The role of the p90 ribosomal S6 kinase family in prostate cancer progression and therapy resistance.

Prostate cancer (PCa) is the second most commonly occurring cancer in men, with over a million new cases every year worldwide. Tumor growth and disease progression is mainly dependent on the Androgen Receptor (AR), a ligand dependent transcription factor. Standard PCa therapeutic treatments include androgen-deprivation therapy and AR signaling inhibitors. Despite being successful in controlling the disease in the majority of men, the high frequency of disease progression to aggressive and therapy resistant stages (termed castrate resistant prostate cancer) has led to the search for new therapeutic targets. The p90 ribosomal S6 kinase (RSK1-4) family is a group of highly conserved Ser/Thr kinases that holds promise as a novel target. RSKs are effector kinases that lay downstream of the Ras/Raf/MEK/ERK signaling pathway, and aberrant activation or expression of RSKs has been reported in several malignancies, including PCa. Despite their structural similarities, RSK isoforms have been shown to perform nonredundant functions and target a wide range of substrates involved in regulation of transcription and translation. In this article we review the roles of the RSKs in proliferation and motility, cell cycle control and therapy resistance in PCa, highlighting the possible interplay between RSKs and AR in mediating disease progression. In addition, we summarize the current advances in RSK inhibitor development and discuss their potential clinical benefits.

Factors associated with diverticular bleeding and re-bleeding: A United States hospital study.

OBJECTIVE: Diverticular bleeding is the most common cause of lower gastrointestinal bleeding. Arteriovascular disease, metabolic syndromes, non-steroidal anti-inflammatory drugs (NSAIDs), anti-thrombotics, and anticoagulants have been suggested as risk factors. There is a paucity of studies addressing factors associated with diverticular re-bleeding, especially in the United States. The aim of this study is to evaluate factors associated with colonic diverticular bleeding and re-bleeding in a US community-based hospital. METHODS: We conducted a retrospective case-control study to analyze the factors associated with diverticular bleeding. Between January 2010 and July 2011, 93 patients were admitted to our hospital with a primary diagnosis of acute diverticular bleeding. We compared them to 152 patients who were admitted with a primary diagnosis of diverticulitis in the same period. We collected data from the medical records of each patient in relation to the demographics, comorbidities, medications, social habits, location of diverticulosis, length of stay in the hospital, and re-bleeding rate within 2 years of the first bleeding episode. RESULTS: Factors such as cerebrovascular accident (p=0.009), coronary artery disease (p=0.037), diabetes mellitus (p=0.046), obstructive sleep apnea (p=0.033), NSAIDs (p=0.038), use of anti-thrombotics (p=0.001), anticoagulants (p=0.002) or calcium channel blockers (p=0.009), and bilateral diverticulosis (p=0.001) were significantly associated with diverticular bleeding as compared to diverticulitis. Recurrence of bleeding was noted in 26 out of 93 patients (28%) within 2 years of the first bleeding episode (p=0.001). Bilateral colonic involvement, anticoagulants, and elderly age (≥65 years) were found to have a closer relationship to diverticular re-bleeding, although it was not statistically significant. CONCLUSION: This study reveals that arteriovascular disease, diabetes mellitus, NSAIDs, the use of anti-thrombotics, anticoagulants or calcium channel blockers, and obstructive sleep apnea are factors that are significantly associated with diverticular bleeding. It also shows that bilateral colonic involvement, elderly age, and anticoagulants have a closer relationship to diverticular re-bleeding. More prospective studies in patients with diverticular bleeding should be conducted to shed light on the causality of these factors and the prevalence of diverticulitis.