Purpose: Although Src family kinase (SFK) inhibitors are now in clinical trials for the treatment of androgen-independent prostate cancer (AIPC), there are no studies relating SFK activation to patient survival. This study was designed to determine if SFK activation was up-regulated with the development of AIPC and if patients could be selected who were more likely to respond to therapy. Experimental Design: A unique cohort of matched prostate tumor samples, taken before hormone deprivation therapy and following hormone relapse, was used to determine by immunohistochemistry on an individual patient basis if SFK activity changed with progression to AIPC and whether this related to patient outcome measures. Using matched, hormone-sensitive and hormone-refractory cell lines, we determined if hormone status affected the way prostate cancer cells respond to suppression of SFK activity by the small-molecule inhibitor dasatinib.Results: In the current study, 28% of patients with AIPC exhibited an increase in SFK activity in prostate cancer tissue, these patients had significantly shorter overall survival (P < 0.0001), and activated SFK expression correlated with the presence of distant metastases. Dasatinib inhibited phosphorylation of Src and Lyn and the downstream substrate FAK in hormone-sensitive and hormone-refractory cell lines. Although migration was reduced by dasatinib in both cell lines, proliferation of hormone-refractory cells only was inhibited. Conclusion: Appropriate patient selection may allow better targeting of prostate cancer patients who are likely to respond to the treatment with SFK inhibitors at the same time improving the outcome of clinical trials.Prostate cancer is the most common cancer in men and is the second leading cause of cancer-related deaths in men in the United States and United Kingdom (1). Treatment options for locally advanced and metastatic prostate cancer are limited to androgen deprivation therapy or surgical castration. Unfortunately, nearly all of these patients eventually develop androgenindependent prostate cancer (AIPC) for which currently there are no established effective therapies.Our understanding of the mechanisms involved in the development of AIPC has considerably improved over the last decade. When deprived of androgen stimulation, androgensensitive prostate cancer (ASPC) cells develop the ability to survive and thrive by up-regulating oncogenic pathways where tyrosine kinases often play a crucial role (2). The nonreceptor tyrosine kinase Src is thought to facilitate the interaction between intracellular molecular cascades as well as form complexes with the androgen receptor (AR), which is expressed by the majority of AIPC cells. Tyrosine phosphorylation is an important factor in the regulation of AR activity resulting in translocation of the receptor into the nucleus and increase in DNA synthesis. Src activation by growth factors in prostate cancer cells has been shown to correlate with AR tyrosine phosphorylation, especially under androgen-depleted condi...

Elevated c-Src protein expression has been shown in breast cancer and in vitro evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan -Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (P ¼ 0.047) and lower recurrence rates on tamoxifen (P ¼ 0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (Po0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (P ¼ 0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in de novo endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome.

Src was the first proto-oncogene to be discovered. Since then the role of Src has been extensively studied in vitro. Src is a key regulator of multiple signal transduction pathways and plays a significant part in cellular transformation. Dysfunction of Src, through overexpression or increased activation, has profound effects on basic cellular functions. Elevated Src expression and/or activation is evident across a wide range of solid tumour types, highlighting its place in carcinogenesis and making it an attractive therapeutic target. In this review, we discuss in vitro and in vivo data examining the role of Src in the different cellular processes involved in oncogenesis and metastasis, covering the association of Src with increased cell proliferation and survival, decreased cellular adhesion, increased cell motility and invasiveness, accelerated/advanced angiogenesis and pathogenic bone activity. We also review evidence gathered from human tumour tissue and translational research studies that further substantiates the role of Src in oncogenesis. A summary of Src inhibitors currently being developed and trialled as therapeutic agents is provided to underline Src as a potential molecular target for solid tumour therapy. Further clinical data are needed to conclusively demonstrate that Src inhibitors have clinical utility in the treatment of solid tumors.

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Background Whilst competence in the management of a wide range of urological emergencies is a requirement for certification in urology, many conditions are uncommon and exposure during training may be limited. This prospective observational study sought to evaluate the feasibility and effectiveness of a standardised cadaveric emergency urology simulation course aimed at improving operative confidence and competence prior to independent on-call practice in the United Kingdom. Methods A two-day cadaveric emergency urology simulation course supported by the British Association of Urological Surgeons (BAUS) was implemented at two pilot centres. All delegates that undertook one of the initial series of courses were invited to complete online pre- and post-course questionnaires relating to prior operative experience, documented competence and perceived confidence in being able to perform specific emergency procedures independently. Primary outcome was a self-reported ‘confidence score’ selected from a linear numeric scale ranging from 1 (not at all confident to perform a given procedure independently) to 10 (fully confident). Statistical analysis was undertaken using SPSS Statistics for Mac Version 25 and the paired student’s t-test used to compare mean pre- and post-course scores. Results One hundred and four delegates undertook the course during the study period. Of these, 85 (81.7%) completed the pre-course survey and 67 (64.4%) completed the post-course survey, with 61 (58.7%) completing both. The greatest proportion of respondents were Speciality Trainees in Urology of ST5 level or higher (equivalent of Resident/Fellows with 4 or more years of surgical training; n = 31, 36.5%). Delegates reported variable pre-course exposure, with most experience reported in loin approach to the kidney (median 10) and least in exploration and packing of a transurethral resection cavity and emergency nephrectomy (median 0). Following course completion, a statistically significant increase in confidence score was observed for each procedure, with the greatest increases seen for shunt for priapism (4.87 to 8.80, p < 0.001), ureteric reimplantation (3.52 to 7.33, p < 0.001) and primary ureteric anastomosis (3.90 to 7.49, p < 0.001). Conclusions A standardised high fidelity cadaveric simulation course is feasible and significantly improves the confidence of trainees in performing a wide range of emergency procedures to which exposure is currently limited.