TRIMming p53's anticancer activity.

Several TRIM proteins control abundance and activity of p53. Along this route, TRIM proteins have a serious impact on carcinogenesis and prognosis for cancer patients. In the past years, a significant increase has been made in our understanding of how the TRIM protein family controls p53 activity.

TRIM25 has a dual function in the p53/Mdm2 circuit.

P53 is an important tumor suppressor that, upon activation, induces growth arrest and cell death. Control of p53 is thus of prime importance for proliferating cells, but also for cancer therapy, where p53 activity contributes to the eradication of tumors. Mdm2 functionally inhibits p53 and targets the tumor suppressor protein for degradation. In a genetic screen, we identified TRIM25 as a novel regulator of p53 and Mdm2. TRIM25 increased p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26 S proteasomes. TRIM25 co-precipitated with p53 and Mdm2 and interfered with the association of p300 and Mdm2, a critical step for p53 polyubiquitination. Despite the increase in p53 levels, p53 activity was inhibited in the presence of TRIM25. Downregulation of TRIM25 resulted in an increased acetylation of p53 and p53-dependent cell death in HCT116 cells. Upon genotoxic insults, TRIM25 dampened the p53-dependent DNA damage response. The downregulation of TRIM25 furthermore resulted in massive apoptosis during early embryogenesis of medaka, which was rescued by the concomitant downregulation of p53, demonstrating the functional relevance of the regulation of p53 by TRIM25 in an organismal context.

Oxytocin as a novel therapeutic option for type I diabetes and diabetic osteopathy.

OBJECTIVE: The aim of the present study was to highlight the newly discovered metabolic role of oxytocin (OT) in the type I diabetic rats. Previous studies have demonstrated that OT has a beneficial role on bone physiology and therefore, the OT effect on the diabetic osteopathy will be assessed as well. METHODS: Induction of the type I diabetes was carried out by an intraperitoneal injection of 60 mg/kg body weight of streptozotocin. The metabolic role of OT on diabetic rats after OT treatment with intramuscular injection of 40 µIU/kg body weight for 6 weeks was assessed. Histological and ultrastructural studies of rat pancreas samples, before and after the OT injection, were performed and compared with the obtained physiological results. RESULTS: Oxytocin treatment had positive metabolic effects in diabetic rats. This is based on the change in glucose metabolism, lipid profile, and insulin sensitivity in experimental animals. In addition, OT treatment showed histological regenerative changes of pancreatic islet cells of diabetic rats. Moreover, OT administration showed that it has an anabolic effect on the bone biology. CONCLUSIONS: The results suggest that activation of the oxytocin receptor (OTR) pathway by infusion of OT, OT analogs, or OT agonists may represent a promising approach for the treatment of diabetes and some of its complications, including diabetic osteopathy.

Possible neuroendocrine role for oxytocin in bone remodeling.

OBJECTIVE: The present study was carried out to evaluate the assumption that oxytocin (OT) plays a neuroendocrine role in bone remodeling. For this purpose the changes in serum calcium, serum RANKL and OPG levels were detected in addition to morphological examination of the bone. METHODS: Two regimes for OT administration were used: 1. one group of rats was treated with a high OT dose of 40 microIU/kg b.w. for 6 weeks; 2. second group was treated with a low OT dose of 8 microIU/kg b.w. for a longer period of treatment (12 weeks). To evaluate the possible role of OT in bone remodeling, the changes in serum calcium, serum RANKL (sRANKL--Receptor Activator of Nuclear factor K-beta Ligand) and OPG (Osteoprotegerin) levels were detected and sRANKL/OPG ratio was calculated. To confirm the biochemical data, a histological and ultrastructural study of rat bone samples, before and after injection with oxytocin, was also performed. RESULTS: In general, the present study shows that intramuscular injection of OT at both concentrations and durations of treatment caused a significant decrease in serum calcium and sRANKL levels and a significant increase in OPG level. The sRANKL/OPG ratio was decreased as well. Morphological observations showed that both OT treatments induced a slight effect on bone remodeling in favor of bone formation. CONCLUSION: Oxytocin was found to posses a growth promoting effects on bone. The results also clearly showed that treatment with a high OT dose for a short duration was more effective than the low dose for a longer period of treatment.

Use of endoscopy in the management of postoperative ureterovaginal fistula.

The aim of the study was to evaluate endourological techniques in the management of iatrogenic ureterovaginal fistula. Seventeen patients referred to us after gynecologic surgery were diagnosed as having iatrogenic ureterovaginal fistula. First, retrograde double-J stenting was tried. If this failed, percutaneous nephrostomy using an antegrade double-J stent was performed. If this also failed, open surgical repair was performed. The retrograde double-J stent bypassed the fistula in 2 patients (11.8%). Percutaneous nephrostomy was performed in the remaining 15. The antegrade double-J stent bypassed the fistula in another 2 of these patients (11.8%). Open surgical repair was performed in the remaining 13 patients (67.5%) (direct ureteroneocystostomy) with nipple valve in 11 patients and Boari flap with psoas hitch in 2 patients). Of all patients, 2 had ureteral stricture, one after antegrade double-J stenting and the other after open repair. It was concluded that early intervention is recommended in the treatment of iatrogenic uretrovaginal fistula, causing minimal morbidity and discomfort, and being less expensive.

Long-term results of endourologic and percutaneous management of ureteral strictures in bilharzial patients.

We have managed 164 bilharzial ureteral strictures endourologically. The site was at the pelviureteral junction in 4, at the pelvic inlet in 22, juxtavesical in 78, and intramural in 60. These lesions were categorized according to the line of management. Type I or simple stricture, present in 116 cases, was managed by retrograde bougie dilation to 16F. Dilation was preceded by transurethral ureterotomy in 54 cases. Type II or difficult strictures (24 cases) were managed by percutaneous antegrade dilation. Type III or complicated strictures (24 cases) were managed by antegrade placement of a guidewire down to the bladder followed by transureteral meatotomy and bougie dilation in one sitting under C-arm fluoroscopy. Three types of stenting procedures and diversion were used according to the length of the stricture and the quality of renal function. After 6 to 72 months, an overall successful clinical outcome with decompression of the upper urinary system and improved drainage pattern was achieved in 87.8% (144 cases) v only 50% in patients with strictures longer than 2 cm. Postoperative reflux was seen in 21 cases (18%) of Type I strictures compared with 4 (17%) of Type II and 13 (54%) of Type III strictures. We concluded that this scheme of combined endourologic management for ureteral strictures is safe, simple, and less traumatic and produces excellent results. It should be the approach of choice, although it needs special equipment and operator experience. Open surgery should be restricted to the lesions that prove undilatable on both retrograde and antegrade procedures.