KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and drives cell proliferation in bladder cancer

UNLABELLED: Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differentiation. KDM6A-deficient cells displayed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn repressed FOXA1-target genes and activated cell-cycle progression genes. Importantly, ATF3 depletion reversed the cell proliferation phenotype induced by KDM6A deficiency. These data establish that KDM6A loss engenders an epigenetic state that drives tumor growth in an ATF3-dependent manner, creating a potentially targetable molecular vulnerability. SIGNIFICANCE: A gain-of-function epigenetic switch that disrupts differentiation is triggered by inactivating KDM6A mutations in bladder cancer and can serve as a potential target for novel therapies

“Brachilenos” e outros recortes migratórios : elementos significativos da imigração brasileira em Santiago do Chile

Dissertação (mestrado)—Universidade de Brasília, Instituto de Ciências Sociais, Departamento de Estudos Latino-Americanos, Programa de Pós-Graduação em Estudos Comparados Sobre as Américas, 2017.Aborda-se o tema das migrações internacionais dando principal relevância às “migrações sul-sul”. A pesquisa tem como objetivo traçar o histórico da imigração brasileira para o Chile a partir da década de 70. Como metodologia utiliza-se da pesquisa qualitativa com observação participante e técnica da „bola de neve‟. Entender as características dos diferentes fluxos dentro de cada contexto através de relatos de vida dos sujeitos migrantes. Desenvolvimento das categorias de análise para interpretar a experiência dos participantes da pesquisa em base dos debates atuais do campo dos estudos migratórios. A pesquisa retrata casos de imigrantes que possuam laços parentais ou tenham fortalecidos relações afetivas com cidadãos chilenos/as, assim como motivos laborais. Há também casos excepcionais de descendentes de brasileiros/as que foram perseguidos pela ditadura militar chilena (1973-1990), em uma perspectiva de retratação histórica. Trago revisão de literatura sobre o campo teórico dos estudos migratórios abordando temas como feminização das migrações, discriminação racial e precarização do trabalho.The approach of this investigation is about international migration mainly considering “south-south immigration”. The research present as objective drawing the Brazilian immigration history towards Chile, since the 1970‟s. The methodology used is qualitative and based on the “snowball” technique. To understand the features of the different influx inside every context through the life of the immigrants‟ reports. Development of categories of analysis to interpret the experience of those who participate in the research in basis of the actual debates in the field of migration studies. The sample of this research was made with those immigrants who have parents or have strained relationships with chilean citizens. The research also shows the exceptional cases of Brazilian descendants who have been persecuted by the Chilean military dictatorship (1973-1990) in a perspective of historic retraction. It also address a literature revision about the theoretical field of the migration studies regarding topics related to female immigration, racial discrimination, and precariousness of the work environment

Hydroclimatic extremes contribute to asymmetric trends in ecosystem productivity loss

Gross primary production is the basis of global carbon uptake. Gross primary production losses are often related to hydroclimatic extremes such as droughts and heatwaves, but the trend of such losses driven by hydroclimatic extremes remains unclear. Using observationally-constrained and process-based model data from 1982-2016, we show that drought-heat events, drought-cold events, droughts and heatwaves are the dominant drivers of gross primary production loss. Losses associated with these drivers increase in northern midlatitude ecosystem but decrease in pantropical ecosystems, thereby contributing to around 70% of the variability in total gross primary production losses. These asymmetric trends are caused by an increase in the magnitude of gross primary production losses in northern midlatitudes and by a decrease in the frequency of gross primary production loss events in pantropical ecosystems. Our results suggest that the pantropics may have become less vulnerable to hydroclimatic variability over recent decades whereas gross primary production losses and hydroclimatic extremes in northern midlatitudes have become more closely entangled

Development of an alternative low-cost cereal-based weaning food fortified with iron and vitamin A (retinol acetate)

The main objective of the study was to develop an alternative low-cost pearl millet-based weaning food followed by the fortification with iron and vitamin A (retinol acetate). The product was formulated as per the guidelines of Food Safety and Standards Regulations, 2010 and prepared by using extruded pearl millet flour, extruded wheat flour, skim milk powder, whey protein concentrate-70 and sucrose in the ratio of 35, 25, 15, 5 and 20%, respectively. Electrolytic iron and vitamin A acetate were fortified at the level of 12mg/100g and 360 µg/100g of the product to meet 100 and 98.25% of the RDA for iron and vitamin A, respectively. The developed weaning food was analyzed for proximate composition and physicochemical properties. The average moisture content was 3.73±0.02% and average protein, fat, carbohydrate, ash and crude fiber content (on dry weight basis) was 15.32±0.06, 1.96±0.07, 79.58±0.06, 2.02±0.02 and 1.12±0.10%, respectively. The iron, vitamin A and ß-Carotene content were found to be 15mg, 393µg and 30.62µg per 100g of the product, respectively. Physical properties namely flow-ability, water absorption index, water solubility index were analyzed and values were observed to be 33.80±0.27, 9.28±0.17, 9.12±0.35%, respectively. The lightness (L*), redness (a*), yellowness (b*) values of color for the developed product were 77.87±0.26, 2.15±0.12 and 17.43±0.08, respectively. Overall, it can be concluded that the well- developed product could serve as a potential delivery system of iron and vitamin A and could be an effective tool to deal with the micronutrients deficiency in infants

Glucocorticoid Receptor Confers Resistance to Antiandrogens by Bypassing Androgen Receptor Blockade

SummaryThe treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Here, we identify induction of glucocorticoid receptor (GR) expression as a common feature of drug-resistant tumors in a credentialed preclinical model, a finding also confirmed in patient samples. GR substituted for the androgen receptor (AR) to activate a similar but distinguishable set of target genes and was necessary for maintenance of the resistant phenotype. The GR agonist dexamethasone was sufficient to confer enzalutamide resistance, whereas a GR antagonist restored sensitivity. Acute AR inhibition resulted in GR upregulation in a subset of prostate cancer cells due to relief of AR-mediated feedback repression of GR expression. These findings establish a mechanism of escape from AR blockade through expansion of cells primed to drive AR target genes via an alternative nuclear receptor upon drug exposure

Effectiveness of postoperative radiotherapy after radical cystectomy for locally advanced bladder cancer

BACKGROUND: Local-regional failure (LF) for locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity/mortality. Postoperative radiotherapy (PORT) can reduce LF and may enhance overall survival (OS) but has no defined role. We hypothesized that the addition of PORT would improve OS in LABC in a large nationwide oncology database. METHODS: We identified ≥ pT3pN0-3M0 LABC patients in the National Cancer Database diagnosed 2004-2014 who underwent RC ± PORT. OS was calculated using Kaplan-Meier and Cox proportional hazards regression modeling was used to identify predictors of OS. Propensity matching was performed to match RC patients who received PORT vs those who did not. RESULTS: 15,124 RC patients were identified with 512 (3.3%) receiving PORT. Median OS was 20.0 months (95% CI, 18.2-21.8) for PORT vs 20.8 months (95% CI, 20.3-21.3) for no PORT (P = 0.178). In multivariable analysis, PORT was independently associated with improved OS: hazard ratio 0.87 (95% CI, 0.78-0.97); P = 0.008. A one-to-three propensity match yielded 1,858 patients (24.9% receiving PORT and 75.1% without). In the propensity-matched cohort, median OS was 19.8 months (95% CI, 18.0-21.6) for PORT vs 16.9 months (95% CI, 15.6-18.1) for no PORT (P = 0.030). In the propensity-matched cohort of urothelial carcinoma patients (N = 1,460), PORT was associated with improved OS for pT4, pN+, and positive margins (P \u3c 0.01 all). CONCLUSION: In this observational cohort, PORT was associated with improved OS in LABC. While the data should be interpreted cautiously, these results lend support to the use of PORT in selected patients with LABC, regardless of histology. Prospective trials of PORT are warranted