Mdm2 promotes Cdc25C protein degradation and delays cell cycle progression through the G2/M phase.

Upon different types of stress, the gene encoding the mitosis-promoting phosphatase Cdc25C is transcriptionally repressed by p53, contributing to p53's enforcement of a G2 cell cycle arrest. In addition, Cdc25C protein stability is also decreased following DNA damage. Mdm2, another p53 target gene, encodes a ubiquitin ligase that negatively regulates p53 levels by ubiquitination. Ablation of Mdm2 by siRNA led to an increase in p53 protein and repression of Cdc25C gene expression. However, Cdc25C protein levels were actually increased following Mdm2 depletion. Mdm2 is shown to negatively regulate Cdc25C protein levels by reducing its half-life independently of the presence of p53. Further, Mdm2 physically interacts with Cdc25C and promotes its degradation through the proteasome in a ubiquitin-independent manner. Either Mdm2 overexpression or Cdc25C downregulation delays cell cycle progression through the G2/M phase. Thus, the repression of the Cdc25C promoter by p53, together with p53-dependent induction of Mdm2 and subsequent degradation of Cdc25C, could provide a dual mechanism by which p53 can enforce and maintain a G2/M cell cycle arrest.

Identification of a novel class of genomic DNA-binding sites suggests a mechanism for selectivity in target gene activation by the tumor suppressor protein p53.

There are two response elements for p53 in the promoter of the gene for the cyclin-dependent kinase inhibitor p21. The binding of p53 to the 5' site was enhanced by incubation with monoclonal antibody 421, whereas the binding of p53 to the 3' site was inhibited. Mutational analysis showed that a single-base change caused one element to behave like the other. A response element in the human cdc25C promoter is bound by p53 with properties similar to the 3' site. These results identify two classes of p53-binding sites and suggest a mechanism for target gene selectivity by p53.

Pelvic lymphadenectomy can be omitted in selected patients with carcinoma of the prostate: development of a system of patient selection.

OBJECTIVES: The prevalence of pelvic lymph node metastases in men with clinically localized prostate cancer has decreased dramatically over the past decade, possibly due to efforts at early detection. With a significantly lower incidence of pelvic node involvement, it may be possible to identify a segment of patients for whom pelvic lymph node dissection (PLND) may be omitted. This study was conducted to develop a method to select patients for whom PLND could be omitted. METHODS: We analyzed serum prostate-specific antigen (PSA), clinical stage, biopsy Gleason score, and final pathologic stage in 481 men with clinically localized prostate cancer. These variables were compared to the risk of positive pelvic lymph nodes. RESULTS: Logistic regression analysis determined that combining all three variables provided the best determination of final pathologic stage. A series of probability curves have been created to estimate the risk of positive lymph nodes in a given patient. Based on the distribution of patients in this study and using these probability functions, PLND could be avoided in up to 50% of patients with localized prostate cancer diagnosed by contemporary methods. CONCLUSIONS: In properly selected patients, pelvic lymphadenectomy can be omitted in the staging and treatment of localized prostate cancer.

Functional characteristics of enterocystoplasty after interruption of the mesenteric blood supply.

Previous studies have suggested that small (5 to 7 cm.) enteral patches used for bladder augmentation could remain viable following ligation of the mesenteric vascular pedicle. We performed subtotal cystectomy and ileocystoplasty in 5 female mongrel dogs using a 25 cm. segment of detubularized ileum. Functional bladder capacity, compliance and size of the bowel segment were measured 4 months later, and the mesenteric blood supply was interrupted. Immediately after pedicle ligation all patches appeared dusky and had diminished or absent Doppler pulsations with poor fluorescein uptake. However, all animals had an uneventful postoperative course without any signs of urine leak or peritonitis. Urodynamic studies were performed 2 months later and the animals were re-explored with removal of the augmented bladder for histological examination. All of the bowel segments were viable on exploration at that time but a decrease in patch size was noted ranging from 9 to 63%. Functional bladder capacity was also decreased in 4 animals. Although the integrity of augmentation was maintained in all animals, changes in bladder capacity and size of the enteral segment occurred in the majority after interruption of the mesenteric blood supply. These changes could possibly negate the clinical benefits that had been achieved by the bladder augmentation. This finding would suggest the need to consider revision of the enterocystoplasty in the event of inadvertent ligation of the vascular pedicle.

Viability and functional characteristics of enterocystoplasty after ligation of the vascular pedicle.

A canine model was developed to evaluate the effect of ligation of the mesenteric blood supply of enterocystoplasty. In 5 dogs with an ileocystoplasty and 6 with a gastrocystoplasty the blood supply was interrupted 4 months postoperatively. Re-exploration 2 to 8 weeks later revealed sufficient collateral blood flow to maintain integrity of the bowel wall and none of the animals had urine leak or other signs of perforation. Two animals had a significant decrease in the size of the cystoplasty. Intraoperative measurements of bowel viability after pedicle ligation were not predictive of the outcome. The functional outcome after pedicle division seems to be variable and probably reflects how well the patch has been vascularized before interruption of the blood supply. The augmented bladder may remain viable if sufficient time has elapsed to allow revascularization of the intestinal segment before its mesenteric blood supply is divided.

Current management of choroid plexus carcinoma in children.

Eleven children with choroid plexus carcinoma are reviewed with respect to presentation, radiographic diagnosis, treatment and pathologic histology. These cases accumulated over a 33-year period and represent 39% of all of our choroid plexus tumors (n = 28). Characteristically, choroid plexus carcinomas are associated with a poor prognosis for long-term survival. Unfortunately, efforts at total resection are hindered in part by the extreme vascularity of the tumor which itself may be of considerable volume. We have recently treated four children who had biopsy or minimal resection of their tumor after which adjuvant chemotherapy was given. Chemotherapy is not curative but it does cause a reduction in tumor volume and, more importantly, has tended to reduce the tumor vascularity. This allows for a second stage operation which is more safely performed and typically allows for more complete tumor removal. At this point, our length of follow-up is insufficient to conclude if total removal in this manner significantly increases survival but it would seem that consistent gross total removal may be an initial step toward better overall management and prognosis in this tumor type.