Clinical Research
Abstract
Community-acquired infectious meningoencephalitis is associated with high rates of mortality and morbidity, compounded by limited access to diagnostic resources. The current study assessed acute central nervous system (CNS) infections in patients with meningoencephalitis enrolled in a hospital-based diagnostic surveillance study in São Paulo, Brazil. Cerebrospinal fluid (CSF) was collected from 600 subjects between March 2018 and November 2019 and initially screened for a broad range of pathogens according to a local diagnostic algorithm. Standard microbiological and molecular diagnostic methods were applied. Metagenomic sequencing was used as a complementary approach to investigating etiology in cases where no pathogen was initially identified. Standard testing identified infectious etiologies in 292 cases (48.6%), with 227 (77.7%) confirmed as viral infections, predominantly caused by enteroviruses (n=144) and herpesviruses (n=40). Non-viral agents were identified in 65 cases (22.3%). Metagenomic sequencing (mNGS) of 279 out of 308 undiagnosed cases revealed several additional potential etiologies, including Parvovirus B19, Toxoplasma gondii, Picobirnavirus, other enterovirus species and Vesivirus, the latter being associated with CNS infection for the first time. These findings underscore the complexity of CNS infections and highlight the potential of metagenomics to improve diagnostic accuracy, inform treatment strategies, and support efforts to address future pandemics.
Authors
Noely Evangelista Ferreira, Michael G. Berg, Antonio C. da Costa, Mary A. Rodgers, Esper G. Kallas, Cassia G. Terrasani Silveira, Mateus Vailant Thomazella, Ana Carolina Soares de Oliveira, Layla Honorato, Heuder G.O. Paião, Renan Barros Domingues, Carlos Senne, Marina F. Côrtes, Tania R. Tozetto-Mendoza, Hélio R. Gomes, Maria Laura Mariano Matos, Geovani de Oliveria Ribeiro, Steven S. Witkin, Gavin A. Cloherty, Maria Cassia Mendes-Correa
Abstract
Mutations in genome maintenance factors drive sporadic and hereditary breast cancers. Here, we searched for potential drivers based on germline DNA analysis from a cohort consisting of early-onset breast cancer patients negative for BRCA1/BRCA2 mutations. This revealed candidate genes that subsequently were subjected to RNAi-based phenotype screens to reveal genome integrity impacts. We identified several genes with functional roles in genome maintenance, including Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3), SMC4, and CCDC108. Notably, G6PC3-deficient cells exhibited increased levels of γH2AX and micronuclei formation, along with defects in homologous recombination (HR) repair. Consistent with these observations, G6PC3 was required for the efficient recruitment of BRCA1 to sites of DNA double-strand breaks (DSBs). RNA sequencing analysis revealed that G6PC3 promotes the expression of multiple homologous recombination repair genes, including BRCA1. Through CRISPR-Select functional-genetic phenotype analysis of G6PC3 germline mutations, we identified two germline G6PC3 variants displaying partial loss-of-function. Furthermore, our study demonstrated that G6pc3 deficiency accelerates mammary tumor formation induced by Trp53 loss in mice. In conclusion, our cohort-based functional analysis has unveiled genome maintenance factors and identified G6PC3 as a potential candidate tumor suppressor in breast cancer.
Authors
Xin Li, Maria Rossing, Ana Moisés da Silva, Muthiah Bose, Thorkell Gudjónsson, Jan Benada, Jayashree Thatte, Jens Vilstrup Johansen, Judit Börcsök, Hanneke van der Gulden, Ji-Ying Song, Renée Menezes, Asma Tajik, Lucía Sena, Zoltan Szallasi, Morten Frödin, Jos Jonkers, Finn Cilius Nielsen, Claus Storgaard Sørensen
Abstract
BACKGROUND. A priori knowledge of recurrence risk in patients with non-metastatic (FIGO stage I) uterine serous carcinoma (USC) would enable a risk-stratified approach to the use of adjuvant chemotherapy. This would greatly reduce treatment-related morbidity and be predicted to improve survival. METHODS. GATA2 expression was scored by immunohistochemistry (IHC) across a retrospective multi-institutional cohort of 195 primary USCs. Associations between GATA2 levels and clinicopathologic metrics were evaluated using Student’s t-test, Fisher’s exact test, Kaplan-Meier method, and Cox proportional hazards ratio. Invasion in patient-derived USC cells was assessed by Student’s t-test. RNA-seq, anti-GATA2 ChIP-seq, and confirmatory western blotting enabled identification of GATA2 targets. RESULTS. Patients with FIGO stage I GATA2high USCs had 100% recurrence-free and 100% cancer related survival, which was significantly better than patients with GATA2low USCs. In patients for whom adjuvant chemotherapy was omitted, patients with GATA2high USC had 100% recurrence free 5-year survival compared to 60% recurrence free survival in patients with GATA2low USC. Depletion of GATA2 in patient-derived USC cells increased invasion in vitro. CONCLUSIONS. Routine GATA2 IHC identifies 33% of FIGO stage I USC patients who have a greatly reduced risk of post-hysterectomy USC recurrence. Our results suggest that a GATA2 guided personalized medicine approach could be rapidly implemented in most hospital settings, would reduce treatment-related morbidity, and likely improve outcomes in USC patients. FUNDING. NIH grants R01 DK068634, P30 CA014520, S10 OD023526, K08 DK127244, T32 HL007899, the UW-Madison Department of Pathology and Laboratory Medicine, the UW-Madison Centennial Scholars Program, the Diane Lindstrom Foundation, the American Cancer Society, the V Foundation, The Hartwell Foundation, and the UMN Department of Obstetrics, Gynecology, and Women's Health.
Authors
Usha S. Polaki, Trey E. Gilpin, Apoorva T. Patil, Emily Chiu, Ruth Baker, Peng Liu, Tatiana S. Pavletich, Morteza Seifi, Paula M. Mañán-Mejías, Jordan Morrissey, Jenna Port, Rene Welch Schwartz, Irene M. Ong, Dina El-Rayes, Mahmoud A. Khalifa, Pei Hui, Vanessa L. Horner, María Virumbrales-Muñoz, Britt K. Erickson, Lisa Barroilhet, Stephanie M. McGregor, Emery H. Bresnick, Daniel R. Matson
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