Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G>A

8 figuras, 2 tablasBackground Mutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation. Methodology/Principal Findings We performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal. Conclusion/Significance The use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDPThis work has been supported by grants from Ministry of Education and Science (SAF2007-61701, SAF2010-15700, SAF2011-28603), Fundación Eugenio Rodríguez Pascual, and Basque Government (Saiotek program 2008–2009). NE holds a fellowship of the JAE predoctoral program of the CSICPeer reviewe

Underlined Vulnerabilities of the Gulf Region: A New Understanding

The rift between the Gulf States that opened in 2017 has served to intensify centuries-old debates and tensions in the Middle East. The Gulf crisis has also engendered significant diplomatic tensions between GCC countries, resulting in economic sanctions, the closure of intraregional borders, and even the unleashing of new political struggles upon the region. Since the very beginning of the dispute, studies have seen the Gulf crisis as emerging out of the Arab Spring, and in particular the disagreements between GCC countries on the future of these Arab revolts

Clinical Outcomes for Patients With Gleason Score 9-10 Prostate Adenocarcinoma Treated With Radiation Therapy or Radical Prostatectomy: A Comparative Analysis

Purpose/Objective(s): To compare outcomes of patients with Gleason score (GS) 9-10 prostate adenocarcinoma (CaP) following external beam radiation therapy (EBRT), extremely dose-escalated radiation therapy (as exemplified by EBRT with a brachytherapy boost [EBRT+BT]), and radical prostatectomy (RP)

Clinical Outcomes for Patients With Gleason Score 9-10 Prostate Adenocarcinoma Treated With Radiation Therapy or Radical Prostatectomy: A Comparative Analysis

Purpose/Objective(s): To compare outcomes of patients with Gleason score (GS) 9-10 prostate adenocarcinoma (CaP) following external beam radiation therapy (EBRT), extremely dose-escalated radiation therapy (as exemplified by EBRT with a brachytherapy boost [EBRT+BT]), and radical prostatectomy (RP)

Clinical Outcomes for Patients with Gleason Score 9-10 Prostate Adenocarcinoma Treated With Radiotherapy or Radical Prostatectomy: A Multi-institutional Comparative Analysis.

BackgroundThe long natural history of prostate cancer (CaP) limits comparisons of efficacy between radical prostatectomy (RP) and external beam radiotherapy (EBRT), since patients treated years ago received treatments considered suboptimal by modern standards (particularly with regards to androgen deprivation therapy [ADT] and radiotherapy dose-escalation]. Gleason score (GS) 9-10 CaP is particularly aggressive, and clinically-relevant endpoints occur early, facilitating meaningful comparisons.ObjectiveTo compare outcomes of patients with GS 9-10 CaP following EBRT, extremely-dose escalated radiotherapy (as exemplified by EBRT+brachytherapy [EBRT+BT]), and RP.Design, setting, participantsRetrospective analysis of 487 patients with biopsy GS 9-10 CaP treated between 2000 and 2013 (230 with EBRT, 87 with EBRT+BT, and 170 with RP). Most radiotherapy patients received ADT and dose-escalated radiotherapy.Outcome measurements and statistical analysisKaplan-Meier analysis and multivariate Cox regression estimated and compared 5-yr and 10-yr rates of distant metastasis-free survival, cancer-specific survival (CSS), and overall survival (OS).Results and limitationsThe median follow-up was 4.6 yr. Local salvage and systemic salvage were performed more frequently in RP patients (49.0% and 30.1%) when compared with either EBRT patients (0.9% and 19.7%) or EBRT+BT patients (1.2% and 16.1%, p<0.0001). Five-yr and 10-yr distant metastasis-free survival rates were significantly higher with EBRT+BT (94.6% and 89.8%) than with EBRT (78.7% and 66.7%, p=0.0005) or RP (79.1% and 61.5%, p<0.0001). The 5-yr and 10-yr CSS and OS rates were similar across all three cohorts.ConclusionsRadiotherapy and RP provide equivalent CSS and OS. Extremely dose-escalated radiotherapy with ADT in particular offers improved systemic control when compared with either EBRT or RP. These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9-10 CaP.Patient summaryWhile some prostate cancers are slow-growing requiring many years, sometimes decades, of follow-up in order to compare between radiation and surgery, high-risk and very aggressive cancers follow a much shorter time course allowing such comparisons to be made and updated as treatments, especially radiation, rapidly evolve. We showed that radiation-based treatments and surgery, with contemporary standards, offer equivalent survival for patients with very aggressive cancers (defined as Gleason score 9-10). Extremely-dose escalated radiotherapy with short-course androgen deprivation therapy offered the least risk of developing metastases, and equivalent long term survival