Carcinoma-associated fibroblasts (CAF) play a critical role in malignant progression. Loss of TGF-β receptor II (TGFβR2) in the prostate stroma is correlated with prostatic tumorigenesis. To ...determine the mechanisms by which stromal heterogeneity because of loss of TGFβR2 might contribute to cancer progression, we attenuated transforming growth factor beta (TGF-β) signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGFβR2 function in 50% of the stromal cell population resulted in malignant transformation of the nontumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGFβR2 increased the expression of markers of myofibroblast differentiation coexpression of vimentin and alpha smooth muscle actin (αSMA) through elevation of TGF-β1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGFβR2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-β1, SDF1/CXCL12, and members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families. In vivo, tissue recombination of fibroblasts overexpressing TGF-β1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-β signaling to tumor promotion by tumor stromal cells.
Prostate cancer develops through a stochastic mechanism whereby precancerous lesions on occasion progress to multifocal adenocarcinoma. Analysis of human benign and cancer prostate tissues revealed ...heterogeneous loss of TGF-β signaling in the cancer-associated stromal fibroblastic cell compartment. To test the hypothesis that prostate cancer progression is dependent on the heterogeneous TGF-β responsive microenvironment, a tissue recombination experiment was designed in which the ratio of TGF-β responsive and nonresponsive stromal cells was varied. Although 100% TGF-β responsive stromal cells supported benign prostate growth and 100% TGF-β nonresponsive stromal cells resulted in precancerous lesions, only the mixture of TGF-β responsive and nonresponsive stromal cells resulted in adenocarcinoma. A computational model was used to resolve a mechanism of tumorigenic progression in which proliferation and invasion occur in two independent steps mediated by distinct stromally derived paracrine signals produced by TGF-β nonresponsive and responsive stromal cells. Complex spatial relationships of stromal and epithelial cells were incorporated into the model on the basis of experimental data. Informed by incorporation of experimentally derived spatial parameters for complex stromal-epithelial relationships, the computational model indicated ranges for the relative production of paracrine factors by each cell type and provided bounds for the diffusive range of the molecules. Because SDF-1 satisfied model predictions for an invasion-promoting paracrine factor, a more focused computational model was subsequently used to investigate whether SDF-1 was the invasion signal. Simulations replicating SDF-1 expression data revealed the requirement for cooperative SDF-1 expression, a prediction supported biologically by heterotypic stromal interleukin-1β signaling between fibroblastic cell populations. The cancer stromal field effect supports a functional role for the unaltered fibroblasts as a cooperative mediator of cancer progression.
NDRG1 Is Necessary for p53-dependent Apoptosis Stein, Susanne; Thomas, Emily K; Herzog, Birger ...
The Journal of biological chemistry,
11/2004, Letnik:
279, Številka:
47
Journal Article
Recenzirano
Odprti dostop
Although a number of target genes for the tumor suppressor p53 have been described, the mechanism of p53-dependent apoptosis
is incompletely understood. Thus, it is essential to identify and ...characterize additional target genes that could mediate
apoptosis. In the study reported here, we isolated a p53-regulated gene named NDRG1 ( N -Myc d own- r egulated g ene 1 ). Its expression is induced by DNA damage in a p53-dependent fashion. The promoter region of the NDRG1 gene contains a p53 binding site that confers p53-dependent transcriptional activation via a heterologous reporter. RNA interference
and inducible gene expression approaches suggest that NDRG1 is necessary but not sufficient for p53-mediated caspase activation and apoptosis. This report further supports the notion
that p53 controls a network of genes that are required for its apoptotic function.
Abstract Resistance to available therapeutic agents has been a common problem thwarting progress in treatment of castrate-resistant and metastatic prostate cancer (PCa). Overexpression of the Bcl-2 ...family members, including Mcl-1, in PCa cells is known to inhibit intracellular mitochondrial-dependent apoptosis. Here we report the development of a novel transgenic mouse model that spontaneously develops prostatic intraepithelial neoplasia and adenocarcinoma by the inducible, conditional knockout of transforming growth factor β receptor type II in stromal fibroblastic cells (Tgfbr2ColTKO ). The Tgfbr2ColTKO prostate epithelia demonstrated down-regulation of luminal and basal differentiation markers, as well as Pten expression and up-regulation of Mcl-1. However, unlike in men, Tgfbr2ColTKO prostates exhibited no regression acutely after castration. The administration of Sabutoclax (BI-97C1), a pan-active Bcl-2 protein family antagonist mediated apoptosis in castrate-resistant PCa cells of Tgfbr2ColTKO mice and human subcutaneous, orthotopic, and intratibial xenograft PCa models. Interestingly, Sabutoclax had little apoptotic effect on benign prostate tissue in Tgfbr2ColTKO and wild-type mice. Sabutoclax was able to block c-Met activation, a critical axis in PCa metastatic progression. Further, Sabutoclax synergistically sensitized PC-3 cells to the cytotoxic effects of docetaxel (Taxotere). Together, these data suggest that Sabutoclax inhibits castrate-resistant PCa alone at the primary and bone metastatic site as well as support sensitivity to docetaxel treatment.
Abstract Objective To examine the association of perceived racial/ethnic discrimination with smoking and alcohol consumption in adults participating in the Multi-Ethnic Study of Atherosclerosis. ...Methods Data on 6680 black, Chinese, Hispanic and white adults aged 45 to 84 years of age recruited from Illinois, New York, Maryland, North Carolina, Minnesota and California during 2000 and 2002 were used for this analysis. Logistic regression was used to estimate the association of perceived racial/ethnic discrimination with smoking status and alcohol consumption for each racial/ethnic group separately. Results Blacks were more likely to experience racial/ethnic discrimination (43%) than Hispanics (19%), Chinese participants (10%) or whites (4%, P < 0.0001). In the fully-adjusted model, blacks reporting racial/ethnic discrimination had 34% and 51% greater odds of reporting smoking and drinking, respectively, than blacks who did not report racial/ethnic discrimination. Hispanics reporting racial/ethnic discrimination had 62% greater odds of heavy drinking. Whites reporting racial/ethnic discrimination had 88% greater odds of reporting being current smokers than whites who did not report racial/ethnic discrimination. Conclusions Our findings suggest that the experience of discrimination is associated with greater prevalence of unhealthy behaviors. Specifically, the use of smoking and alcohol may be patterned by experience of discrimination.
A number of target genes for the tumor suppressor, p53, have been identified, however, the mechanisms that contribute to p53-dependent apoptosis remain to be fully elucidated. In a comprehensive ...screen for p53 target genes, we have identified Cytoplasmic FMR Interacting Protein 2 (CYFIP2) as a p53-inducible gene. Here we show that the CYFIP2 promoter contains a p53-responsive element that confers p53 binding as well as transcriptional activation of a heterologous reporter. Inducible expression of CYFIP2 is sufficient for caspase activation and cellular apoptosis, reminiscent of p53 activation. Together, these results suggest that CYFIP2 is a direct p53 target gene that may be part of a redundant network of genes responsible for p53-dependent apoptosis. In addition, the sensitivity of CYFIP2 protein subcellular localization to Leptomycin-B, a Crm-1/Exportin inhibitor, suggests that the biological functions of CYFIP2 may extend from the cytoplasmic compartment into the nucleus of the cell.
Genetic coessentiality analysis, a computational approach which identifies genes sharing a common effect on cell fitness across large-scale screening datasets, has emerged as a powerful tool to ...identify functional relationships between human genes. However, widespread implementation of coessentiality to study individual genes and pathways is limited by systematic biases in existing coessentiality approaches and accessibility barriers for investigators without computational expertise. We created FIREWORKS, a method and interactive tool for the construction and statistical analysis of coessentiality networks centered around gene(s) provided by the user. FIREWORKS incorporates a novel bias reduction approach to reduce false discoveries, enables restriction of coessentiality analyses to custom subsets of cell lines, and integrates multiomic and drug-gene interaction datasets to investigate and target contextual gene essentiality. We demonstrate the broad utility of FIREWORKS through case vignettes investigating gene function and specialization, indirect therapeutic targeting of "undruggable" proteins, and context-specific rewiring of genetic networks.
Although mania is the hallmark symptom of bipolar I disorder (BD-I), most patients initially present for treatment with depressive symptoms. Misdiagnosis of BD-I as major depressive disorder (MDD) is ...common, potentially resulting in poor outcomes and inappropriate antidepressant monotherapy treatment. Screening patients with depressive symptoms is a practical strategy to help healthcare providers (HCPs) identify when additional assessment for BD-I is warranted. The new 6-item Rapid Mood Screener (RMS) is a pragmatic patient-reported BD-I screening tool that relies on easily understood terminology to screen for manic symptoms and other BD-I features in <2 minutes. The RMS was validated in an observational study in patients with clinically confirmed BD-I (n=67) or MDD (n=72). When 4 or more items were endorsed ("yes"), the sensitivity of the RMS for identifying patients with BP-I was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. To more thoroughly understand screening tool use among HCPs, a 10-minute survey was conducted.
A nationwide sample of HCPs (N=200) was selected using multiple HCP panels; HCPs were asked to describe their opinions/current use of screening tools, assess the RMS, and evaluate the RMS versus the widely recognized Mood Disorder Questionnaire (MDQ). Results were reported by grouped specialties (primary care physicians, general nurse practitioners NPs/physician assistants PAs, psychiatrists, and psychiatric NPs/PAs). Included HCPs were in practice <30 years, spent at least 75% of their time in clinical practice, saw at least 10 patients with depression per month, and diagnosed MDD or BD in at least 1 patient per month. Findings were reported using descriptive statistics; statistical significance was reported at the 95% confidence interval.
Among HCPs, 82% used a tool to screen for MDD, while 32% used a tool for BD. Screening tool attributes considered to be of the greatest value included sensitivity (68%), easy to answer questions (66%), specificity (65%), confidence in results (64%), and practicality (62%). Of HCPs familiar with screening tools, 70% thought the RMS was at least somewhat better than other screening tools. Most HCPs were aware of the MDQ (85%), but only 29% reported current use. Most HCPs (81%) preferred the RMS to the MDQ, and the RMS significantly outperformed the MDQ across valued attributes; 76% reported that they were likely to use the RMS to screen new patients with depressive symptoms. A total of 84% said the RMS would have a positive impact on their practice, with 46% saying they would screen more patients for bipolar disorder.
The RMS was viewed positively by HCPs who participated in a brief survey. A large percentage of respondents preferred the RMS over the MDQ and indicated that they would use it in their practice. Collectively, responses indicated that the RMS is likely to have a positive impact on screening behavior.
AbbVie Inc.
Effective screening for bipolar I disorder can lead to enhanced assessment, improved diagnosis, and better patient outcomes. The Rapid Mood Screener (RMS), a new bipolar I disorder screening tool, ...was evaluated in a nationwide survey of health care providers (HCPs).
Eligible HCPs were asked to describe their opinions/current use of screening tools, assess the RMS, and evaluate the RMS versus the Mood Disorder Questionnaire (MDQ). Results were stratified by primary care and psychiatric specialty. Findings were reported using descriptive statistics; statistical significance was reported at the 95% confidence level.
Among respondents (N = 200), 82% used a tool to screen for major depressive disorder (MDD), while 32% used a tool for bipolar disorder. Most HCPs were aware of the MDQ (85%), but only 29% reported current use. According to HCPs, the RMS was significantly better than the MDQ on all screening tool attributes (eg, sensitivity/specificity, brevity, practicality, easy scoring;
< .05 for all). Significantly more HCPs reported that they would use the RMS versus the MDQ (81% vs 19%,
< .05); 76% reported that they would screen new patients with depressive symptoms, and 68% indicated they would rescreen patients with a depression diagnosis. Most HCPs (84%) said the RMS would have a positive impact on their practice, with 46% saying they would screen more patients for bipolar disorder.
In our survey, the RMS was favorably evaluated by HCPs. A large percentage of respondents preferred the RMS over the MDQ and indicated that it would likely have a positive impact on clinicians' screening behavior.
Outbreaks of highly pathogenic avian influenza A subtype H5N1 have occurred in Vietnam as a series of epidemic waves since December 2003. We describe the spatial and temporal patterns of the HPAI ...H5N1 epidemics in the Red River Delta in the north (785 outbreaks in 606 communes) and the Mekong River Delta in the south of Vietnam (1313 outbreaks in 837 communes), where the epidemics were concentrated. Throughout the study period the percentage of outbreaks affecting ducks increased steadily to a peak of 78% during the 2006/2007 epidemic in both deltas. Five of the seven epidemic waves occurred in the period of active poultry population buildup immediately prior to the Vietnamese New Year (Tết festival). Recorded outbreaks were clustered in space and time within both deltas, consistent with infection transmission occurring via a combination of local and long-distance spread. Our analyses demonstrate that the epidemiology of HPAI in Vietnam has changed over the 4-year study period, with outbreaks now occurring in the warmer months of the year and ducks featuring more prominently as affected species. To determine the relative importance of local and long-distance spread on infection transmission, precise details of outbreak location, date of onset of clinical signs, and size and composition of the poultry population at risk need to be recorded during future outbreak responses.
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