Impact of Risk Factors on COVID-19 Outcomes in Unvaccinated People With Rheumatic Diseases: A Comparative Analysis of Pandemic Epochs Using the COVID-19 Global Rheumatology Alliance Registry.

OBJECTIVE: Approximately one third of individuals worldwide have not received a COVID-19 vaccine. Although studies have investigated risk factors linked to severe COVID-19 among unvaccinated people with rheumatic diseases (RDs), we know less about whether these factors changed as the pandemic progressed. We aimed to identify risk factors associated with severe COVID-19 in unvaccinated individuals in different pandemic epochs corresponding to major variants of concern. METHODS: Patients with RDs and COVID-19 were entered into the COVID-19 Global Rheumatology Alliance Registry between March 2020 and June 2022. An ordinal logistic regression model (not hospitalized, hospitalized, and death) was used with date of COVID-19 diagnosis, age, sex, race and/or ethnicity, comorbidities, RD activity, medications, and the human development index (HDI) as covariates. The main analysis included all unvaccinated patients across COVID-19 pandemic epochs; subanalyses stratified patients according to RD types. RESULTS: Among 19,256 unvaccinated people with RDs and COVID-19, those who were older, male, had more comorbidities, used glucocorticoids, had higher disease activity, or lived in lower HDI regions had worse outcomes across epochs. For those with rheumatoid arthritis, sulfasalazine and B-cell-depleting therapy were associated with worse outcomes, and tumor necrosis factor inhibitors were associated with improved outcomes. In those with connective tissue disease or vasculitis, B-cell-depleting therapy was associated with worse outcomes. CONCLUSION: Risk factors for severe COVID-19 outcomes were similar throughout pandemic epochs in unvaccinated people with RDs. Ongoing efforts, including vaccination, are needed to reduce COVID-19 severity in this population, particularly in those with medical and social vulnerabilities identified in this study.

Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma.

BACKGROUND: Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. METHODS: Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2-/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models. RESULTS: Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential. CONCLUSIONS: This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.

USP13 promotes development and metastasis of high-grade serous ovarian carcinoma in a novel mouse model.

Epithelial ovarian cancer is the most lethal gynecologic malignancy and one of the most common causes of cancer mortality among women worldwide. Ubiquitin-Specific Peptidase 13 (USP13) gene copy is strongly amplified in human epithelial ovarian cancer, and high USP13 expression is correlated with poor survival outcomes. Yet, its pathological contribution to ovarian tumorigenesis remains unknown. We crossed a conditional Usp13 overexpressing knock-in mouse with a conditional knockout of Trp53 and Pten mouse and generated a novel ovarian cancer genetically engineered mouse model (GEMM), which closely recapitulates the genetic changes driving ovarian cancer in humans. Overexpression of USP13 with deletion of Trp53 and Pten in murine ovarian surface epithelium accelerated ovarian tumorigenesis and led to decreased survival in mice. Notably, USP13 greatly enhanced peritoneal metastasis of ovarian tumors with frequent development of hemorrhagic ascites. The primary and metastatic tumors exhibited morphology and clinical behavior similar to human high-grade serous ovarian cancer. Co-inhibition of USP13 and AKT significantly decreased the viability of the primary murine ovarian cancer cells isolated from the GEMM. USP13 also increased the tumorigenic and metastatic abilities of primary murine ovarian cancer cells in a syngeneic mouse study. These findings suggest a critical role of USP13 in ovarian cancer development and reveal USP13 as a potential therapeutic target for ovarian cancer.

Utilization of Multiparametric MRI of Prostate in Patients under Consideration for or Already in Active Surveillance: Correlation with Imaging Guided Target Biopsy.

This study sought to assess the value of multiparametric magnetic resonance image (mp-MRI) in patients with a prostate cancer (PCa) Gleason score of 6 or less under consideration for or already in active surveillance and to determine the rate of upgrading by target biopsy. Three hundred and fifty-four consecutive men with an initial transrectal ultrasound-guided (TRUS) biopsy-confirmed PCa Gleason score of 6 or less under clinical consideration for or already in active surveillance underwent mp-MRI and were retrospectively reviewed. One hundred and nineteen of 354 patients had cancer-suspicious regions (CSRs) at mp-MRI. Each CSR was assigned a Prostate Imaging Reporting and Data System (PI-RADS) score based on PI-RADS v2. One hundred and eight of 119 patients underwent confirmatory imaging-guided biopsy for CSRs. Pathology results including Gleason score (GS) and percentage of specimens positive for PCa were recorded. Associations between PI-RADS scores and findings at target biopsy were evaluated using logistic regression. At target biopsy, 81 of 108 patients had PCa (75%). Among them, 77 patients had upgrading (22%, 77 of 354 patients). One hundred and forty-six CSRs in 108 patients had PI-RADS 3 n = 28, 4 n = 66, and 5 n = 52. The upgraded rate for each category of CSR was for PI-RADS 3 (5 of 28, 18%), 4 (47 of 66, 71%) and 5 (49 of 52, 94%). Using logistic regression analysis, differences in PI-RADS scores from 3 to 5 are significantly associated with the probability of disease upgrade (20%, 73%, and 96% for PI-RADS score of 3, 4, and 5, respectively). Adding mp-MRI to patients under consideration for or already in active surveillance helps to identify undiagnosed PCa of a higher GS or higher volume resulting in upgrading in 22%.