Physiologic and structural characterization of desisobutyryl-ciclesonide, a selective glucocorticoid receptor modulator in newborn rats.

Bronchopulmonary dysplasia, the most prevalent chronic lung disease of prematurity, is often treated with glucocorticoids (GCs) such as dexamethasone (DEX), but their use is encumbered with several adverse somatic, metabolic, and neurologic effects. We previously reported that systemic delivery of the GC prodrug ciclesonide (CIC) in neonatal rats activated glucocorticoid receptor (GR) transcriptional responses in lung but did not trigger multiple adverse effects caused by DEX. To determine whether limited systemic metabolism of CIC was solely responsible for its enhanced safety profile, we treated neonatal rats with its active metabolite desisobutyryl-ciclesonide (Des-CIC).

Cardiac matrix-bound Nanovesicles provide insight into mechanisms of clinical heart disease progression to failure.

Aims: Remodeling of the extracellular matrix (ECM) is critical for effective wound healing and maintaining organ homeostasis. The ECM of soft tissues, including cardiac, contains embedded nanovesicles; or matrix-bound nanovesicles (MBV). The luminal cargo of MBV consists of lipids, microRNAs (miRNAs), and proteins that influence the function of immune and stromal cells.

Leveraging diverse genomic data to guide equitable carrier screening: Insights from gnomAD v.4.1.0.

Analysis of exome data from the latest release of the Genome Aggregation Database (gnomAD v.4.1.

Ferroptosis of select skin epithelial cells initiates and maintains chronic systemic immune-mediated psoriatic disease.

Dysregulations of epithelial-immune interactions frequently culminate in chronic inflammatory diseases of the skin, lungs, kidneys, and gastrointestinal tract. Yet, the intraepithelial processes which initiate and perpetuate inflammation in these organs are poorly understood. Here, by utilizing redox lipidomics we identified ferroptosis-associated peroxidation of polyunsaturated phosphatidylethanolamines in the epithelia of patients with asthma, cystic fibrosis, psoriasis and renal failure.

Single-cell RNA-seq reveals a resolving immune phenotype in the oral mucosa.

The oral mucosa is the interface between the host immune response and the oral microbiota. In periodontal disease, the microbial plaque elicits a tissue-destructive immune response. Removal of the microbial stimulus initiates active resolution of inflammatory.

Whole genome sequencing for metastatic mutational burden in extraskeletal myxoid chondrosarcoma.

Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare cancer that makes up less than 3% of all soft tissue sarcomas. It most often arises in the soft tissues of the proximal limbs and has a higher incidence in males. Though EMC has a good prognosis, it has an indolent course with high rates of local recurrence as well as metastasis to the lungs.

Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies.

De Novo Purine Metabolism is a Metabolic Vulnerability of Cancers with Low p16 Expression.

Unlabelled: p16 is a tumor suppressor encoded by the CDKN2A gene whose expression is lost in approximately 50% of all human cancers. In its canonical role, p16 inhibits the G1-S-phase cell cycle progression through suppression of cyclin-dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway.

Mid-term Results of Total Hip Arthroplasty for Posttraumatic Osteoarthritis after Acetabular Fracture.

Purpose: The prognosis of total hip replacement (THR) after open reduction and internal fixation (ORIF) versus THR following non-operative treatment of acetabular fractures is unclear. Few studies have been conducted in this regard. Therefore, the purpose of the current study was to perform an assessment and compare the functional outcomes for study subjects in the ORIF and non-ORIF groups during the follow-up period compared to baseline.

Grade 2, 3 and Dedifferentiated Chondrosarcomas: A Comparative Study of Isocitrate Dehydrogenase-Mutant and Wild-Type Tumors with Implications for Prognosis and Therapy.

Background: Grade 2 and 3 and dedifferentiated chondrosarcomas (CS) are frequently associated with isocitrate dehydrogenase () mutations and often exhibit a poor clinical outcome. Treatment is limited mainly to surgery. Defining status (wild type (WT) and mutant) and the associated transcriptome may prove useful in determining other therapeutic options in these neoplasms.

Recurrence-Free Survival in Patients With Surgically Resected Non-Small Cell Lung Cancer: A Systematic Literature Review and Meta-Analysis.

Background: Standard treatment for early-stage or locoregionally advanced non-small cell lung cancer (NSCLC) includes surgical resection. Recurrence after surgery is commonly reported, but a summary estimate for postsurgical recurrence-free survival (RFS) in patients with NSCLC is lacking.

Research Question: What is the RFS after surgery in patients with stage I-III NSCLC at different time points, and what factors are associated with RFS?

Study Design And Methods: A systematic search was performed in MEDLINE, EMBASE, and Cochrane databases between January 2011 and June 2021.

Single-cell Transcriptional Analysis of the Cellular Immune Response in the Oral Mucosa of Mice.

Periodontal health is dependent on a symbiotic relationship of the host immune response with the oral microbiota. Pathologic shifts of the microbial plaque elicit an immune response that eventually leads to the recruitment and activation of osteoclasts and matrix metalloproteinases and the eventual tissue destruction that is evident in periodontal disease. Once the microbial stimulus is removed, an active process of inflammatory resolution begins.

Brief Report: HIV Drug Resistance Assessment Among Women Who Seroconverted During the MTN-025/HOPE Open-Label Extension Dapivirine Vaginal Ring Trial.

Background: Clinical trials of dapivirine (DPV) vaginal ring have shown it is safe, effective, and desired by women as an HIV prevention option. The risk of drug resistance is a potential concern for DPV ring users who acquire HIV. We conducted a comprehensive resistance evaluation of plasma samples from the women who seroconverted during the Microbicide Trials Network-025/HIV Open-label Prevention Extension (HOPE) study of DPV ring.

De novo purine metabolism is a metabolic vulnerability of cancers with low p16 expression.

p16 is a tumor suppressor encoded by the gene whose expression is lost in ~50% of all human cancers. In its canonical role, p16 inhibits the G1-S phase cell cycle progression through suppression of cyclin dependent kinases. Interestingly, p16 also has roles in metabolic reprogramming, and we previously published that loss of p16 promotes nucleotide synthesis via the pentose phosphate pathway.

Rapid Emergence of Potentially Transmissible Severe Acute Respiratory Syndrome Coronavirus 2 With Resistance to Combination Monoclonal Antibody Therapy.

Prolonged coronavirus disease 2019 may generate new viral variants. We report an immunocompromised patient treated with monoclonal antibodies who experienced rebound of viral RNA and emergence of an antibody-resistant (>1000-fold) variant containing 5 mutations in the spike gene. The mutant virus was isolated from respiratory secretions, suggesting the potential for secondary transmission.

Mitotic CDK1 and 4E-BP1 I: Loss of 4E-BP1 serine 82 phosphorylation promotes proliferative polycystic disease and lymphoma in aged or sublethally irradiated mice.

4E-BP1 is a tumor suppressor regulating cap-dependent translation that is in turn controlled by mechanistic target of rapamycin (mTOR) or cyclin-dependent kinase 1 (CDK1) phosphorylation. 4E-BP1 serine 82 (S82) is phosphorylated by CDK1, but not mTOR, and the consequences of this mitosis-specific phosphorylation are unknown. Knock-in mice were generated with a single 4E-BP1 S82 alanine (S82A) substitution leaving other phosphorylation sites intact.

Melanoma-associated repair-like Schwann cells suppress anti-tumor T-cells via 12/15-LOX/COX2-associated eicosanoid production.

Peripheral glia, specifically the Schwann cells (SCs), have been implicated in the formation of the tumor microenvironment (TME) and in cancer progression. However, and analyses of how cancers reprogram SC functions in different organs of tumor-bearing mice are lacking. We generated Plp1-CreERT/tdTomato mice which harbor fluorescently labeled myelinated and non-myelin forming SCs.

Genomic glucocorticoid action in embryonic mouse neural stem cells.

Prenatal exposure to synthetic glucocorticoids (sGCs) reprograms brain development and predisposes the developing fetus towards potential adverse neurodevelopmental outcomes. Using a mouse model of sGC administration, previous studies show that these changes are accompanied by sexually dimorphic alterations in the transcriptome of neural stem and progenitor cells (NSPCs) derived from the embryonic telencephalon. Because cell type-specific gene expression profiles tightly regulate cell fate decisions and are controlled by a flexible landscape of chromatin domains upon which transcription factors and enhancer elements act, we multiplexed data from four genome-wide assays: RNA-seq, ATAC-seq (assay for transposase accessible chromatin followed by genome wide sequencing), dual cross-linking ChIP-seq (chromatin immunoprecipitation followed by genome wide sequencing), and microarray gene expression to identify novel relationships between gene regulation, chromatin structure, and genomic glucocorticoid receptor (GR) action in NSPCs.

Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis.

The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2.

Machine Learning and Real-World Data to Predict Lung Cancer Risk in Routine Care.

Background: This study used machine learning to develop a 3-year lung cancer risk prediction model with large real-world data in a mostly younger population.

Methods: Over 4.7 million individuals, aged 45 to 65 years with no history of any cancer or lung cancer screening, diagnostic, or treatment procedures, with an outpatient visit in 2013 were identified in Optum's de-identified Electronic Health Record (EHR) dataset.

Risk of transmission of respiratory viruses during aerosol-generating medical procedures (AGMPs) revisited in the COVID-19 pandemic: a systematic review.

Background: In many jurisdictions healthcare workers (HCWs) are using respirators for aerosol-generating medical procedures (AGMPs) performed on adult and pediatric populations with all suspect/confirmed viral respiratory infections (VRIs). This systematic review assessed the risk of VRIs to HCWs in the presence of AGMPs, the role respirators versus medical/surgical masks have on reducing that risk, and if the risk to HCWs during AGMPs differed when caring for adult or pediatric patient populations.

Main Text: We searched MEDLINE, EMBASE, Cochrane Central, Cochrane SR, CINAHL, COVID-19 specific resources, and MedRxiv for English and French articles from database inception to September 9, 2021.