Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

Androgen deprivation therapy reduces prostate cancer (PCa) tumour growth; however, disease relapse often ensues independently of androgen stimulation, producing androgen-refractory tumours with increased invasion, proliferation, and malignancy. Androgens downregulate epidermal growth factor receptor (EGFR) in normal prostate but not in PCa. Thus, loss of EGFR regulation and altered signalling may, in part, explain the transition of prostate tumours from androgen dependent to androgen independent. Studies in animal models, PCa cell lines, and tumour specimens suggest that androgens modulate prostate growth and function through mechanisms that involve ‘cross-talk' between androgen receptor (AR) and growth factor receptor signalling pathways. The objective of this review is to discuss the paradoxical relationship between androgen regulation of EGFR in normal prostate and PCa. We reviewed the literature from mid-1980s through 2009 to assess the relationship between androgens and EGFR function in modulating the growth of normal prostate and PCa. Loss of androgen regulation of EGFR in PCa may be responsible for increased tumour growth, invasion, and metastasis, with important implications on the clinical management of PCa. We advance the hypothesis that a molecular switch, responsible for downregulating EGFR expression by androgens in the normal prostate, is either lost or modified in PCa

Immunodetection of nmt55/p54(nrb) isoforms in human breast cancer

BACKGROUND: We previously identified and characterized a novel 55 kDa nuclear protein, termed nmt55/p54(nrb), whose expression was decreased in a subset of human breast tumors. The objective of this study was to determine if this reduced expression in human breast tumors was attributed to the regulation of mRNA transcription or the presence of altered forms of this protein. RESULTS: Northern blot analysis and ribonuclease protection assay indicated that nmt55/p54(nrb) mRNA is expressed at varying levels in estrogen receptor positive (ER+) and estrogen receptor negative (ER-) human breast tumors suggesting that reduced expression of nmt55/p54(nrb) protein in ER- tumors was not due to transcriptional regulation. To determine if multiple protein isoforms are expressed in breast cancer, we utilized Western blot and immunohistochemical analyses, which revealed the expression of an nmt55/p54(nrb) protein isoform in a subset of ER+ tumors. This subset of ER+ human breast tumors expressed an altered form of nmt55/p54(nrb) that was undetectable with an amino-terminal specific antibody suggesting that this isoform contains alterations or modifications within the amino terminal domain. CONCLUSIONS: Our study indicates that nmt55/p54(nrb) protein is post-transcriptionally regulated in human breast tumors leading to reduced expression in ER- tumors and the expression of an amino terminal altered isoform in a subset of ER+ tumors. The potential involvement of nmt55/p54(nrb) in RNA binding and pre-mRNA splicing may be important for normal cell growth and function; thus, loss or alteration of protein structure may contribute to tumor growth and progression

Dyspnea in Patients Receiving Radical Radiotherapy for Non-Small Cell Lung Cancer: A Prospective Study

Background and Purpose: Dyspnea is an important symptomatic endpoint for assessment of radiation-induced lung injury (RILI) following radical radiotherapy in locally advanced disease, which remains the mainstay of treatment at the time of significant advances in therapy including combination treatments with immunotherapy and chemotherapy and the use of local ablative radiotherapy techniques. We investigated the relationship between dose-volume parameters and subjective changes in dyspnea as a measure of RILI and the relationship to spirometry. Material and Methods: Eighty patients receiving radical radiotherapy for non-small cell lung cancer were prospectively assessed for dyspnea using two patient-completed tools: EORTC QLQ-LC13 dyspnea quality of life assessment and dyspnea visual analogue scale (VAS). Global quality of life, spirometry and radiation pneumonitis grade were also assessed. Comparisons were made with lung dose-volume parameters. Results: The median survival of the cohort was 26 months. In the evaluable group of 59 patients there were positive correlations between lung dose-volume parameters and a change in dyspnea quality of life scale at 3 months (V30 p=0.017; V40 p=0.026; V50 p=0.049; mean lung dose p=0.05), and a change in dyspnea VAS at 6 months (V30 p=0.05; V40 p=0.026; V50 p=0.028) after radiotherapy. Lung dose-volume parameters predicted a 10% increase in dyspnea quality of life score at 3 months (V40; p=0.041, V50; p=0.037) and dyspnea VAS score at 6 months (V40; p=0.027) post-treatment. Conclusions: Worsening of dyspnea is an important symptom of RILI. We demonstrate a relationship between lung dose-volume parameters and a 10% worsening of subjectiv

A critical analysis of the role of testosterone in erectile function: From pathophysiology to treatment - A systematic review

Context: Androgen modulation of erectile function (EF) is widely accepted. However, the use of testosterone replacement therapy (TRT) in men with erectile dysfunction (ED) has generated an unprecedented debate. Objective: To summarize the relevant data on the incidence, diagnosis, and management of ED coexisting with hypogonadism and to develop a pathophysiology-based treatment algorithm. Evidence acquisition: We reviewed the relevant medical literature, with a particular emphasis on original molecular studies, prospective observational data, and randomized controlled trials performed in the past 20 yr. Evidence synthesis: Testosterone modulates nearly every component involved in EF, from pelvic ganglions to smooth muscle and the endothelial cells of the corpora cavernosa. It also regulates the timing of the erectile process as a function of sexual desire, coordinating penile erection with sex. Epidemiologic studies confirm the significant overlap of hypogonadism and ED; however, most guidelines do not consider the differential diagnosis of hypogonadism or the relevance of subclinical disease. Various clinical tools can help the physician to assess and restore androgen levels in men with ED. Special attention is given to fertility-sparing treatments, due to the increasing number of older men desiring fatherhood. The simultaneous use of phosphodiesterase type 5 inhibitors (PDE5-Is) and TRT has recently been questioned. Originally proposed as a salvage therapy for nonresponders to PDE5-Is, this approach has been inappropriately transformed into a combination therapy. Clinical data are consistent when reinterpreted in the proper framework, whereas molecular evidence remains controversial. Conclusions: A body of molecular and clinical evidence supports the use of TRT in hypogonadal patients with ED, although the benefit-risk ratio is uncertain in advanced age. Critical appraisal of this evidence enabled the development of a pathophysiology-oriented algorithm designed to avoid inappropriate treatments and support whether to start with TRT, PDE5-I only, or both. Apparently divergent findings are reconciled when TRT is correctly indicated. An improved diagnosis and individualized management is desirable in light of the many available options. © 2013 European Association of Urology

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Effect of 12 months of testosterone replacement therapy on metabolic syndrome components in hypogonadal men: data from the Testim Registry in the US (TRiUS)

<p>Abstract</p> <p>Background</p> <p>Recent evidence suggests that there may be a bidirectional, physiological link between hypogonadism and metabolic syndrome (MetS), and testosterone replacement therapy (TRT) has been shown to improve some symptoms of MetS in small patient populations. We examined the effect of 12 months of TRT on MetS components in a large cohort of hypogonadal men.</p> <p>Methods</p> <p>Data were obtained from TRiUS (Testim^®Registry in the United States), a 12-month, multicenter, prospective observational registry (N = 849) of hypogonadal men prescribed Testim 1% testosterone gel (5-10 g/day). Data analyzed included age, total testosterone (TT), free testosterone (FT), sex hormone-binding globulin (SHBG), and MetS components: waist circumference, blood pressure, fasting blood glucose, plasma triglycerides, and HDL cholesterol.</p> <p>Results</p> <p>Of evaluable patients (581/849) at baseline, 37% were MetS+ (n = 213) and 63% were MetS- (n = 368). MetS+ patients had significantly lower TT (p < 0.0001) and SHBG (p = 0.01) levels. Patients with the lowest quartile TT levels (<206 ng/dL [<7.1 nmol/L]) had a significantly increased risk of MetS+ classification vs those with highest quartile TT levels (≥331 ng/dL [≥11.5 nmol/L]) (odds ratio 2.66; 95% CI, 1.60 to 4.43). After 12 months of TRT, TT levels significantly increased in all patients (p < 0.005). Despite having similar TT levels after TRT, only MetS+ patients demonstrated significant decreases in waist circumference, fasting blood glucose levels, and blood pressure; lowest TT quartile patients demonstrated significant decreases in waist circumference and fasting blood glucose. Neither HDL cholesterol nor triglyceride levels changed significantly in either patient population.</p> <p>Conclusion</p> <p>Hypogonadal MetS+ patients were more likely than their MetS- counterparts to have lower baseline TT levels and present with more comorbid conditions. MetS+ patients and those in the lowest TT quartile showed improvement in some metabolic syndrome components after 12 months of TRT. While it is currently unclear if further cardiometabolic benefit can be seen with longer TRT use in this population, testing for low testosterone may be warranted in MetS+ men with hypogonadal symptoms.</p