Digital Commons Network^™

Dissecting Cell Identity Via Network Inference And In Silico Gene Perturbation, Kenji Kamimoto, Blerta Stringa, Christy M Hoffmann, Kunal Jindal, Lilianna Solnica-Krezel, Samantha A Morris

2020-Current year OA Pubs

Cell identity is governed by the complex regulation of gene expression, represented as gene-regulatory networks

Effect Of Histology On Stereotactic Body Radiotherapy For Non-Small Cell Lung Cancer Oligometastatic Pulmonary Lesions, Alexander J. Allen, Dominic A. Labella, Roman O. Kowalchuk, Michael R. Waters, Charles R. Kersh

2020-Current year OA Pubs

BACKGROUND: Stereotactic body radiotherapy (SBRT) is commonly used to provide targeted treatment to metastatic lung disease. Investigation is needed to understand the influence of histology on treatment outcomes. We report how tumor histology affects local control (LC) in a cohort of patients with non-small cell lung cancer (NSCLC) receiving SBRT for oligometastatic and recurrent pulmonary lesions.

METHODS: Patients who received SBRT to recurrent or oligometastatic NSCLC pulmonary lesions from 2015-2019 at our institution were included in this retrospective cohort study. Minimum follow-up was 2 months. Kaplan-Meier (KM) analysis was performed to assess local progression-free survival (LPFS). Local failure cumulative incidence …

The Hepatic Mitochondrial Pyruvate Carrier As A Regulator Of Systemic Metabolism And A Therapeutic Target For Treating Metabolic Disease, Kyle S Mccommis, Brian N Finck

2020-Current year OA Pubs

Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways …

Exploration Of The Nuclear Proteomes In The Ciliate Oxytricha Trifallax, Michael W Lu, Leslie Y Beh, V Talya Yerlici, Wenwen Fang, Katarzyna Kulej, Benjamin A Garcia, Laura F Landweber

2020-Current year OA Pubs

Nuclear dimorphism is a fundamental feature of ciliated protozoa, which have separate somatic and germline genomes in two distinct organelles within a single cell. The transcriptionally active somatic genome, contained within the physically larger macronucleus, is both structurally and functionally different from the silent germline genome housed in the smaller micronucleus. This difference in genome architecture is particularly exaggerated in

Chronic Anti-Coagulation Therapy Reduced Mortality In Patients With High Cardiovascular Risk Early In Covid-19 Pandemic, Mohamed S Zaghloul, Momodou Jammeh, Andrew Gibson, Suhong Luo, Kelley Chadwick-Mansker, Qianjin Liu, Yan Yan, Mohamed A Zayed

2020-Current year OA Pubs

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with provoked thrombo-inflammatory responses. Early in the COVID-19 pandemic this was thought to contribute to hypercoagulability and multi-organ system complications in infected patients. Limited studies have evaluated the impact of therapeutic anti-coagulation therapy (AC) in alleviating these risks in COVID-19 positive patients. Our study aimed to investigate whether long-term therapeutic AC can decrease the risk of multi-organ system complications (MOSC) including stroke, limb ischemia, gastrointestinal (GI) bleeding, in-hospital and intensive care unit death in COVID-19 positive patients hospitalized during the early phase of the pandemic in the United States.

METHODS: A retrospective analysis …

Neuroimaging Studies Of The Neural Correlates Of Heart Rate Variability: A Systematic Review, Patrycja S Matusik, Chuwen Zhong, Paweł T Matusik, Omar Alomar, Phyllis K Stein

2020-Current year OA Pubs

Direct and indirect links between brain regions and cardiac function have been reported. We performed a systematic literature review to summarize current knowledge regarding the associations of heart rate variability (HRV) and brain region morphology, activity and connectivity involved in autonomic control at rest in healthy subjects. Both positive and negative correlations of cortical thickness and gray matter volumes of brain structures with HRV were observed. The strongest were found for a cluster located within the cingulate cortex. A decline in HRV, as well as cortical thickness with increasing age, especially in the orbitofrontal cortex were noted. When associations of …

Drug Specificity And Affinity Are Encoded In The Probability Of Cryptic Pocket Opening In Myosin Motor Domains, Artur Meller, Jeffrey M Lotthammer, Louis G Smith, Borna Novak, Lindsey A Lee, Catherine C Kuhn, Lina Greenberg, Leslie A Leinwand, Michael J Greenberg, Gregory R Bowman

2020-Current year OA Pubs

The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the …

Development Of De Novo Nonalcoholic Fatty Liver Disease Following Pancreatectomy, Vanisha Patel, Parth Shah, Daniel R. Ludwig, Chet W. Hammill, Motaz Ashkar

2020-Current year OA Pubs

De novo non-alcoholic fatty liver disease (NAFLD) after pancreatectomy is a recognized phenomenon; however, its pathophysiology is poorly understood. This study aimed to determine the incidence and identify peri-operative risk factors for the development of de novo NAFLD within various pancreatectomy groups. This single-center retrospective cohort study included patients who underwent pancreatectomy between 2000 and 2020. The incidence rate of de novo NAFLD and time to diagnosis were recorded across patients with malignant versus benign indications for pancreatectomy. The overall incidence of de novo NAFLD after pancreatectomy was 17.5% (24/136). Twenty-one percent (20/94) of patients with malignant indications for surgery …

Gold Nanoparticle-Enhanced X-Ray Microtomography Of The Rodent Reveals Region-Specific Cerebrospinal Fluid Circulation In The Brain, Shelei Pan, Peter H Yang, Dakota Defreitas, Sruthi Ramagiri, Peter O Bayguinov, Carl D Hacker, Abraham Z Snyder, Jackson Wilborn, Hengbo Huang, Gretchen M Koller, Dhvanii K Raval, Grace L Halupnik, Sanja Sviben, Rui Tang, Gabriel Haller, James D Quirk, James A J Fitzpatrick, Prabagaran Esakky, Jennifer M Strahle, Et Al.

2020-Current year OA Pubs

Cerebrospinal fluid (CSF) is essential for the development and function of the central nervous system (CNS). However, the brain and its interstitium have largely been thought of as a single entity through which CSF circulates, and it is not known whether specific cell populations within the CNS preferentially interact with the CSF. Here, we develop a technique for CSF tracking, gold nanoparticle-enhanced X-ray microtomography, to achieve micrometer-scale resolution visualization of CSF circulation patterns during development. Using this method and subsequent histological analysis in rodents, we identify previously uncharacterized CSF pathways from the subarachnoid space (particularly the basal cisterns) that mediate …

A Broad Characterization Of Glycogen Storage Disease Iv Patients: A Clinical, Genetic, And Histopathological Study, Matheus Vernet Machado Bressan Wilke, Bibiana Mello De Oliveira, Rodrigo Tzovenos Starosta, Marwan Shinawi, Liang Lu, Mai He, Yamin Ma, Janis Stoll, Carolina Fischinger Moura De Souza, Ana Cecilia Menezes De Siqueira, Sandra Maria Gonçalves Vieira, Carlos Thadeu Cerski, Lilia Farret Refosco, Ida Vanessa Doederlein Schwartz

2020-Current year OA Pubs

Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disease caused by variants in the

Cross Center Single-Cell Rna Sequencing Study Of The Immune Microenvironment In Rapid Progressing Multiple Myeloma, William Pilcher, Reyka G Jayasinghe, Lijun Yao, Mark Fiala, Ravi Vij, Li Ding, Et Al.

2020-Current year OA Pubs

Despite advancements in understanding the pathophysiology of Multiple Myeloma (MM), the cause of rapid progressing disease in a subset of patients is still unclear. MM's progression is facilitated by complex interactions with the surrounding bone marrow (BM) cells, forming a microenvironment that supports tumor growth and drug resistance. Understanding the immune microenvironment is key to identifying factors that promote rapid progression of MM. To accomplish this, we performed a multi-center single-cell RNA sequencing (scRNA-seq) study on 102,207 cells from 48 CD138

Enhanced Vwf Clearance In Low Vwf Pathogenesis: Limitations Of The Vwfpp/Vwf:Ag Ratio And Clinical Significance, Dearbhla Doherty, Michelle Lavin, Mary Byrne, Margaret Nolan, Jamie M O'Sullivan, Kevin Ryan, Niamh M O'Connell, Sandra L Haberichter, Pamela A Christopherson, Jorge Di Paola, Paula D James, James S O'Donnell

2020-Current year OA Pubs

Increased von Willebrand factor (VWF) clearance plays a key role in the pathogenesis of type 1 and type 2 von Willebrand disease (VWD). However, the pathological mechanisms involved in patients with mild to moderate reductions in plasma VWF:Ag (range, 30-50 IU/dL; low VWF) remain poorly understood. In this study, we investigated the hypothesis that enhanced VWF clearance may contribute to the pathobiology of low VWF. Patients with low VWF were recruited to the LoVIC study after ethics approval and receipt of informed consent. Desmopressin was administered IV in 75 patients, and blood samples were drawn at baseline and at the …

Gut Microbiota And Microbiota-Derived Metabolites Promotes Endometriosis, Sangappa B Chadchan, Sumanta K Naik, Pooja Popli, Chandni Talwar, Satwikreddy Putluri, Chandrasekhar R Ambati, Michael A Lint, Andrew L Kau, Christina L Stallings, Ramakrishna Kommagani

2020-Current year OA Pubs

Endometriosis is a pathological condition of the female reproductive tract characterized by the existence of endometrium-like tissue at ectopic sites, affecting 10% of women between the age 15 and 49 in the USA. However, currently there is no reliable non-invasive method to detect the presence of endometriosis without surgery and many women find hormonal therapy and surgery as ineffective in avoiding the recurrences. There is a lack of knowledge on the etiology and the factors that contribute to the development of endometriosis. A growing body of recent evidence suggests an association between gut microbiota and endometriosis pathophysiology. However, the direct …

Quantification Of Localized Nad+ Changes Reveals Unique Specificity Of Nad+ Regulation In The Hypothalamus, Sean Johnson, Kiyoshi Yoshioka, Cynthia S Brace, Shin-Ichiro Imai

2020-Current year OA Pubs

Recently, it has become a consensus that systemic decreases in NAD

Structure-Function Correlates Of Fibrinogen Binding By Acinetobacter Adhesins Critical In Catheter-Associated Urinary Tract Infections, Kevin O Tamadonfar, Gisela Di Venanzio, Jerome S Pinkner, Karen W Dodson, Vasilios Kalas, Maxwell I Zimmerman, Jesus Bazan Villicana, Gregory R Bowman, Mario F Feldman, Scott J Hultgren

2020-Current year OA Pubs

Multidrug-resistant

Comparison Of State-Of-The-Art Neural Network Survival Models With The Pooled Cohort Equations For Cardiovascular Disease Risk Prediction, Yu Deng, Lei Liu, Et Al.

2020-Current year OA Pubs

BACKGROUND: The Pooled Cohort Equations (PCEs) are race- and sex-specific Cox proportional hazards (PH)-based models used for 10-year atherosclerotic cardiovascular disease (ASCVD) risk prediction with acceptable discrimination. In recent years, neural network models have gained increasing popularity with their success in image recognition and text classification. Various survival neural network models have been proposed by combining survival analysis and neural network architecture to take advantage of the strengths from both. However, the performance of these survival neural network models compared to each other and to PCEs in ASCVD prediction is unknown.

METHODS: In this study, we used 6 cohorts from …

Osteoclasts, Master Sculptors Of Bone, Deborah J Veis, Charles A O'Brien

2020-Current year OA Pubs

Osteoclasts are multinucleated cells with the unique ability to resorb bone matrix. Excessive production or activation of osteoclasts leads to skeletal pathologies that affect a significant portion of the population. Although therapies that effectively target osteoclasts have been developed, they are associated with sometimes severe side effects, and a fuller understanding of osteoclast biology may lead to more specific treatments. Along those lines, a rich body of work has defined essential signaling pathways required for osteoclast formation, function, and survival. Nonetheless, recent studies have cast new light on long-held views regarding the origin of these cells during development and homeostasis, …

Evaluation Of Raavrh74 Gene Therapy Vector Seroprevalence By Measurement Of Total Binding Antibodies In Patients With Duchenne Muscular Dystrophy, Natalie L Goedeker, Sachi D Dharia, Danielle A Griffin, Jesantha Coy, Todd Truesdale, Rajan Parikh, Kasen Whitehouse, Sourav Santra, Damon R Asher, Craig M Zaidman

2020-Current year OA Pubs

BACKGROUND: Adeno-associated virus (AAV) vectors are a promising platform for

OBJECTIVE: To evaluate prevalence of total binding antibodies (neutralizing and non-neutralizing) against rAAVrh74 in patients with DMD.

METHODS: Eligible individuals (

RESULTS: A large preponderance (86.1%) of patients with DMD in this data set was seronegative for anti-rAAVrh74 total binding antibodies. These patients would potentially meet the antibody status eligibility criterion for entry into rAAVrh74-based gene therapy clinical trials.

CONCLUSION: Measuring total binding antibodies is a more comprehensive approach to assess pre-existing immune response

A Selective Inhibitor Of The Sperm-Specific Potassium Channel Slo3 Impairs Human Sperm Function, Maximilian Lyon, Ping Li, Juan J Ferreira, Aluet Borrego Alvarez, Lis C Puga Molina, Pascale Lybaert, Saayli Khambekar, Alicia Liu, Celia M Santi, Et Al.

2020-Current year OA Pubs

To fertilize an oocyte, the membrane potential of both mouse and human sperm must hyperpolarize (become more negative inside). Determining the molecular mechanisms underlying this hyperpolarization is vital for developing new contraceptive methods and detecting causes of idiopathic male infertility. In mouse sperm, hyperpolarization is caused by activation of the sperm-specific potassium (K

E. Coli Catheter-Associated Urinary Tract Infections Are Associated With Distinctive Virulence And Biofilm Gene Determinants, Zongsen Zou, Robert F. Potter, William H. Mccoy, John A. Wildenthal, George L. Katumba, Peter J. Mucha, Gautam Dantas, Jeffrey P. Henderson

2020-Current year OA Pubs

Urinary catheterization facilitates urinary tract colonization by E. coli and increases infection risk. Here, we aimed to identify strain-specific characteristics associated with the transition from colonization to infection in catheterized patients. In a single-site study population, we compared E. coli isolates from patients with catheter-associated asymptomatic bacteriuria (CAASB) to those with catheter-associated urinary tract infection (CAUTI). CAUTI isolates were dominated by a phylotype B2 subclade containing the multidrug-resistant ST131 lineage relative to CAASB isolates, which were phylogenetically more diverse. A distinctive combination of virulence-associated genes was present in the CAUTI-associated B2 subclade. Catheter-associated biofilm formation was widespread among isolates and …

Distinct Clonal Identities Of B-Alls Arising After Lenolidomide Therapy For Multiple Myeloma, Erica K Barnell, Zachary L Skidmore, Kenneth F Newcomer, Monique Chavez, Katie M Campbell, Kelsy C Cotto, Nicholas C Spies, Marianna B Ruzinova, Tianjiao Wang, Brooj Abro, Bijal A Parikh, Eric J Duncavage, John L Frater, Yi-Shan Lee, Anjum Hassan, Justin A King, Daniel R Kohnen, Mark A Fiala, John S Welch, Geoffrey L Uy, Kiran Vij, Ravi Vij, Malachi Griffith, Obi L Griffith, Lukas D Wartman, Et Al.

2020-Current year OA Pubs

Patients with multiple myeloma (MM) who are treated with lenalidomide rarely develop a secondary B-cell acute lymphoblastic leukemia (B-ALL). The clonal and biological relationship between these sequential malignancies is not yet clear. We identified 17 patients with MM treated with lenalidomide, who subsequently developed B-ALL. Patient samples were evaluated through sequencing, cytogenetics/fluorescence in situ hybridization (FISH), immunohistochemical (IHC) staining, and immunoglobulin heavy chain (IgH) clonality assessment. Samples were assessed for shared mutations and recurrently mutated genes. Through whole exome sequencing and cytogenetics/FISH analysis of 7 paired samples (MM vs matched B-ALL), no mutational overlap between samples was observed. Unique dominant …

Clinical Outcomes In Patients Relapsed/Refractory After ≥2 Prior Lines Of Therapy For Follicular Lymphoma: A Systematic Literature Review And Meta-Analysis, Steve Kanters, Graeme Ball, Brad Kahl, Adriana Wiesinger, Eve H Limbrick-Oldfield, Akshay Sudhindra, Julia Thornton Snider, Anik R Patel

2020-Current year OA Pubs

BACKGROUND: Patients with follicular lymphoma (FL) can have high response rates to early lines of treatment. However, among FL patients relapsed/refractory (r/r) after ≥2 prior lines of therapy (LOT), remission tends to be shorter and there is limited treatment guidance. This study sought to evaluate the clinical outcomes for r/r FL after ≥2 prior LOT identified through systematic literature review.

METHODS: Eligible studies included comparative or non-comparative interventional or observational studies of systemic therapies among adults with FL r/r after ≥2 prior LOT published prior to 31st May 2021. Prior LOT must have included an anti-CD20 monoclonal antibody and an …

Lateral Line Ablation By Ototoxic Compounds Results In Distinct Rheotaxis Profiles In Larval Zebrafish, Kyle C Newton, Dovi Kacev, Simon R O Nilsson, Allison L Saettele, Sam A Golden, Lavinia Sheets

2020-Current year OA Pubs

The zebrafish lateral line is an established model for hair cell organ damage, yet few studies link mechanistic disruptions to changes in biologically relevant behavior. We used larval zebrafish to determine how damage via ototoxic compounds impact rheotaxis. Larvae were treated with CuSO

Synthetic Biology Design As A Paradigm Shift Toward Manufacturing Affordable Adeno-Associated Virus Gene Therapies, Logan Thrasher Collins, Selvarangan Ponnazhagan, David T Curiel

2020-Current year OA Pubs

Gene therapy has demonstrated enormous potential for changing how we combat disease. By directly engineering the genetic composition of cells, it provides a broad range of options for improving human health. Adeno-associated viruses (AAVs) represent a leading gene therapy vector and are expected to address a wide range of conditions in the coming decade. Three AAV therapies have already been approved by the FDA to treat Leber's congenital amaurosis, spinal muscular atrophy, and hemophilia B. Yet these therapies cost around $850,000, $2,100,000, and $3,500,000, respectively. Such prices limit the broad applicability of AAV gene therapy and make it inaccessible to …

A Pleiotropic Chemoreceptor Facilitates The Production And Perception Of Mating Pheromones, Cassondra L Vernier, Nicole Leitner, Kathleen M Zelle, Merrin Foltz, Sophia Dutton, Xitong Liang, Sean Halloran, Jocelyn G Millar, Yehuda Ben-Shahar

2020-Current year OA Pubs

Optimal mating decisions depend on the robust coupling of signal production and perception because independent changes in either could carry a fitness cost. However, since the perception and production of mating signals are often mediated by different tissues and cell types, the mechanisms that drive and maintain their coupling remain unknown for most animal species. Here, we show that in

Personalized Therapeutics For Katp-Dependent Pathologies, Colin G Nichols

2020-Current year OA Pubs

Ubiquitously expressed throughout the body, ATP-sensitive potassium (K

Identifying Biomarkers Of Differential Chemotherapy Response In Tnbc Patient-Derived Xenografts With A Ctd/Wgcna Approach, Varduhi Petrosyan, Shunqiang Li, Et Al.

2020-Current year OA Pubs

Although systemic chemotherapy remains the standard of care for TNBC, even combination chemotherapy is often ineffective. The identification of biomarkers for differential chemotherapy response would allow for the selection of responsive patients, thus maximizing efficacy and minimizing toxicities. Here, we leverage TNBC PDXs to identify biomarkers of response. To demonstrate their ability to function as a preclinical cohort, PDXs were characterized using DNA sequencing, transcriptomics, and proteomics to show consistency with clinical samples. We then developed a network-based approach (CTD/WGCNA) to identify biomarkers of response to carboplatin (MSI1, TMSB15A, ARHGDIB, GGT1, SV2A, SEC14L2, SERPINI1, ADAMTS20, DGKQ) and docetaxel (c, MAGED4, …

Impact Of The Covid-19 Pandemic On Burnout And Perceived Workplace Quality Among Addiction Treatment Providers, Andrea Fentem, Raven Riordan, Christine Doroshenko, Xiao Li, Erin Kasson, Devin Banks, Rachel P Winograd, Patricia Cavazos-Rehg

2020-Current year OA Pubs

BACKGROUND: This study examines the impact of the COVID-19 pandemic on work satisfaction, work-related stress, and perceived work quality among substance use treatment providers to better understand challenges faced among this group during the pandemic.

METHODS: Participants of this study were 91 addiction treatment providers (e.g., therapists, physicians, community support specialists, administrative staff) recruited from various treatment facilities (e.g., inpatient and outpatient settings). Mixed method analyses were conducted to assess self-reported burnout, sources of work-related stress, and perceived work quality during the pandemic. Responses from providers reporting COVID-19 related decreases in work quality were compared to responses from providers who …

Treatment Outcomes And Roles Of Transplantation And Maintenance Rituximab In Patients With Previously Untreated Mantle Cell Lymphoma: Results From Large Real-World Cohorts, Peter Martin, Jonathon B Cohen, Michael Wang, Anita Kumar, Brian Hill, Diego Villa, Jeffrey M Switchenko, Brad Kahl, Kami Maddocks, Natalie S Grover, Keqin Qi, Lori Parisi, Katherine Daly, Angeline Zhu, Gilles Salles

2020-Current year OA Pubs

PURPOSE: Commonly used first-line (1L) treatments for mantle cell lymphoma include high-dose cytarabine-based induction followed by autologous stem-cell transplant (ASCT) for younger patients and several chemoimmunotherapy regimens for older patients. Continuous debates exist on the role of ASCT in younger patients and maintenance rituximab (MR) after bendamustine plus rituximab (BR).

METHODS: Retrospective data from 4,216 patients with mantle cell lymphoma in the Flatiron Health electronic record-derived deidentified database diagnosed between 2011 and 2021, mostly in US community oncology settings, were evaluated for treatment patterns and outcomes. The efficacy findings with ASCT and MR were validated in an independent cohort of …

Virome Analysis And Association Of Positive Coxsackievirus B Serology During Pregnancy With Congenital Heart Disease, Mathieu Garand, Susie S Y Huang, Lisa S Goessling, Fei Wan, Donna A Santillan, Mark K Santillan, Anoop Brar, Todd N Wylie, Kristine M Wylie, Pirooz Eghtesady

2020-Current year OA Pubs

BACKGROUND: We have previously shown coxsackievirus B (CVB) to be a potent inducer of congenital heart disease (CHD) in mice. The clinical relevance of these findings in humans and the roles of other viruses in the pathogenesis of CHD remain unknown.

METHODS: We obtained plasma samples, collected at all trimesters, from 89 subjects (104 pregnancies), 73 healthy controls (88 pregnancies), and 16 with CHD-affected birth (16 pregnancies), from the Perinatal Family Tissue Bank (PFTB). We performed CVB IgG/IgM serological assays on plasma. We also used ViroCap sequencing and PCR to test for viral nucleic acid in plasma, circulating leukocytes from …