Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer.

Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4's hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

Nephrolithiasis in autosomal dominant polycystic kidney disease.

BACKGROUND AND PURPOSE: Autosomal dominant polycystic kidney disease (ADPKD) manifests with renal and extrarenal abnormalities and is inherited in an autosomal dominant fashion. In addition to multiple renal cysts, abnormalities such as liver cysts (80%), pancreatic cysts, splenic cysts, pulmonary cysts, berry aneurysms in the distribution of arterial circle of Willis (8%), colonic diverticula, mitral valve prolapse, etc., can be present. The condition will develop in half of the offspring of affected persons because of its 100% penetrance. Nephrolithiasis in patients with ADPKD is not infrequent and, given the importance of preservation of renal function in this subset of patients, a clear understanding of the management options available and their advantages and disadvantages is absolutely essential and critical in better patient outcomes. This article is an endeavor in this direction and provides a review of the current available literature. MATERIALS AND METHODS: An electronic database search of Medline, Embase, and Cochrane library was performed to search for the available literature in January 2010 with no restrictions in terms of date or language. The search terms used were ADPKD, nephrolithiasis, percutaneous nephrolithotomy, shockwave lithotripsy, flexible ureterorenoscopy, congenital kidney disorders, etc., separately and in various combinations. The articles so extracted were scrutinized for relevance and selected for the review.

Anejaculation as an atypical presentation of prostate cancer: a case report.

Anejaculation may occur as a result of neurological disease, iatrogenic injury or be drug induced. We report a case of a 66 year old man who presented with anejaculation following an emergency abdominal aortic aneurysm repair. Due to an elevated prostate specific antigen (PSA) level, the patient underwent a prostate biopsy and was diagnosed with a prostate adenocarcinoma. This was effectively managed using active surveillance, a treatment modality that aims to select only those patients with significant cancer for radical treatment. Despite the possible cause of anejaculation to be iatrogenic, the reader should be aware that prostate cancer may co-exist in, or cause any disorder of the lower urinary tract.