Oncosis and apoptosis induction by activation of an overexpressed ion channel in breast cancer cells.

The critical role of calcium signalling in processes related to cancer cell proliferation and invasion has seen a focus on pharmacological inhibition of overexpressed ion channels in specific cancer subtypes as a potential therapeutic approach. However, despite the critical role of calcium in cell death pathways, pharmacological activation of overexpressed ion channels has not been extensively evaluated in breast cancer. Here we define the overexpression of transient receptor potential vanilloid 4 (TRPV4) in a subgroup of breast cancers of the basal molecular subtype. We also report that pharmacological activation of TRPV4 with GSK1016790A reduced viability of two basal breast cancer cell lines with pronounced endogenous overexpression of TRPV4, MDA-MB-468 and HCC1569. Pharmacological activation of TRPV4 produced pronounced cell death through two mechanisms: apoptosis and oncosis in MDA-MB-468 cells. Apoptosis was associated with PARP-1 cleavage and oncosis was associated with a rapid decline in intracellular ATP levels, which was a consequence of, rather than the cause of, the intracellular ion increase. TRPV4 activation also resulted in reduced tumour growth in vivo. These studies define a novel therapeutic strategy for breast cancers that overexpress specific calcium permeable plasmalemmal ion channels with available selective pharmacological activators.

Use of Urodynamic Studies among Certifying and Recertifying Urologists from 2003 to 2014.

INTRODUCTION: Guidelines for the use of urodynamics have undergone a significant narrowing of scope in recent years, particularly as they pertain to the use of urodynamics for stress incontinence in women. Whether these changes have affected the use of urodynamics in practice is unknown. The goal of this study is to quantify the percentage of urologists who are performing urodynamics, to determine how trends have changed during the time studied and to better understand why these studies are being performed by identifying the associated diagnosis codes. METHODS: We queried the 6-month procedure logs submitted by applicants for part II ABU (American Board of Urology) certification or recertification between 2003 and 2014. The number of procedures with urodynamics CPT codes were abstracted (51725, 51726, 51772, 51784, 51785, 51792, 51795, 5179, 51797) along with the certification year, patient gender and ICD-9 diagnosis used for each procedure. RESULTS: During the 11-year period of data 7,849 practice logs were submitted to the ABU. Overall 91% of certifying applicants and 89.5% of recertifying applicants performed urodynamics. This number increased from 82.6% of certifying urologists and 70.3% of recertifying urologists in 2003 to 94.7% of recertifying urologists and 93.7% of certifying urologists in 2014. In 2003, on average, each certifying applicant performed 99 urodynamics procedures. This number increased to 149 procedures per applicant in 2014, for a 49.8% increase overall from the start of the study period. For recertification candidates an average of 125 procedures was performed per candidate in 2003. The average increased to 187 procedures per candidate in 2014 for a 49.5% increase in procedures performed. Videourodynamics were performed by 8.1% of certification or recertification applicants overall. This increased from 1% of recertification applicants and 1.8% of certification applicants in 2003 to 6% and 12.5% of recertification and certification applicants, respectively, in 2013. The ICD-9 codes most frequently associated with pressure flow studies were 625.6 (stress urinary incontinence-female) and 788.41 (urinary frequency). The ICD-9 code most commonly associated with videourodynamics across our study was 625.6 (stress urinary incontinence-female). CONCLUSIONS: Since 2003 the percentage of applicants for ABU certification or recertification using urodynamics in their practice has increased from 76.5% to 94.2%. There has also been a 49.7% increase in the number of urodynamics procedures performed per candidate during that period, indicating an overall increase in the use of urodynamic studies.

Repair of megameatus: a modified approach.

OBJECTIVE: To demonstrate surgical reconstruction of a megameatus variant of hypospadias by using a modified, patient-specific approach. METHODS: An 8-month-old male had a megameatus, which was discovered after newborn circumcision. In repair of megameatus, it is important to recognize the full extent to which the distal urethra is widened, in order to avoid inadvertent urethrotomy during mobilization of the glans wings and skin immediately proximal to the glans. In this case, a small wedge of tissue was excised from the ventral aspect of the urethra, and a midline relaxing incision of the urethral plate was made. Standard principles of hypospadias repair should be followed, with tension-free urethral tubularization, coverage of the neourethra with well-vascularized tissue, and adequate mobilization of the glans wings to allow midline reconstruction without compression of the underlying neourethra. RESULTS: There were no perioperative or postoperative complications in this case. The urethral meatus was positioned near the tip of the glans penis, and there was no evidence of meatal stenosis or urethrocutaneous fistula at 5-months follow-up. CONCLUSION: Each case of megameatus is unique, and a variety of surgical techniques can be used in formulating an approach that achieves optimal cosmetic and functional outcomes.