Revisiting G3BP1 as a RasGAP binding protein: sensitization of tumor cells to chemotherapy by the RasGAP 317-326 sequence does not involve G3BP1.

RasGAP is a multifunctional protein that controls Ras activity and that is found in chromosomal passenger complexes. It also negatively or positively regulates apoptosis depending on the extent of its cleavage by caspase-3. RasGAP has been reported to bind to G3BP1 (RasGAP SH3-domain-binding protein 1), a protein regulating mRNA stability and stress granule formation. The region of RasGAP (amino acids 317-326) thought to bind to G3BP1 corresponds exactly to the sequence within fragment N2, a caspase-3-generated fragment of RasGAP, that mediates sensitization of tumor cells to genotoxins. While assessing the contribution of G3BP1 in the anti-cancer function of a cell-permeable peptide containing the 317-326 sequence of RasGAP (TAT-RasGAP₃₁₇₋₃₂₆), we found that, in conditions where G3BP1 and RasGAP bind to known partners, no interaction between G3BP1 and RasGAP could be detected. TAT-RasGAP₃₁₇₋₃₂₆ did not modulate binding of G3BP1 to USP10, stress granule formation or c-myc mRNA levels. Finally, TAT-RasGAP₃₁₇₋₃₂₆ was able to sensitize G3BP1 knock-out cells to cisplatin-induced apoptosis. Collectively these results indicate that G3BP1 and its putative RasGAP binding region have no functional influence on each other. Importantly, our data provide arguments against G3BP1 being a genuine RasGAP-binding partner. Hence, G3BP1-mediated signaling may not involve RasGAP

Management of Pediatric Tumor Lysis Syndrome

Introduction: Tumor lysis syndrome (TLS) is a serious complication of malignancies and can result in renal failure or death. Review: In tumors with a high proliferative rate with a relatively large mass and a high sensitivity to cytotoxic agents, the initiation of therapy often results in the rapid release of intracellular anions, cations and the metabolic products of proteins and nucleic acids into the bloodstream. The increased concentrations of uric acid, phosphates, potassium and urea can overwhelm the body’s homeostatic mechanisms to process and excrete these materials and result in the clinical spectrum associated with TLS. Typical clinical sequelae include gastrointestinal disturbances, neuromuscular effects, cardiovascular complications, acute renal failure and death. Tumor lysis syndrome can also compromise the efficacy or administration of curative therapies. Available evidence suggests that the incidence of clinical TLS is approximately 3–7% for acute leukemias and 4–11% for lymphomas. Pediatric cancers are the leading cause of death by disease in children. The most common pediatric cancers include the leukemias, lymphomas, central nervous system tumors and neuroblastoma. Thus, TLS is a major concern to practitioners caring for pediatric oncology patients. Given the complexity of TLS prevention and treatment, a multidisciplinary approach involving the collaboration of medical oncologists/ hematologists and nephrologists has the greatest potential of ensuring optimal patient outcomes. Rehydration is fundamental in the management of TLS in addition to the current standard therapy for hyperuricemia which include rasburicase and allopurinol. Conclusion: The early recognition and treatment of metabolic abnormalities often prevents the severe and life-threatening complications associated with tumor lysis syndrome.Keyswords: Acute Renal Failure; Burkitt’s Lymphoma; Hematologic Malignancies; Hydration; Tumor Lysis Syndrom

Metastatic collecting duct carcinoma of the kidney treated with sunitinib

Collecting duct carcinoma (CDC) of the kidney is a rare and aggressive malignant tumor arising from the distal collecting tubules which has been shown to have a poor response to several kinds of systemic therapy. We present a case of metastatic CDC that responded favorably to a multiple tyrosine kinase inhibitor, sunitinib, achieving a partial response in both lung and skeletal metastases. To our knowledge, this is the first report showing therapeutic activity of sunitinib against CDC. Considering these findings, it would be worthwhile prospectively investigating the role of multiple tyrosine kinase inhibitors, particularly sunitinib, in the management of metastatic CDC

Abord trans-symphysaire des ruptures posttramatiques de l’urètre postérieur chez l’adulte

Objectif: Etudier la place de la voie trans-symphysaire dans le traitement des ruptures posttraumatiques de l’urètre postérieur vues tardivement et en évaluer ses résultats. Patients et méthodes: Cinq malades ayant une rupture complète post-traumatique de l’urètre postérieur (> 2,5 cm et/ou échec d’un traitement antérieur) ont été traités dans notre service au stade de sténose urétrale. Tous les patients ont eu une urétrorraphie termino-terminale par voie trans-symphysaire seule. Une description technique et une évaluation clinique et paraclinique des résultats sur le plan mictionnel et sexuel ont été réalisées dans ce travail. Résultats: Les résultats ont été évalués avec un suivi médian de 19 mois. Aucune complication post-opératoire immédiate (saignement, fistule, douleur) n’a été rapportée. Sur le plan mictionnel, on a constaté dans tous les cas une miction satisfaisante, sans troubles de la continence et un cas de dysfonction érectile améliorée par le traitement médical. Aucun patient ne s’est plaint de troubles de la statique pelvienne. Conclusion: La voie trans-symphysaire constitue un excellent abord pour le traitement des lésions complexes de l’urètre postérieur vues tardivement. Cette technique permet d’avoir un abord direct sur l’urètre postérieur et de réaliser une suture termino-terminale sans tension. Les résultats sont satisfaisants et les inconvénients sont plus théoriques que réels.Mots clés : Rupture de l’urètre postérieur, sténose de l’urètre postérieur, urétrorraphie, voie transsymphysair

Faecal occult blood screening and reduction of colorectal cancer mortality: a case-control study

To estimate the efficacy of screening on colorectal cancer mortality, a population-based case–control study was conducted in well-defined areas of Burgundy (France). Screening by faecal occult blood test prior to diagnosis in cases born between 1914 and 1943 and who died of colorectal cancer diagnosed in 1988–94 was compared with screening in controls matched with the case for age, sex and place of residence. Cases were less likely to have been screened than controls, with an odds ratio (OR) of 0.67 [95% confidence interval (CI) 0.48–0.94]. The negative overall association did not differ by gender or by anatomical location. The odds ratio of death from colorectal cancer was 0.64 (95% CI 0.46–0.91) for those screened within 3 years of case diagnosis compared with those not screened. It was 1.14 (95% CI 0.50–2.63) for those screened more than 3 years before case diagnosis. There was a negative association between the risk of death from colorectal cancer and the number of participations in the screening campaigns. The inverse association between screening for faecal occult blood and fatal colorectal cancer suggests that screening can reduce colorectal cancer mortality. This report further supports recommendations for population-based mass screening with faecal occult blood test. © 1999 Cancer Research Campaig

Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFβ signalling and EMT

Ubiquitin-dependent mechanisms have emerged as essential regulatory elements controlling cellular levels of Smads and TGFß-dependent biological outputs such as epithelial–mesenchymal transition (EMT). In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners. We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFß pathway. Interestingly, the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. In addition, WWP2-FL and WWP2-C have a preference for Smad7 based on protein turnover and ubiquitination studies. Unexpectedly, we also find that WWP2-N, which lacks the HECT ubiquitin ligase domain, can also interact with WWP2-FL in a TGFß-regulated manner and activate endogenous WWP2 ubiquitin ligase activity causing degradation of unstimulated Smad2 and Smad3. Consistent with our protein interaction data, overexpression and knockdown approaches reveal that WWP2 isoforms differentially modulate TGFß-dependent transcription and EMT. Finally, we show that selective disruption of WWP2 interactions with inhibitory Smad7 can stabilise Smad7 protein levels and prevent TGFß-induced EMT. Collectively, our data suggest that WWP2-N can stimulate WWP2-FL leading to increased activity against unstimulated Smad2 and Smad3, and that Smad7 is a preferred substrate for WWP2-FL and WWP2-C following prolonged TGFß stimulation. Significantly, this is the first report of an interdependent biological role for distinct HECT E3 ubiquitin ligase isoforms, and highlights an entirely novel regulatory paradigm that selectively limits the level of inhibitory and activating Smads

Fertility Intentions and Their Realization in Couples : How the Division of Household Chores Matters

Most research on Europe indicates that a gender-balanced division of family work tends to increase childbearing probabilities, but empirical results vary substantially. The present article proposes explanations for this observed discrepancy. It develops prior research further by (1) studying short-term fertility intentions and their realization within the subsequent 4 years, (2) analyzing the role of the spouses’ satisfaction with the division for the effects that the division may have on childbearing, (3) proving a mediation by relationship satisfaction, and (4) considering gender as well as parity as moderators. Using data from two waves of the Generations and Gender Survey, we show that the division of work affects childbearing intentions. We find that the effect (a) depends on the spouses’ satisfaction with the division, (b) is partly moderated by relationship satisfaction, and (c) varies by parity. The division of household labor, however, seems of less importance for the realization of childbearing intentions

Rare recurrence of a rare ovarian stromal tumor with luteinized cells: a case report

<p>Abstract</p> <p>Introduction</p> <p>Sex cord-stromal tumors of the ovary are uncommon. They behave unpredictably and often have a late recurrence, making counseling, management, and prediction of prognosis challenging.</p> <p>Case presentation</p> <p>A 52-year-old Moroccan woman with an sex cord-stromal tumors underwent a bilateral oophorectomy. The histology was unusual but was likely to be a luteinized thecoma with suspicious features for invasion. Seven years later, after a gastrointestinal bleed, a metastasis within the small bowel mucosa was detected. This represents probable isolated hematogenous or lymphatic spread, which is highly unusual, especially in the absence of concurrent peritoneal disease.</p> <p>Conclusions</p> <p>To the best of our knowledge, this is the second reported case of an sex cord-stromal tumors recurring in small bowel mucosa and mimicking a primary colorectal tumor. This highlights the diverse nature and behavior of these tumors.</p