Biology subjects

Reis, R. M.

Publications and source records attributed to Reis, R. M..

4 recordsLinked to original sources

bioRxiv2026

Systemic mutagen exposures reported by normal kidney cell genomes

Lifestyle, environmental and other exposures to exogenous mutagens generate somatic mutations in normal human cells in vivo and increase cancer risk. However, the global repertoire of exogenous mutagen exposures is uncertain. The mutational signatures of mutagens in normal tissues offer opportunities to detect such exposures and survey them at population level. Using single-molecule duplex sequencing of normal kidney (n=319) and blood (n=272) samples from 10 countries, we show that normal kidney cell genomes report an extensive repertoire of somatic mutational signatures. Microdissection of kidney structures revealed that proximal tubules exhibit higher mutation rates than other components of the nephron and most normal cell types despite low cell division rates. This is explained by marked enrichment of mutational signatures due to known exogenous carcinogenic mutagens including the plant-derived aristolochic acids, as well as several signatures of unknown causes including an unknown agent prevalent in Japan (SBS12), and signatures of uncertain origins (SBS40b and SBS40c). The results suggest the existence of multiple, common, systemically circulating mutagens affecting human populations and indicate that the genomes of kidney proximal tubule cells report such exposures with high sensitivity.

genomics↗

bioRxiv2019

Squamous differentiation portends poor prognosis in low and intermediate-risk endometrioid endometrial cancer.

BackgroundEndometrial cancer presents well-defined risk factors (myometrial invasion, histological subtype, tumor grade, lymphovascular space invasion (LVSI)). Some low and intermediate-risk endometrioid endometrial cancer patients exhibited unexpected outcomes. The aim of this study was to investigate other clinical-pathological factors that might influence the recurrence rates of patients diagnosed with low and intermediate-risk endometrioid endometrial cancer.\n\nMethodsA case-control study from a cohort retrospective of 196 patients diagnosed with low and intermediate-risk endometrioid endometrial cancer at a single institution between 2009 and 2014 was conducted. Medical records were reviewed to compare clinical (race, smoking, menopause age, body mass index) and pathological (histological characteristics (endometrioid vs endometrioid with squamous differentiation), tumor differentiation grade, tumor location, endocervical invasion, LVSI) features of patients with recurrence (case) and without recurrence (control) of disease. Three controls for each case were matched for age and staging.\n\nResultsTwenty-one patients with recurrence were found (10.7%), of which 14 were stage IA, and 7 were stage IB. In accordance, 63 patients without recurrence were selected as controls. There were no significant differences in any clinical characteristics between cases and controls. Among pathological variables, presence of squamous differentiation (28.6% vs. 4.8%, p=0.007), tumor differentiation grade 2 or 3 (57.1% vs. 30.2%, p=0.037) and presence of endocervical invasion (28.6% vs. 12.7%, p=0.103) were associated with disease recurrence on univariate analysis. On multivariable analysis, only squamous differentiation was a significant risk factor for recurrence (p=0.031).\n\nConclusionOur data suggest that squamous differentiation may be an adverse prognostic factor in patients with low and intermediate-risk endometrioid endometrial cancer, that showed a 5.6-fold increased risk for recurrence.

pathology↗

bioRxiv2018

Reactivation of latent HIV-1 in vitro using an alcoholic extract from Euphorbia umbellata (Euphorbiaceae) latex.

Euphorbia umbellata (E. umbellata) belongs to Euphorbiaceae family, popularly known as Janauba, and contains in its latex a combination of phorbol esters with biological activities described to different cellular protein kinase C (PKC) isoforms. Here, we identified deoxi-phorbol esters present in E. umbellata latex alcoholic extract able to increase HIV transcription and reactivate HIV from latency models. This activity was mediated by NF-kB activation followed by nuclear translocation and binding to HIV LTR promoter. In addition, E. umbellate latex extract induced the production of pro inflammatory cytokines together with IL21 in in vitro human PBMC cultures. Our latex extract activates latent HIV in human PBMCs isolated from HIV positive patients as well as latent SIV in non-human primate primary CD4+ T lymphocytes. These results strongly indicate that the phorbol esters present in E. umbellata latex are promising candidate compounds for future clinical trials for shock and kill therapy to promote HIV cure and eradication.

microbiology↗

bioRxiv2018

Self-assembly of the RZZ complex into filaments drives kinetochore expansion in the absence of microtubule attachment

The kinetochore is a dynamic multi-protein assembly that forms on each sister chromatid and interacts with microtubules of the mitotic spindle to drive chromosome segregation. In animals, kinetochores without attached microtubules expand their outermost layer into crescent and ring shapes to promote microtubule capture and spindle assembly checkpoint (SAC) signalling. Kinetochore expansion is an example of protein co-polymerization, but the mechanism is not understood. Here, we present evidence that kinetochore expansion is driven by oligomerization of the Rod-Zw10-Zwilch (RZZ) complex, an outer kinetochore component that recruits the motor dynein and the SAC proteins Mad1-Mad2. Depletion of ROD in human cells suppresses kinetochore expansion, as does depletion of Spindly, the adaptor that connects RZZ to dynein, while dynein itself is dispensable. Expansion is also suppressed by mutating ZWILCH residues implicated in Spindly binding. Conversely, supplying cells with excess ROD facilitates kinetochore expansion under otherwise prohibitive conditions. Using the C. elegans early embryo, we demonstrate that ROD-1 has a concentration-dependent propensity for oligomerizing into {micro}m-scale filaments, and we identify the ROD-1 {beta}-propeller as a key regulator of self-assembly. Finally, we show that a minimal ROD-1-Zw10 complex efficiently oligomerizes into filaments in vitro. Our results suggest that RZZs capacity for oligomerization is harnessed by kinetochores to assemble the expanded outermost domain, in which RZZ filaments serve as recruitment platforms for SAC components and microtubule-binding proteins. Thus, we propose that RZZ self-assembly into filaments underlies the adaptive change in kinetochore size that contributes to chromosome segregation fidelity.

cell biology↗