Estrogen receptor–β activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFα mediated

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor–β (ERβ) in BPH and PCa. ERβ agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFα knock-out mice fail to respond to ERβ agonist, demonstrating the requirement for TNFα signaling. In human tissues, ERβ agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133⁺ enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERβ causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERβ agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERβ agonist for treatment of PCa and/or BPH with or without androgen withdrawal.     

Predictors of chronic breathlessness: a large population study

Background  

Breathlessness causes significant burden in our community but the underlying socio-demographic and lifestyle factors that may influence it are not well quantified. This study aims to define these predictors of chronic breathlessness at a population level.     

Prevalence and short-term mortality of acute-on-chronic liver failure: A national cohort study from the USA

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Evaluations of HIV type 1 rev gene diversity and functional domains following perinatal transmission

The human immunodeficiency virus type 1 (HIV-1) rev exons 1 and 2 sequences were analyzed from six mother-infant pairs following perinatal transmission. The rev open reading frame was maintained with a frequency of 93.96% in six mother-infant pairs' sequences. There was a low degree of viral heterogeneity and estimates of genetic diversity in mother-infant pairs' rev sequences. However, the distances of rev sequences between epidemiologically unlinked individuals were greater than in epidemiologically linked mother-infant pairs. Furthermore, phylogenetic parameters revealed that the epidemiologically linked mother-infant pairs were closer evolutionarily to each other as compared with epidemiologically unlinked mother-infant pairs. Both mothers and infants were under positive selection pressure as determined by the ratios of nonsynonymous to synonymous substitutions. The functional domains required for Rev activity, including nuclear export of RNA, RNA binding domain, and nuclear import signals, were conserved in all mother-infant pairs' sequences. The conservation of functional domains of rev and a low degree of heterogeneity following vertical transmission are consistent with an indispensable role of rev in the HIV-1 life cycle.     

Clinical characteristics and therapeutic outcome of patients with febrile neutropenia who present in shock: need for better strategies

OBJECTIVE: To study the frequency of neutropenic febrile patients who present in shock, to evaluate the influence of this presenting feature on response to antibiotic therapy, morbidity, and mortality and to identify discriminating demographic features and clinical characteristics of these individuals. METHODS: Prospectively collected data on all episodes of fever and neutropenia observed in cancer patients who were hospitalized for parenteral antibiotic therapy. RESULTS: Five hundred and seventy-six patients were evaluated; 22 (3.8%) presented in shock. This group of individuals was compared with the remainder. Patients presenting in shock were more likely to be older (P< 0.01) and have progressive unresponsive cancer (P< 0.01). They were also more likely to present with septic appearance (P< 0.01), dehydration (P< 0.01), diarrhoea (P< 0.01), altered mental status (P< 0.01) clinical bleeding (P= 0.02) and dyspnoea (P< 0.01). They more often had anaemia (P< 0.01), thrombocytopenia (P= 0.02) and abnormal liver function tests (P< 0.01). Eight of the 22 patients presenting in shock had documented bacteraemia. Non-bacteraemic microbiological infections were observed in three patients. Five patients had clinical evidence of infection and another five were severely dehydrated and volume depleted. One patient had cardiogenic shock. Three patients were managed with monotherapy, 19 received combination antibiotics as initial empirical therapy. Overall outcome of these patients was extremely poor, particularly those with infectious aetiology. Eighteen (82%) patients expired. CONCLUSION: Neutropenic febrile patients who present in shock have extremely poor outcomes irrespective of type of initial antibiotic therapy. Intense efforts are required to improve their outcome.