Digital Commons Network^™

Opioid Use Disorder Risk Alleles In Self-Reported Assigned African American/Afro-Caribbean And European Biogeographical Genetic Ancestry Groups And In Males And Females, Jon E Sprague, Caroline E Freiermuth, Joshua Lambert, Robert Braun, Jennifer A Frey, Daniel J Bachmann, Jason J Bischof, Lauren Beaumont, Michael S Lyons, Michael V Pantalon, Brittany E Punches, Rachel Ancona, David F Kisor

2020-Current year OA Pubs

The influence of genetic variants related to opioid use disorder (OUD) was evaluated using multiple logistic regression analysis in self-reported assigned African American/Afro-Caribbean and European biogeographical ancestry groups (BGAGs) and by sex. From a sample size of 1301 adult patients (>18 years of age) seen in emergency departments of three medical centers in Ohio, six variants were found to be associated with OUD. Two of the variants, rs2740574 (CYP3A4) and rs324029 (DRD3), were included in the analysis having met criteria of at least five subjects for each BGAG, variant carrier status, and OUD status combinations. Variant carriers in the …

Estimation Of Differential Pathlength Factor From Nirs Measurement In Skeletal Muscle, B Koirala, A Concas, A Cincotti, Yi Sun, A Hernández, M L Goodwin, L B Gladden, N Lai

2020-Current year OA Pubs

The utilization of continuous wave (CW) near-infrared spectroscopy (NIRS) device to measure non-invasively muscle oxygenation in healthy and disease states is limited by the uncertainties related to the differential path length factor (DPF). DPF value is required to quantify oxygenated and deoxygenated heme groups' concentration changes from measurement of optical densities by NIRS. An integrated approach that combines animal and computational models of oxygen transport and utilization was used to estimate the DPF value in situ. The canine model of muscle oxidative metabolism allowed measurement of both venous oxygen content and tissue oxygenation by CW NIRS under different oxygen delivery …

Head And Neck Squamous Cell Carcinomas Of Unknown Primary: Can Ancillary Studies Help Identify More Primary Tumor Sites?, Troy Hutchens, Wade Thorstad, Xiaowei Wang, Yuanxiang Li, Eric J Duncavage, Lulu Sun, Rebecca D Chernock

2020-Current year OA Pubs

A subset of head and neck squamous cell carcinomas present solely as metastatic disease in the neck and are of unknown primary origin (SCCUP). Most primary tumors will ultimately be identified, usually in the oropharynx. In a minority of cases, the primary site remains elusive. Here, we examine the role of ancillary testing, including mutational signature analysis (MSA), to help identify likely primary sites in such cases. Twenty-two cases of SCCUP in the neck, collected over a 10-year period, were classified by morphology and viral status; including human papillomavirus (HPV) testing by p16 immunohistochemistry (IHC) and RT-qPCR, as well as …

Customization Of Computed Tomography Radio-Opacity In 3d-Printed Contrast-Injectable Tumor Phantoms, Yuktesh Kalidindi, Aravinda Krishna Ganapathy, Liam Cunningham, Adriene Lovato, Brian Albers, Anup S Shetty, David H Ballard

2020-Current year OA Pubs

Medical Imaging Phantoms (MIPs) calibrate imaging devices, train medical professionals, and can help procedural planning. Traditional MIPs are costly and limited in customization. Additive manufacturing allows for customizable, patient-specific phantoms. This study examines the CT attenuation characteristics of contrast-injectable, chambered 3D-printed phantoms to optimize tissue-mimicking capabilities. A MIP was constructed from a CT of a complex pelvic tumor near the iliac bifurcation. A 3D reconstruction of these structures composed of three chambers (aorta, inferior vena cava, tumor) with ports for contrast injection was 3D printed. Desired attenuations were 200 HU (arterial I), 150 HU (venous I), 40 HU (tumor I), …

Meta-Analysis Identifies Common Gut Microbiota Associated With Multiple Sclerosis, Qingqi Lin, Yair Dorsett, Ali Mirza, Helen Tremlett, Laura Piccio, Erin E Longbrake, Siobhan Ni Choileain, David A Hafler, Laura M Cox, Howard L Weiner, Takashi Yamamura, Kun Chen, Yufeng Wu, Yanjiao Zhou

2020-Current year OA Pubs

BACKGROUND: Previous studies have identified a diverse group of microbial taxa that differ between patients with multiple sclerosis (MS) and the healthy population. However, interpreting findings on MS-associated microbiota is challenging, as there is no true consensus. It is unclear whether there is gut microbiota commonly altered in MS across studies.

METHODS: To answer this, we performed a meta-analysis based on the 16S rRNA gene sequencing data from seven geographically and technically diverse studies comprising a total of 524 adult subjects (257 MS and 267 healthy controls). Analysis was conducted for each individual study after reprocessing the data and also …

Gabaa Receptor Subunit Composition Regulates Circadian Rhythms In Rest–Wake And Synchrony Among Cells In The Suprachiasmatic Nucleus, Daniel Granados-Fuentes, Peter Lambert, Tatiana Simon, Steven Mennerick, Erik D Herzog

2020-Current year OA Pubs

The mammalian circadian clock located in the suprachiasmatic nucleus (SCN) produces robust daily rhythms including rest-wake. SCN neurons synthesize and respond to γ-aminobutyric acid (GABA), but its role remains unresolved. We tested the hypothesis that γ2- and δ-subunits of the GABA

Gemykibivirus Detection In Acute Encephalitis Patients From Nepal, Eans Tara Tuladhar, Smita Shrestha, Susan Vernon, Lindsay Droit, Kathie A Mihindukulasuriya, Mamta Tamang, Lata Karki, Annie Elong Ngono, Bimlesh Jha, Bal Krishna Awal, Bimal Sharma Chalise, Runa Jha, Sujan Shresta, David Wang, Krishna Das Manandhar

2020-Current year OA Pubs

UNLABELLED: Acute encephalitis syndrome (AES) causes significant morbidity and mortality worldwide. In Nepal, Japanese encephalitis virus (JEV) accounts for ~5-20% of AES cases, but ~75% of AES cases are of unknown etiology. We identified a gemykibivirus in CSF collected in 2020 from an 8-year-old male patient with AES using metagenomic next-generation sequencing. Gemykibiviruses are single stranded, circular DNA viruses in the family

IMPORTANCE: Viral encephalitis is a devastating disease, but unfortunately, worldwide, the causative virus in many cases is unknown. Therefore, it is important to identify viruses that could be responsible for cases of human encephalitis. Here, using metagenomic sequencing …

Impact Of Esophageal Motility On Microbiome Alterations In Symptomatic Gastroesophageal Reflux Disease Patients With Negative Endoscopy: Exploring The Role Of Ineffective Esophageal Motility And Contraction Reserve, Ming-Wun Wong, I-Hsuan Lo, Wei-Kai Wu, Po-Yu Liu, Yu-Tang Yang, Chun-Yao Chen, Ming-Shiang Wu, Sunny H Wong, Wei-Yi Lei, Chih-Hsun Yi, Tso-Tsai Liu, Jui-Sheng Hung, Shu-Wei Liang, C Prakash Gyawali, Chien-Lin Chen

2020-Current year OA Pubs

BACKGROUND/AIMS: Ineffective esophageal motility (IEM) is common in patients with gastroesophageal reflux disease (GERD) and can be associated with poor esophageal contraction reserve on multiple rapid swallows. Alterations in the esophageal microbiome have been reported in GERD, but the relationship to presence or absence of contraction reserve in IEM patients has not been evaluated. We aim to investigate whether contraction reserve influences esophageal microbiome alterations in patients with GERD and IEM.

METHODS: We prospectively enrolled GERD patients with normal endoscopy and evaluated esophageal motility and contraction reserve with multiple rapid swallows during high-resolution manometry. The esophageal mucosa was biopsied for …

Treatment Response With Potassium-Competitive Acid Blockers Based On Clinical Phenotypes Of Gastroesophageal Reflux Disease: A Systematic Literature Review And Meta-Analysis, Seungyeon Seo, Hye-Kyung Jung, C Prakash Gyawali, Hye Ah Lee, Hyung Seok Lim, Eui Sun Jeong, Seong Eun Kim, Chang Mo Moon

2020-Current year OA Pubs

BACKGROUND/AIMS: Gastroesophageal reflux disease (GERD) is typically managed based on the clinical phenotype. We evaluated the efficacy and safety of potassium-competitive acid blockers (PCABs) in patients with various clinical GERD phenotypes.

METHODS: Core databases were searched for studies comparing PCABs and proton pump inhibitors (PPIs) in clinical GERD phenotypes of erosive reflux disease (ERD), non-erosive reflux disease (NERD), PPI-resistant GERD and night-time heartburn. Additional analysis was performed based on disease severity and drug dosage, and pooled efficacy was calculated.

RESULTS: In 9 randomized controlled trials (RCTs) evaluating the initial treatment of ERD, the risk ratio for healing with PCABs versus …

Veritac-2: A Phase Iii Study Of Vepdegestrant, A Protac Er Degrader, Versus Fulvestrant In Er+/Her2- Advanced Breast Cancer, Erika P Hamilton, Cynthia Ma, Michelino De Laurentiis, Hiroji Iwata, Sara A Hurvitz, Seth A Wander, Michael Danso, Dongrui R Lu, Julia Perkins Smith, Yuan Liu, Lana Tran, Sibyl Anderson, Mario Campone

2020-Current year OA Pubs

Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds an E3 ubiquitin ligase and ER to directly trigger ubiquitination of ER and its subsequent proteasomal degradation. In a first-in-human Phase I/II study, vepdegestrant monotherapy was well tolerated with clinical activity in pretreated patients with ER+/HER2- advanced breast cancer. The global, randomized Phase III VERITAC-2 study compares efficacy and safety of vepdegestrant versus fulvestrant in adults with ER+/HER2- advanced breast cancer after treatment with a CDK4/6 inhibitor plus endocrine therapy. Progression-free survival by blinded independent central review (primary end point) will be assessed in the intention-to-treat population and

An Executive Summary On The Global Conceptual Definition Of Sarcopenia, Ben Kirk, Ellen F Binder, Et Al.

2020-Current year OA Pubs

No abstract provided.

Nucleolytic Processing Of Abasic Sites Underlies Parp Inhibitor Hypersensitivity In Alc1-Deficient Brca Mutant Cancer Cells, Natasha Ramakrishnan, Tyler M Weaver, Lindsey N Aubuchon, Ayda Woldegerima, Taylor Just, Kevin Song, Alessandro Vindigni, Bret D Freudenthal, Priyanka Verma

2020-Current year OA Pubs

Clinical success with poly (ADP-ribose) polymerase inhibitors (PARPi) is impeded by inevitable resistance and associated cytotoxicity. Depletion of Amplified in Liver Cancer 1 (ALC1), a chromatin-remodeling enzyme, can overcome these limitations by hypersensitizing BReast CAncer genes 1/2 (BRCA1/2) mutant cells to PARPi. Here, we demonstrate that PARPi hypersensitivity upon ALC1 loss is reliant on its role in promoting the repair of chromatin buried abasic sites. We show that ALC1 enhances the ability of the abasic site processing enzyme, Apurinic/Apyrimidinic endonuclease 1 (APE1) to cleave nucleosome-occluded abasic sites. However, unrepaired abasic sites in ALC1-deficient cells are readily accessed by APE1 at …

Phase Ii Basket Trial Of Dual Anti-Ctla-4 And Anti-Pd-1 Blockade In Rare Tumors (Dart) Swog S1609: Adrenocortical Carcinoma Cohort, Sandip P Patel, Megan Othus, Young Kwang Chae, Tridu Huynh, Benjamin Tan, Timothy Kuzel, Christine Mcleod, Gabby Lopez, Helen X Chen, Elad Sharon, Howard Streicher, Christopher W Ryan, Charles Blanke, Razelle Kurzrock

2020-Current year OA Pubs

OBJECTIVES: Multiple common cancers benefit from immunotherapy; however, less is known about efficacy in rare tumors. We report the results of the adrenocortical carcinoma cohort of NCI/SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors.

DESIGN/SETTING: A prospective, phase 2 clinical trial of ipilimumab plus nivolumab was conducted by the SWOG Early Therapeutics and Rare Cancers Committee for multiple rare tumor cohorts across >1,000 National Clinical Trial Network sites.

PARTICIPANTS: 21 eligible patients were registered. Median age was 53 years (range 26-69); 16 (76%) were women.

INTERVENTIONS: Ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously …

Macrophage Depletion Protects Against Cisplatin-Induced Ototoxicity And Nephrotoxicity, Cathy Yea Won Sung, Naoki Hayase, Peter S T Yuen, John Lee, Katharine Fernandez, Xuzhen Hu, Hui Cheng, Robert A Star, Mark E Warchol, Lisa L Cunningham

2020-Current year OA Pubs

Cisplatin is a widely used anticancer drug with notable side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced toxicities, we used PLX3397, a U.S. Food and Drug Administration-approved inhibitor of the colony-stimulating factor 1 receptor, to eliminate tissue-resident macrophages. Mice treated with cisplatin alone had considerable hearing loss (ototoxicity) and kidney injury (nephrotoxicity). Macrophage ablation resulted in significantly reduced hearing loss and had greater outer hair cell survival. Macrophage ablation also protected against cisplatin-induced …

Penetrating Posterior Urethral Injuries: Case Report And Management Strategies, Seyed Sajjad Tabei, Brandon Lippold, Wesley Baas, Gregory Murphy

2020-Current year OA Pubs

Penetrating posterior urethral trauma from gunshot wounds (GSW) is rare and requires prompt treatment to minimize complications. Data regarding the management of such cases is scarce in the literature and poorly addressed in the guidelines. Different management approaches exist, including urinary diversion with immediate versus delayed urethroplasty/fistula repair. We present our case series to add to our experience to the literature. Three patients aged 18-44 presented with ballistic posterior urethra injuries from GSW. Initial management involved urethral catheter placement, with one patient requiring operative placement of urethral and suprapubic catheters (SPTs). Complications included recurrent membranous stricture, urinary retention, rectourethral fistula, …

Blinatumomab For Mrd-Negative Acute Lymphoblastic Leukemia In Adults, Mark R Litzow, Geoffrey L Uy, Et Al.

2020-Current year OA Pubs

BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission.

METHODS: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with

RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full …

Review Of The Impact And Burden Of Urinary Urgency On Adults With Overactive Bladder, Adrian Wagg, A Lenore Ackerman, H Henry Lai, Diane K. Newman

2020-Current year OA Pubs

No abstract provided.

Comparing The Clinical Features Of Lateral And Medial Approaches Of Costoclavicular Technique Versus Traditional Lateral Sagittal Technique As Infraclavicular Brachial Plexus Block Methods: A Randomized Controlled Trial, Emre Sertaç Bingül, Mert Canbaz, Mehmet Güzel, Emine Aysu Şalvız, Bora Edim Akalın, Ömer Berköz, Ebru Emre Demirel, Zerrin Sungur, Meltem Savran Karadeniz

2020-Current year OA Pubs

BACKGROUND: It is aimed to compare the block onset times and performance features of costoclavicular techniques (medial and lateral approach) versus lateral sagittal technique.

METHODS: Patients were randomized into three groups. For costoclavicular techniques, ultrasound probe was placed parallel to clavicle obtaining nerve cords, axillary artery and axillary vein visual from lateral-to-medial, respectively. The block needle was advanced from lateral (Group CLB) or medial (Group CMB) to perform costoclavicular block. For lateral sagittal technique (Group LSB), ultrasound probe was placed sagittal and perpendicular below the coracoid process to obtain sagittal artery image with the cords around. Total 20 ml of …

A Correctable Immune Niche For Epithelial Stem Cell Reprogramming And Post-Viral Lung Diseases, Kangyun Wu, Yong Zhang, Huiqing Yin-Declue, Kelly Sun, Dailing Mao, Kuangying Yang, Stephen R. Austin, Erika C. Crouch, Steven L. Brody, Derek E. Byers, Christy M. Hoffmann, Michael E. Hughes, Michael J. Holtzman

2020-Current year OA Pubs

Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cells (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identified a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functioned as an early sentinel niche for basal ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depended on moDC delivery of ligand GPNMB to the basal ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor …

Instrumentation Failure In Adult Spinal Deformity Patients, David P Falk, Ravi Agrawal, Bijan Dehghani, Rohit Bhan, Sachin Gupta, Munish C Gupta

2020-Current year OA Pubs

In recent years, advances in the surgical treatment of adult spinal deformity (ASD) have led to improved outcomes. Although these advances have helped drive the development of deformity surgery to meet the rising volume of patients seeking surgical treatment, many challenges have yet to be solved. Instrumentation failure remains one of the most common major complications following deformity surgery, associated with significant morbidity due to elevated re-operation rates among those experiencing mechanical complications. The two most frequently encountered subtypes of instrumentation failure are rod fracture (RF) and proximal junctional kyphosis/proximal junctional failure (PJK/PJF). While RF and PJK/PJF are both modes …

Pannexin-1 Channel Inhibition Alleviates Opioid Withdrawal In Rodents By Modulating Locus Coeruleus To Spinal Cord Circuitry, Charlie H T Kwok, Tamara Markovic, Nicolas Massaly, Hye Jean Yoon, Jose A Morón, Et Al.

2020-Current year OA Pubs

Opioid withdrawal is a liability of chronic opioid use and misuse, impacting people who use prescription or illicit opioids. Hyperactive autonomic output underlies many of the aversive withdrawal symptoms that make it difficult to discontinue chronic opioid use. The locus coeruleus (LC) is an important autonomic centre within the brain with a poorly defined role in opioid withdrawal. We show here that pannexin-1 (Panx1) channels expressed on microglia critically modulate LC activity during opioid withdrawal. Within the LC, we found that spinally projecting tyrosine hydroxylase (TH)-positive neurons (LC

Lipid-Associated Macrophages Reshape Bat Cell Identity In Obesity, Francesca Sciarretta, Wentong Jia, Jonathan R Brestoff, Et Al.

2020-Current year OA Pubs

Obesity and type 2 diabetes cause a loss in brown adipose tissue (BAT) activity, but the molecular mechanisms that drive BAT cell remodeling remain largely unexplored. Using a multilayered approach, we comprehensively mapped a reorganization in BAT cells. We uncovered a subset of macrophages as lipid-associated macrophages (LAMs), which were massively increased in genetic and dietary model of BAT expansion. LAMs participate in this scenario by capturing extracellular vesicles carrying damaged lipids and mitochondria released from metabolically stressed brown adipocytes. CD36 scavenger receptor drove LAM phenotype, and CD36-deficient LAMs were able to increase brown fat genes in adipocytes. LAMs released …

A Pre-Vaccination Immune Metabolic Interplay Determines The Protective Antibody Response To A Dengue Virus Vaccine, Adam-Nicolas Pelletier, Gabriela Pacheco Sanchez, Abdullah Izmirly, Mark Watson, Tiziana Di Pucchio, Karina Inacio Carvalho, Abdelali Filali-Mouhim, Eustache Paramithiotis, Maria Do Carmo S T Timenetsky, Alexander Roberto Precioso, Jorge Kalil, Michael S Diamond, Elias K Haddad, Esper G Kallas, Rafick Pierre Sekaly

2020-Current year OA Pubs

Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-β signaling expressed by CD68

Transcriptional Analysis Of Primary Ciliary Dyskinesia Airway Cells Reveals A Dedicated Cilia Glutathione Pathway, Jeffrey R. Koenitzer, Deepesh Kumar Gupta, Wang Kyaw Twan, Huihui Xu, Nicholas Hadas, Finn J. Hawkins, Mary Lou Beermann, Gervette M. Penny, Nathan T. Wamsley, Andrew Berical, Michael B. Major, Susan K. Dutcher, Steven L. Brody, Amjad Horani

2020-Current year OA Pubs

Primary ciliary dyskinesia (PCD) is a genetic condition that results in dysmotile cilia. The repercussions of cilia dysmotility and gene variants on the multiciliated cell remain poorly understood. We used single-cell RNA-Seq, proteomics, and advanced microscopy to compare primary culture epithelial cells from patients with PCD, their heterozygous mothers, and healthy individuals, and we induced pluripotent stem cells (iPScs) generated from a patient with PCD. Transcriptomic analysis revealed unique signatures in PCD airway cells compared with their mothers' cells and the cells of healthy individuals. Gene expression in heterozygous mothers' cells diverged from both control and PCD cells, marked by …

A Comparative Analysis Of Sars-Cov-2 Variants Of Concern (Voc) Spike Proteins Interacting With Hace2 Enzyme, Jiawei Chen, Lingtao Chen, Heng Quan, Soongoo Lee, Kaniz Fatama Khan, Ying Xie, Qiaomu Li, Maria Valero, Zhiyu Dai, Yixin Xie

2020-Current year OA Pubs

In late 2019, the emergence of a novel coronavirus led to its identification as SARS-CoV-2, precipitating the onset of the COVID-19 pandemic. Many experimental and computational studies were performed on SARS-CoV-2 to understand its behavior and patterns. In this research, Molecular Dynamic (MD) simulation is utilized to compare the behaviors of SARS-CoV-2 and its Variants of Concern (VOC)-Alpha, Beta, Gamma, Delta, and Omicron-with the hACE2 protein. Protein structures from the Protein Data Bank (PDB) were aligned and trimmed for consistency using Chimera, focusing on the receptor-binding domain (RBD) responsible for ACE2 interaction. MD simulations were performed using Visual Molecular Dynamics …

Effects Of Protein Restriction On Insulin-Like Growth Factor (Igf)-1 In Men With Prostate Cancer: Results From A Randomized Clinical Trial, Maria L Cagigas, Giovanni Fiorito, Beatrice Bertozzi, Andrius Masedunskas, Edda Cava, Francesco Spelta, Nicola Veronese, Valeria Tosti, Gayathiri Rajakumar, Tiana Pelaia, Arnold D Bullock, Robert S Figenshau, Gerald L Andriole, Luigi Fontana

2020-Current year OA Pubs

BACKGROUND: Insulin-like growth factor (IGF)-1 and its binding proteins are important in cancer growth, especially in prostate cancer. Observational studies suggest that protein restriction can lower IGF-1 levels. However, it is unclear whether an isocaloric protein-restricted diet affects IGF-1 and IGFBPs in men with prostate cancer.

METHODS: In this academic, single-center, parallel-group, prospective, randomized, open-label, blinded end-point trial, 38 consenting overweight (BMI 30.5 ± 5.5 kg/m

RESULTS: Contrary to our hypothesis, feeding individuals an isocaloric protein-restricted diet did not result in a significant reduction in serum IGF-1. Moreover, there was no observed increase in serum IGFBP-1 or IGFBP-3 concentration.

CONCLUSION: …

Reconciling Shared Versus Context-Specific Information In A Neural Network Model Of Latent Causes, Qihong Lu, Tan T Nguyen, Qiong Zhang, Uri Hasson, Thomas L Griffiths, Jeffrey M Zacks, Samuel J Gershman, Kenneth A Norman

2020-Current year OA Pubs

It has been proposed that, when processing a stream of events, humans divide their experiences in terms of inferred latent causes (LCs) to support context-dependent learning. However, when shared structure is present across contexts, it is still unclear how the "splitting" of LCs and learning of shared structure can be simultaneously achieved. Here, we present the Latent Cause Network (LCNet), a neural network model of LC inference. Through learning, it naturally stores structure that is shared across tasks in the network weights. Additionally, it represents context-specific structure using a context module, controlled by a Bayesian nonparametric inference algorithm, which assigns …

Senescent Cancer-Associated Fibroblasts In Pancreatic Adenocarcinoma Restrict Cd8+ T Cell Activation And Limit Responsiveness To Immunotherapy In Mice, Benjamin Assouline, Sheila A Stewart, Et Al.

2020-Current year OA Pubs

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8

Targeted Degradation Of Extracellular Mitochondrial Aspartyl-Trna Synthetase Modulates Immune Responses, Benjamin S Johnson, Janet S Lee, Et Al.

2020-Current year OA Pubs

The severity of bacterial pneumonia can be worsened by impaired innate immunity resulting in ineffective pathogen clearance. We describe a mitochondrial protein, aspartyl-tRNA synthetase (DARS2), which is released in circulation during bacterial pneumonia in humans and displays intrinsic innate immune properties and cellular repair properties. DARS2 interacts with a bacterial-induced ubiquitin E3 ligase subunit, FBXO24, which targets the synthetase for ubiquitylation and degradation, a process that is inhibited by DARS2 acetylation. During experimental pneumonia, Fbxo24 knockout mice exhibit elevated DARS2 levels with an increase in pulmonary cellular and cytokine levels. In silico modeling identified an FBXO24 inhibitory compound with immunostimulatory …

Implantable And Semi-Implantable Biosensors For Minimally Invasive Disease Diagnosis, Yameng Xu, Jingyuan Zhang, Wilson Z. Ray, Matthew R. Macewan

2020-Current year OA Pubs

No abstract provided.