216 research outputs found
HALON-hysterectomy by transabdominal laparoscopy or natural orifice transluminal endoscopic surgery : a randomised controlled trial (study protocol)
Acknowledgments The authors acknowledge the NOTES Investigators' team for taking care of the study participants; and Amanda McPhail for language correction and editing of the manuscript.Peer reviewedPublisher PD
Transvaginal natural orifice transluminal endoscopic surgery (vNOTES) adnexectomy for benign pathology compared with laparoscopic excision (NOTABLE) : A protocol for a randomised controlled trial
M1 - 018059 Acknowledgments We thank the vNOTES investigators’ team for taking care of the study participants. We also thank Amanda McPhail for language correction and editing of the manuscript.Peer reviewedPublisher PD
RAB8, RAB10 and RILPL1 contribute to both LRRK2 kinase-mediated centrosomal cohesion and ciliogenesis deficits
Mutations in the LRRK2 kinase are the most common cause of familial Parkinson's disease, and variants increase risk for the sporadic form of the disease. LRRK2 phosphorylates multiple RAB GTPases including RAB8A and RAB10. Phosphorylated RAB10 is recruited to centrosome-localized RILPL1, which may interfere with ciliogenesis in a disease-relevant context. Our previous studies indicate that the centrosomal accumulation of phosphorylated RAB8A causes centrosomal cohesion deficits in dividing cells, including in peripheral patient-derived cells. Here, we show that both RAB8 and RAB10 contribute to the centrosomal cohesion deficits. Pathogenic LRRK2 causes the centrosomal accumulation not only of phosho-RAB8 but also of phospho-RAB10, and the effects on centrosomal cohesion are dependent on RAB8, RAB10 and RILPL1. Conversely, the pathogenic LRRK2-mediated ciliogenesis defects correlate with the centrosomal accumulation of both phospho-RAB8 and phospho-RAB10. LRRK2-mediated centrosomal cohesion and ciliogenesis alterations are observed in patient-derived peripheral cells, as well as in primary astrocytes from mutant LRRK2 mice, and are reverted upon LRRK2 kinase inhibition. These data suggest that the LRRK2-mediated centrosomal cohesion and ciliogenesis defects are distinct cellular readouts of the same underlying phospho-RAB8/RAB10/RILPL1 nexus and highlight the possibility that either centrosomal cohesion and/or ciliogenesis alterations may serve as cellular biomarkers for LRRK2-related PD
Adnexectomy by vaginal Natural Orifice Transluminal Endoscopic Surgery versus laparoscopy : results of a first randomised controlled trial (NOTABLE trial)
Peer reviewedPostprin
PAK6 Phosphorylates 14-3-3 gamma to Regulate Steady State Phosphorylation of LRRK2
Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson’s
disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for
age-related neurodegeneration. Although the cellular functions of LRRK2 in health and
disease are incompletely understood, robust evidence indicates that PD-associated
mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of
the downstream signaling pathways. We have previously demonstrated that one LRRK2
binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the
PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase
dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and
this phosphorylation serves as a switch to dissociate the chaperone from client proteins
including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ
phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935,
causing LRRK2 dephosphorylation. To address whether these interactions are relevant in
a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the
G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our
results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism
of 14-3-3/LRRK2 complex in the brain
Biotechnology for Tomorrow's World:Scenarios to Guide Directions for Future Innovation
Depending on how the future will unfold, today's progress in biotechnology research has greater or lesser potential to be the basis of subsequent innovation. Tracking progress against indicators for different future scenarios will help to focus, emphasize, or de-emphasize discovery research in a timely manner and to maximize the chance for successful innovation. In this paper, we show how learning scenarios with a 2050 time horizon help to recognize the implications of political and societal developments on the innovation potential of ongoing biotechnological research. We also propose a model to further increase open innovation between academia and the biotechnology value chain to help fundamental research explore discovery fields that have a greater chance to be valuable for applied research
Reduced expression of BAX is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, BAX and BCL-2
Traditional clinicopathological features do not predict which patients will develop chemotherapy resistance. The TP53 gene is frequently altered in ovarian cancer but its prognostic implications are controversial. Little is known on the impact of TP53-downstream genes on prognosis. Using molecular and immunohistochemical analyses we examined TP53 and its downstream genes p21 BAX and BCL-2 in ovarian tumour tissues and have evaluated the results in relation to clinico-pathological parameters, clinical outcome and response to platinum-based chemotherapy. Associations of tested factors and patient and tumour characteristics were studied by Spearman rank correlation and Pearsons χ2 test. The Cox proportional hazard model was used for univariate and multivariate analysis. The associations of tested factors with response was tested using logistic regression analysis. TP53 mutation, p21 and BCL-2 expression were not associated with increased rates of progression and death. Expression of TP53 was associated with a shorter overall survival only (relative hazard rate [RHR] 2.01 P = 0.03). Interestingly, when combining TP53 mutation and expression data, this resulted in an increased association with overall survival (P = 0.008). BAX expression was found to be associated with both progression-free (RHR 0.44 P = 0.05) and overall survival (RHR 0.42 P = 0.03). Those patients who simultaneously expressed BAX and BCL-2 had a longer progression-free and overall survival compared to patients whose tumours did not express BCL-2 (P = 0.05 and 0.015 respectively). No relations were observed between tested factors and response to platinum-based chemotherapy. We conclude that BAX expression may represent a prognostic indicator for patients with ovarian cancer and that the combined evaluation of BAX and BCL-2 may provide additional prognostic significance. http://www.bjcancer.com © 2001 Cancer Research Campaig
Local Overexpression of Interleukin-11 in the Central Nervous System Limits Demyelination and Enhances Remyelination
Evaluation of clinical significance of TP53, BCL-2, BAX and MEK1 expression in 229 ovarian carcinomas treated with platinum-based regimen
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