Systemic inflammation and lymphocyte activation precede rheumatoid arthritis.

Some autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a critical subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical 'at-risk' state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified systemic inflammation, proinflammatory-skewed B cells, expanded Tfh17-like cells, epigenetic bias in naive T cells, TNF+IL1B+ monocytes resembling a synovial macrophage population, and CD4 T cell transcriptional features resembling those suppressed by abatacept (CTLA4-Ig) in RA patients.

Longitudinal Multi-omic Immune Profiling Reveals Age-Related Immune Cell Dynamics in Healthy Adults.

The generation and maintenance of protective immunity is a dynamic interplay between host and environment that is impacted by age. Understanding fundamental changes in the healthy immune system that occur over a lifespan is critical in developing interventions for age-related susceptibility to infections and diseases. Here, we use multi-omic profiling (scRNA-seq, proteomics, flow cytometry) to examined human peripheral immunity in over 300 healthy adults, with 96 young and older adults followed over two years with yearly vaccination.

Newcastle Disease Virus Induces Profound Lymphoid Depletion with Different Patterns of Necroptosis, Necrosis, and Oxidative DNA Damage in Bursa, Spleen, and Other Lymphoid Tissues.

This study delves into the pathogenesis of virulent genotype VII strains of the Newcastle disease virus (NDV), focusing on experimentally infected birds. Predominant and consistent lesions observed include bursal atrophy and extensive depletion of all lymphoid tissues. Immunohistochemistry (IHC) analysis, targeting apoptosis (Caspase-3), necroptosis (MLKL), and NDV markers, indicates that bursal atrophy is linked to a non-apoptotic programmed cell death pathway known as "necroptosis".

Sleep Characteristics of an International Sample of Adult Gamers.

 About 65% of adult Americans report playing video games. Despite potential impacts to functioning, there is limited research on the relationship between video game use and sleep, specifically among adults. The present study expands upon the literature by describing demographic, video game, and sleep characteristics of an international adult sample of gamers.

Spatial mapping of the DNA adducts in cancer.

DNA adducts and strand breaks are induced by various exogenous and endogenous agents. Accumulation of DNA damage is implicated in many disease processes, including cancer, aging, and neurodegeneration. The continuous acquisition of DNA damage from exogenous and endogenous stressors coupled with defects in DNA repair pathways contribute to the accumulation of DNA damage within the genome and genomic instability.

Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in epithelial ovarian cancer.

A leading theory for ovarian carcinogenesis proposes that inflammation associated with incessant ovulation is a driver of oncogenesis. Consistent with this theory, nonsteroidal anti-inflammatory drugs (NSAIDs) exert promising chemopreventive activity for ovarian cancer. Unfortunately, toxicity is associated with long-term use of NSAIDs due to their cyclooxygenase (COX) inhibitory activity.

Development and Psychometric Validation of a Novel Self-Report Measure of ICD-11 Gaming Disorder.

Video game use is associated with addiction-like behaviors in 6 to 15.6 percent of video game players. There were no formal diagnostic criteria for video game addiction until gaming disorder (GD) was added to the (ICD-11), and there are no published instruments designed to diagnose GD.

An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases.

Key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown, with a dearth of accurate preclinical models. To address this, we generated 8 GBM patient-derived xenograft (PDX) models of acquired radiation therapy-selected (RTS) resistance compared with same-patient, treatment-naive (radiation-sensitive, unselected; RTU) PDXs. These likely unique models mimic the longitudinal evolution of patient recurrent tumors following serial radiation therapy.

Repair-Assisted Damage Detection Reveals Biological Disparities in Prostate Cancer between African Americans and European Americans.

African Americans (AA) are two times more likely to be diagnosed with and succumb to prostate cancer (PCa) compared to European Americans (EA). There is mounting evidence that biological differences in these tumors contribute to disparities in patient outcomes. Our goal was to examine the differences in DNA damage in AA and EA prostate tissues.

Examining utilization of kidneys as a function of procurement performance.

Questions have arisen around new metrics for organ procurement organizations (OPO) due to the perception that low-performing OPOs may be limited by local centers' acceptance of marginal organs. We reviewed 2013-2019 Organ Procurement and Transplantation Network (OTPN) and National Centers for Health Statistics (NCHS) data to explore the relationship between objectively measured OPO performance and utilization of deceased donor kidneys. We found that although donor recovery declined with rising age and kidney donor profile index (KDPI), OPO performance differences were evident within each age/KDPI group.

Suppression of Colon Tumorigenesis in Mutant Mice by a Novel PDE10 Inhibitor that Reduces Oncogenic β-Catenin.

Previous studies have reported that phosphodiesterase 10A (PDE10) is overexpressed in colon epithelium during early stages of colon tumorigenesis and essential for colon cancer cell growth. Here we describe a novel non-COX inhibitory derivative of the anti-inflammatory drug, sulindac, with selective PDE10 inhibitory activity, ADT 061. ADT 061 potently inhibited the growth of colon cancer cells expressing high levels of PDE10, but not normal colonocytes that do not express PDE10.

Genetic screening reveals phospholipid metabolism as a key regulator of the biosynthesis of the redox-active lipid coenzyme Q.

Mitochondrial energy production and function rely on optimal concentrations of the essential redox-active lipid, coenzyme Q (CoQ). CoQ deficiency results in mitochondrial dysfunction associated with increased mitochondrial oxidative stress and a range of pathologies. What drives CoQ deficiency in many of these pathologies is unknown, just as there currently is no effective therapeutic strategy to overcome CoQ deficiency in humans.

Procurement characteristics of high- and low-performing OPOs as seen in OPTN/SRTR data.

To meet new Centers for Medicare and Medicaid Services (CMS) metrics, organ procurement organizations (OPOs) will benefit from understanding performance across decedent and hospital types. We sought to determine the utility of existing data-reporting structures for this purpose by reviewing Scientific Registry of Transplant Recipient (SRTR) OPO-Specific Reports (OSRs) from 2013 to 2019. OSRs contain both the Standardized donation rate ratio (SDRR) metric and OPO-reported numbers of "eligible deaths" and donors by hospital.

Opportunity to increase deceased donation for United States veterans.

Recent changes to organ procurement organization (OPO) performance metrics have highlighted the need to identify opportunities to increase organ donation in the United States. Using data from the Organ Procurement and Transplantation Network (OPTN), Scientific Registry of Transplant Recipients (SRTR), and Veteran Health Administration Informatics and Computing Infrastructure Clinical Data Warehouse (VINCI CDW), we sought to describe historical donation performance at Veteran Administration Medical Centers (VAMCs). We found that over the period 2010-2019, there were only 33 donors recovered from the 115 VAMCs with donor potential nationwide.

Cytoprotective Effect of Vitamin D on Doxorubicin-Induced Cardiac Toxicity in Triple Negative Breast Cancer.

Background: Doxorubicin (Dox) is a first-line treatment for triple negative breast cancer (TNBC), but its use may be limited by its cardiotoxicity mediated by the production of reactive oxygen species. We evaluated whether vitamin D may prevent Dox-induced cardiotoxicity in a mouse TNBC model.

Methods: Female Balb/c mice received rodent chow with vitamin D (1500 IU/kg; vehicle) or chow supplemented with additional vitamin D (total, 11,500 IU/kg).

Associations between DNA Damage and PD-L1 Expression in Ovarian Cancer, a Potential Biomarker for Clinical Response.

Programmed death ligand-1 (PD-L1) inhibitors are currently under investigation as a potential treatment option for ovarian cancer. Although this therapy has shown promise, its efficacy is highly variable among patients. Evidence suggests that genomic instability influences the expression of PD-L1, but little is known about this relationship in ovarian cancer.

EGFR signaling promotes resistance to CHK1 inhibitor prexasertib in triple negative breast cancer.

: Innate resistance to the CHK1 inhibitor prexasertib has been described, but resistance mechanisms are not understood. We aimed to determine the role epidermal growth factor receptor (EGFR) plays in innate resistance to prexasertib in triple negative breast cancer (TNBC). : Using a panel of pre-clinical TNBC cell lines, we measured the sensitivity to prexasertib.

Exploiting DNA repair defects in triple negative breast cancer to improve cell killing.

Background: The lack of molecular targets for triple negative breast cancer (TNBC) has limited treatment options and reduced survivorship. Identifying new molecular targets may help improve patient survival and decrease recurrence and metastasis. As DNA repair defects are prevalent in breast cancer, we evaluated the expression and repair capacities of DNA repair proteins in preclinical models.

DNA damage measurements within tissue samples with Repair Assisted Damage Detection (RADD).

Exposures to genotoxic carcinogens and reactive species result in strand breaks and a spectrum of covalent modifications to DNA that can induce mutations and contribute to the initiation and progression of cancer. Measurements of DNA damage within tissue or tumor samples can serve as a biomarker for exposures or assess changes in DNA repair capacity relevant in cancer development and treatment. Numerous methods to characterize DNA damage exist.

Defective base excision repair in the response to DNA damaging agents in triple negative breast cancer.

DNA repair defects have been increasingly focused on as therapeutic targets. In hormone-positive breast cancer, XRCC1-deficient tumors have been identified and proposed as targets for combination therapies that damage DNA and inhibit DNA repair pathways. XRCC1 is a scaffold protein that functions in base excision repair (BER) by mediating essential interactions between DNA glycosylases, AP endonuclease, poly(ADP-ribose) polymerase 1, DNA polymerase β (POL β), and DNA ligases.

Design and synthesis of 1,2,4-triazolo[1,5-a]pyrimidine derivatives as PDE 4B inhibitors endowed with bronchodilator activity.

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed, synthesized, and screened for their phosphodiesterase (PDE 4B) inhibitory activity and bronchodilation ability. Compound 7e showed 41.80% PDE 4B inhibition at 10 µM.

Management and Survival of Adult Patients with Pilocytic Astrocytoma in the National Cancer Database.

Background: Adult pilocytic astrocytomas (PAs) are relatively rare central nervous system (CNS) tumors with a favorable prognosis. We sought to investigate existing clinical management strategies and overall survival (OS) as a function of various clinical characteristics in a cohort of adult patients with PA.

Methods: The study cohort comprised all patients age >18 years diagnosed with a CNS PA diagnosed between 2004 and 2014 and included in the National Cancer Database.