3 Year outcome after treatment of uterovaginal prolapse with a 6-point fixation mesh.

INTRODUCTION: The aim of this study was to describe the intermediate outcome of a single-incision 6-point fixation transvaginal mesh for the treatment of primary and recurrent pelvic organ prolapse (POP). STUDY DESIGN: This was a prospective cohort study including consecutive patients undergoing POP repair with the InGYNious anterior transvaginal mesh. Inclusion criteria were women with symptomatic stage II POP or higher. Exclusion criteria were the unwillingness or inability to give written informed consent, malignant diseases, neuro-muscular disorders, chronic pain syndrome or previous radiation in the pelvis. Every study participant completed a structured questionnaire, a urogynecological examination according to the IUGA-ICS POP-Q staging system and the validated P-QoL questionnaire before the operation and three years postoperatively. RESULTS: 254 patients were included into the study, 179 were available for the three-year follow-up (70 %). Sixteen patients (8.2 %) had undergone reoperation for recurrent or de novo prolapse (12/16 patients underwent reoperation in the posterior compartment) and were excluded from the objective outcome analysis. In the final study group, all POP-Q measurements, urge urinary incontinence and voiding dysfunction were significantly improved. The de novo SUI rate was 27/ 120 (23 %) in women without reoperation for SUI and/ or POP and without primary SUI. No serious adverse events occurred. Four (1.5 %) patients had mesh exposure at the one-year follow-up and been treated with local oestrogen. At three-year follow-up, no new mesh exposure was seen. De novo dyspareunia rate was low (n = 5 (3 %)). CONCLUSIONS: In this study, the objective outcome three years after anterior POP repair with the InGYNious transvaginal mesh was good. The reoperation rate both for mesh related problems or prolapse were rare.

NMDA Receptor-Mediated Signaling Pathways Enhance Radiation Resistance, Survival and Migration in Glioblastoma Cells-A Potential Target for Adjuvant Radiotherapy.

Glioblastoma is one of the most aggressive malignant brain tumors, with a survival time less than 15 months and characterized by a high radioresistance and the property of infiltrating the brain. Recent data indicate that the malignancy of glioblastomas depends on glutamatergic signaling via ionotropic glutamate receptors. In this study we revealed functional expression of Ca2+-permeable NMDARs in three glioblastoma cell lines. Therefore, we investigated the impact of this receptor on cell survival, migration and DNA double-strand break (DSB) repair in the presence of both, glutamate and NMDAR antagonists, and after clinically relevant doses of ionizing radiation. Our results indicate that treatment with NMDAR antagonists slowed the growth and migration of glutamate-releasing LN229 cells, suggesting that activation of NMDARs facilitate tumor expansion. Furthermore, we found that DSB-repair upon radiation was more effective in the presence of glutamate. In contrast, antagonizing the NMDAR or the Ca2+-dependent transcription factor CREB impaired DSB-repair similarly and resulted in a radiosensitizing effect in LN229 and U-87MG cells, indicating a common link between NMDAR signaling and CREB activity in glioblastoma. Since the FDA-approved NMDAR antagonists memantine and ifenprodil showed differential radiosensitizing effects, these compounds may constitute novel optimizations for therapeutic interventions in glioblastoma.

1-year outcome after treatment of uterovaginal prolapse with a 6-point fixation mesh.

INTRODUCTION: The aim of this study was to describe the safety and anatomical results of a surgical approach with a single-incision 6-point fixation vaginal mesh for the treatment of pelvic organ prolapse at perioperatively and at 1-year follow-up. MATERIALS AND METHODS: This was a prospective observational study of patients who underwent operation receiving an InGYNious anterior transvaginal mesh. All patients with symptomatic stage II prolapse or higher were included in the study. Exclusion criteria were the unwillingness or inability to give written informed consent, neuromuscular disorders, malignant diseases, previous radiation in the pelvis, or chronic pain syndrome. Every patient completed a structured questionnaire and a full physical examination according to the IUGA-ICS POP-Q staging system before the operation and at 1-year follow-up. RESULTS: Two hundred fifty-four patients (91%) were included in the study. The intraoperative complication rate was 7% with hemorrhage being the most common complication. Six patients (2.4%) had undergone reoperation for prolapse (four out of the six patients had reoperation in the posterior compartment) and were excluded from the objective outcome analysis. In the remaining 248 patients all POP-Q measurements were significantly improved in the anterior and apical compartments. Similarly, urge urinary incontinence and voiding dysfunction improved significantly. CONCLUSIONS: In this series, the objective outcome one year after the InGYNious mesh was good with low numbers of mesh-related problems or reoperation for prolapse.

NMDA Receptor Signaling Mediates cFos Expression via Top2ß-Induced DSBs in Glioblastoma Cells.

The activation of Ca2+-permeable N-methyl-D-aspartic acid (NMDA) receptor channels (NMDARs) is crucial for the development and survival of neurons, but many cancers use NMDAR-mediated signaling as well, enhancing the growth and invasiveness of tumors. Thus, NMDAR-dependent pathways emerge as a promising target in cancer therapy. Here, we use the LN229 and U-87MG glioblastoma multiforme (GBM) cells and immunofluorescence staining of 53BP1 to analyze NMDAR-induced DNA double-strand breaks (DSBs), which represent an important step in the NMDAR signaling pathway in neurons by facilitating the expression of early response genes. Our results show that NMDAR activation leads to the induction of DSBs in a subpopulation of glioma cells. In a further analogy to neurons, our results demonstrate that the induction of DSBs in LN229 cells is dependent on the activity of topoisomerase IIß (Top2ß). Western blot analysis revealed that the inhibition of NMDARs, cAMP-responsive element binding transcription factor (CREB) and Top2ß decreased the expression of the proto-oncogene cFos. Knockdown of Top2ß with siRNAs resulted in a downregulation of cFos and increased the radiosensitivity of LN229 cells in clonogenic survival. We also observed impaired cFos expression upon NMDAR and Top2ß inhibition in a primary GBM cell line, suggesting that NMDAR signaling may be widely used by GBMs, demonstrating the potential of targeting NMDAR signaling proteins for GBM therapy.