportion of reads aligning to each allele containing known exons, …

Baricitinib With Cyclosporine Eliminates Acute Graft Rejection In Fully Mismatched Skin And Heart Transplant Models, Ramzi Abboud, Sena Kim, Karl Staser, Reyka G Jayasinghe, Sora Lim, Parmeshwar Amatya, C Corbin Frye, Benjamin Kopecky, Julie Ritchey, Feng Gao, Kory Lavine, Daniel Kreisel, John F Dipersio, Jaebok Choi

2020-Current year OA Pubs

Solid organ transplant represents a potentially lifesaving procedure for patients suffering from end-stage heart, lung, liver, and kidney failure. However, rejection remains a significant source of morbidity and immunosuppressive medications have significant toxicities. Janus kinase (JAK) inhibitors are effective immunosuppressants in autoimmune diseases and graft versus host disease after allogeneic hematopoietic cell transplantation. Here we examine the role of JAK inhibition in preclinical fully major histocompatibility mismatched skin and heart allograft models. Baricitinib combined with cyclosporine A (CsA) preserved fully major histocompatibility mismatched skin grafts for the entirety of a 111-day experimental period. In baricitinib plus CsA treated mice, circulating …

The Cerebrospinal Fluid Immune Cell Landscape In Animal Models Of Multiple Sclerosis, Gregory F Wu

2020-Current year OA Pubs

The fluid compartment surrounding the central nervous system (CNS) is a unique source of immune cells capable of reflecting the pathophysiology of neurologic diseases. While human clinical and experimental studies often employ cerebrospinal fluid (CSF) analysis, assessment of CSF in animal models of disease are wholly uncommon, particularly in examining the cellular component. Barriers to routine assessment of CSF in animal models of multiple sclerosis (MS) include limited sample volume, blood contamination, and lack of feasible longitudinal approaches. The few studies characterizing CSF immune cells in animal models of MS are largely outdated, but recent work employing transcriptomics have been …

Targeted Aso-Mediated Atp1a2 Knockdown In Astrocytes Reduces Sod1 Aggregation And Accelerates Disease Onset In Mutant Sod1 Mice, Abhirami K. Iyer, Kathleen M. Schoch, Anthony Verbeck, Grant Galasso, Hao Chen, Sarah Smith, Anna Oldenborg, Timothy M. Miller, Celeste M. Karch, Azad Bonni

2020-Current year OA Pubs

Astrocyte-specific ion pump α2-Na+/K+-ATPase plays a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS). Here, we test the effect of Atp1a2 mRNA-specific antisense oligonucleotides (ASOs) to induce α2-Na+/K+-ATPase knockdown in the widely used ALS animal model, SOD1*G93A mice. Two ASOs led to efficient Atp1a2 knockdown and significantly reduced SOD1 aggregation in vivo. Although Atp1a2 ASO-treated mice displayed no off-target or systemic toxicity, the ASO-treated mice exhibited an accelerated disease onset and shorter lifespan than control mice. Transcriptomics studies reveal downregulation of genes involved in oxidative response, metabolic pathways, trans-synaptic signaling, and upregulation of genes involved in glutamate receptor …

Mora And Ensembletfpredictor: An Ensemble Approach To Reveal Functional Transcription Factor Regulatory Networks, Kevin Boyer, Louis Li, Tiandao Li, Bo Zhang, Guoyan Zhao

2020-Current year OA Pubs

MOTIVATION: Our study aimed to identify biologically relevant transcription factors (TFs) that control the expression of a set of co-expressed or co-regulated genes.

RESULTS: We developed a fully automated pipeline, Motif Over Representation Analysis (MORA), to detect enrichment of known TF binding motifs in any query sequences. MORA performed better than or comparable to five other TF-prediction tools as evaluated using hundreds of differentially expressed gene sets and ChIP-seq datasets derived from known TFs. Additionally, we developed EnsembleTFpredictor to harness the power of multiple TF-prediction tools to provide a list of functional TFs ranked by prediction confidence. When applied to …

Enhancing The Therapeutic Activity Of Hyperimmune Igg Against Chikungunya Virus Using Fcγriiia Affinity Chromatography, Julie M Fox, Vicky Roy, Bronwyn M Gunn, Glen R Bolton, Daved H Fremont, Galit Alter, Michael S Diamond, Austin W Boesch

2020-Current year OA Pubs

INTRODUCTION: Chikungunya virus (CHIKV) is a re-emerging mosquito transmitted alphavirus of global concern. Neutralizing antibodies and antibody Fc-effector functions have been shown to reduce CHIKV disease and infection in animals. However, the ability to improve the therapeutic activity of CHIKV-specific polyclonal IgG by enhancing Fc-effector functions through modulation of IgG subclass and glycoforms remains unknown. Here, we evaluated the protective efficacy of CHIKV-immune IgG enriched for binding to Fc-gamma receptor IIIa (FcγRIIIa) to select for IgG with enhanced Fc effector functions.

METHODS: Total IgG was isolated from CHIKV-immune convalescent donors with and without additional purification by FcγRIIIa affinity chromatography. The …

The Function Of Histone Methylation And Acetylation Regulators In Gbm Pathophysiology, Colin Mccornack, Timothy Woodiwiss, Angela Hardi, Hiroko Yano, Albert H Kim

2020-Current year OA Pubs

Glioblastoma (GBM) is the most common and lethal primary brain malignancy and is characterized by a high degree of intra and intertumor cellular heterogeneity, a starkly immunosuppressive tumor microenvironment, and nearly universal recurrence. The application of various genomic approaches has allowed us to understand the core molecular signatures, transcriptional states, and DNA methylation patterns that define GBM. Histone posttranslational modifications (PTMs) have been shown to influence oncogenesis in a variety of malignancies, including other forms of glioma, yet comparatively less effort has been placed on understanding the transcriptional impact and regulation of histone PTMs in the context of GBM. In …

Vigorous-Intensity Exercise As A Modulator Of Cardiac Adipose Tissue In Women With Obesity: A Cross-Sectional And Randomized Pilot Study, Sumsen Thapa, Bharath S Selvaraj, Paige N Davis, Bryan Smith, Amy H Givan, Jose A Perez-Rivera, Pamela K Woodard, Jon D Klingensmith, Maria Fernandez-Del-Valle

2020-Current year OA Pubs

Cardiac adipose tissue (CAT) has become an important target for the reduction of disease risk. Supervised exercise programs have shown potential to "significantly" reduce CAT; however, the impact of different exercise modalities is not clear, and the relationships between CAT, physical activity (PA) levels and fitness (PFit) remain unknown. Therefore, the purpose of this study was to analyze the relationships between CAT, PA and PFit, and to explore the effects of different exercise modalities in a group of women with obesity. A total of 26 women (age: 23.41 ± 5.78 years-old) were enrolled in the cross-sectional study. PA, cardiorespiratory fitness, …

Nrg/Rtog 0837: Randomized, Phase Ii, Double-Blind, Placebo-Controlled Trial Of Chemoradiation With Or Without Cediranib In Newly Diagnosed Glioblastoma, Tracy T Batchelor, Clifford G Robinson, Et Al.

2020-Current year OA Pubs

BACKGROUND: A randomized, phase II, placebo-controlled, and blinded clinical trial (NCT01062425) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, versus placebo in combination with radiation and temozolomide in newly diagnosed glioblastoma.

METHODS: Patients with newly diagnosed glioblastoma were randomly assigned 2:1 to receive (1) cediranib (20 mg) in combination with radiation and temozolomide; (2) placebo in combination with radiation and temozolomide. The primary endpoint was 6-month progression-free survival (PFS) based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans and was tested using a 1-sided …

Feasibility And Acceptability Of Remote Smartphone Cognitive Testing In Frontotemporal Dementia Research, Jack Carson Taylor, Nupur Ghoshal, Et Al.

2020-Current year OA Pubs

INTRODUCTION: Remote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp).

METHODS: A diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [

RESULTS: It was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity …

Functional Trajectories During Innate Spinal Cord Repair, Nicholas O Jensen, Brooke Burris, Lili Zhou, Hunter Yamada, Catrina Reyes, Zachary Pincus, Mayssa H Mokalled

2020-Current year OA Pubs

Adult zebrafish are capable of anatomical and functional recovery following severe spinal cord injury. Axon growth, glial bridging and adult neurogenesis are hallmarks of cellular regeneration during spinal cord repair. However, the correlation between these cellular regenerative processes and functional recovery remains to be elucidated. Whereas the majority of established functional regeneration metrics measure swim capacity, we hypothesize that gait quality is more directly related to neurological health. Here, we performed a longitudinal swim tracking study for 60 individual zebrafish spanning 8 weeks of spinal cord regeneration. Multiple swim parameters as well as axonal and glial bridging were integrated. We …

Carotid Atherosclerotic Plaque Segmentation In Multi-Weighted Mri Using A Two-Stage Neural Network: Advantages Of Training With High-Resolution Imaging And Histology, Ran Li, Jie Zheng, Mohamed A Zayed, Jeffrey E Saffitz, Pamela K Woodard, Abhinav K Jha

2020-Current year OA Pubs

INTRODUCTION: A reliable and automated method to segment and classify carotid artery atherosclerotic plaque components is needed to efficiently analyze multi-weighted magnetic resonance (MR) images to allow their integration into patient risk assessment for ischemic stroke. Certain plaque components such as lipid-rich necrotic core (LRNC) with hemorrhage suggest a greater likelihood of plaque rupture and stroke event. Assessment for presence and extent of LRNC could assist in directing treatment with impact upon patient outcomes.

METHODS: To address the need to accurately determine the presence and extent of plaque components on carotid plaque MRI, we proposed a two-staged deep-learning-based approach that …

Ehealth Technology In Cardiac Exercise Therapeutics For Pediatric Patients With Congenital And Acquired Heart Conditions: A Summary Of Evidence And Future Directions, David A White, Aimee M Layton, Tracy Curran, Naomi Gauthier, William B Orr, Kendra Ward, Meg Vernon, Matthew N Martinez, Malloree C Rice, Katherine Hansen, Megan Prusi, Jesse E Hansen

2020-Current year OA Pubs

Many children and adolescents with congenital and acquired heart disease (CHD) are physically inactive and participate in an insufficient amount of moderate-to-vigorous intensity exercise. Although physical activity (PA) and exercise interventions are effective at improving short- and long-term physiological and psychosocial outcomes in youth with CHD, several barriers including resource limitations, financial costs, and knowledge inhibit widespread implementation and dissemination of these beneficial programs. New and developing eHealth, mHealth, and remote monitoring technologies offer a potentially transformative and cost-effective solution to increase access to PA and exercise programs for youth with CHD, yet little has been written on this topic. …

Higher Intensity Walking Improves Global Cognition During Inpatient Rehabilitation: A Secondary Analysis Of A Randomized Control Trial, Sue Peters, Keith R Lohse, Tara D Klassen, Teresa Liu-Ambrose, Sean P Dukelow, Mark T Bayley, Michael D Hill, Sepideh Pooyania, Jennifer Yao, Janice J Eng

2020-Current year OA Pubs

Cognitive deficits are common poststroke. Cognitive rehabilitation is typically used to improve cognitive deficits. It is unknown whether higher doses of exercise to promote motor recovery influence cognitive outcomes. Our recent trial, Determining Optimal Post-Stroke Exercise (DOSE), shows more than double the steps and aerobic minutes can be achieved during inpatient rehabilitation versus usual care, and translates to improved long-term walking outcomes. Thus, the secondary analysis aim was to determine the effect of the DOSE protocol on cognitive outcomes over 1-year poststroke. The DOSE protocol progressively increased step number and aerobic minutes during inpatient stroke rehabilitation over 20 sessions. The …

Identification Of Prok2 Gene Polymorphisms As Predictors Of Methamphetamine Use Disorder Risk And Indicators Of Craving Scale In The Chinese Han Population, Zhao Jiang, Tianxiao Zhang, Wei Han, Jing Xiao, Wenpei Zhang, Xiaochen Wang, Jianing Liu, Ying Yang, Congying Yang, Fanglin Guan, Tao Li, John P Rice

2020-Current year OA Pubs

No abstract provided.

Assessment Of Cochlear Synaptopathy By Electrocochleography To Low Frequencies In A Preclinical Model And Human Subjects, Raymond A Haggerty, Kendall A Hutson, William J Riggs, Kevin D Brown, Harold C Pillsbury, Oliver F Adunka, Craig A Buchman, Douglas C Fitzpatrick

2020-Current year OA Pubs

Cochlear synaptopathy is the loss of synapses between the inner hair cells and the auditory nerve despite survival of sensory hair cells. The findings of extensive cochlear synaptopathy in animals after moderate noise exposures challenged the long-held view that hair cells are the cochlear elements most sensitive to insults that lead to hearing loss. However, cochlear synaptopathy has been difficult to identify in humans. We applied novel algorithms to determine hair cell and neural contributions to electrocochleographic (ECochG) recordings from the round window of animal and human subjects. Gerbils with normal hearing provided training and test sets for a deep …

Women's Preferences For A New Contraceptive Under Development: An Exploratory Study, Tessa Madden, Sarah Y Cohen, Rachel Paul, Emily G Hurley, Michael A Thomas, Giovanni Pauletti

2020-Current year OA Pubs

OBJECTIVE: Currently available contraceptive methods do not meet the needs of all users. We sought to explore preferences of potential end-users regarding an on-demand, non-hormonal female contraceptive currently under development, using a web-based survey.

STUDY DESIGN: We recruited respondents for an exploratory survey via web link on Amazon Mechanical Turk (MTurk). Individuals were eligible if they were 18-44 years of age, identified as cis-gender female, were English-speaking, not pregnant, and had used barrier contraception previously. Respondents provided demographic characteristics and a basic reproductive history. We then provided a brief description of the potential contraceptive. Respondents were asked about their interest …

Racial Disparities In Access To Dbs: Results Of A Real-World U.S. Claims Data Analysis, Michael Frassica, Drew S Kern, Mitra Afshari, Allison T Connolly, Chengyuan Wu, Nathan Rowland, Juan Ramirez-Castaneda, Mwiza Ushe, Claudia Salazar, Xenos Mason

2020-Current year OA Pubs

INTRODUCTION: Deep brain stimulation (DBS) is an effective and standard-of-care therapy for Parkinson's Disease and other movement disorders when symptoms are inadequately controlled with conventional medications. It requires expert care for patient selection, surgical targeting, and therapy titration. Despite the known benefits, racial/ethnic disparities in access have been reported. Technological advancements with smartphone-enabled devices may influence racial disparities. Real-world evidence investigations can shed further light on barriers to access and demographic disparities for DBS patients.

METHODS: A retrospective cross-sectional study was performed using Medicare claims linked with manufacturer patient data tracking to analyze 3,869 patients who received DBS. Patients were …

Clinical Applications Of Electrical Stimulation For Peripheral Nerve Injury: A Systematic Review, Meredith C Costello, Emily L Errante, Taylor Smartz, Wilson Z Ray, Allan D Levi, Stephen Shelby Burks

2020-Current year OA Pubs

INTRODUCTION: Peripheral nerve injuries are common neurologic injuries that are challenging to treat with current therapies. Electrical stimulation has been shown to accelerate reinnervation and enhance functional recovery. This study aims to review the literature on clinical application of electrical stimulation for peripheral nerve injury.

METHODS: PubMed and Embase were sourced from 1995 to August 2022. Selection was based on predetermined inclusion/exclusion criteria. Eight hundred and thirty-five articles were screened with seven being included in this review.

RESULTS: Two hundred and twenty-nine patients with peripheral nerve injuries were represented. Six of the studies were randomized controlled trials. A variety of …

Caregiver Perspectives On The Continued Impact Of The Covid-19 Pandemic On Children With Intellectual/Developmental Disabilities, R A Northrup, E Jones, V Singh, C Holingue, M Meck, C A Gurnett, M Van Stone, L G Kalb

2020-Current year OA Pubs

The COVID-19 pandemic has significantly impacted caregivers, especially those raising a child with an intellectual/developmental disability (IDD). While research has shown substantial disruption to the family, school, and occupational lives of the IDD community, little is known about the long-term impacts of COVID-19. To address this question, 249 caregivers were surveyed via an online questionnaire, between April and August of 2022 (more than 2 years into the pandemic) about potential impacts of the COVID-19 pandemic on their child's access to health- and school-based therapeutic services, caregiver mental health, and family life. The majority of caregivers reported disruptions in access to …

Oxidation Driven Reversal Of Pip2-Dependent Gating In Girk2 Channels, Sun-Joo Lee, Shoji Maeda, Jian Gao, Colin G Nichols

2020-Current year OA Pubs

Physiological activity of G protein gated inward rectifier K

Intra-Articular Aav9 Α-L-Iduronidase Gene Replacement In The Canine Model Of Mucopolysaccharidosis Type I, Raymond Yu-Jeang Wang, Shih-Hsin Kan, Haoyue Zhang, Jodi D Smith, Afshin Aminian, Elizabeth Snella, Jackie K Jens, Sarah P Young, Patricia I Dickson, N Matthew Ellinwood

2020-Current year OA Pubs

Mucopolysaccharidosis type I (MPS I), an inherited lysosomal storage disorder characterized by deficiency of