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Activation of NK cells is triggered by combined signals from multiple activating receptors that belong to different families. Several NK cell activating receptors have been identified, but their role in the regulation of effector functions is primarily understood in the context of their individual engagement. Therefore, little is known about the signaling pathways broadly implicated by the multiple NK cell activation cues. Here we provide evidence pointing to glycogen synthase kinase (GSK)-3β as a negative regulator of multiple NK cell activating signals. Using an activation model that combines NKG2D and 2B4 and tests different signaling molecules, we found that GSK-3 undergoes inhibitory phosphorylation at regulatory serine residues by the engagement of NKG2D and 2B4, either individually or in combination. The extent of such phosphorylation was closely correlated with the degree of NK cell activation. NK cell functions, such as cytokine production and cytotoxicity, were consistently enhanced by the knockdown of GSK-3β or its inhibition with different pharmacological inhibitors, whereas inhibition of the GSK-3α isoform had no effect. In addition, NK cell function was augmented by the overexpression of a catalytically inactive form of GSK-3β. Importantly, the regulation of NK cell function by GSK-3β was common to diverse activating receptors that signal through both ITAM and non-ITAM pathways. Thus, our results suggest that GSK-3β negatively regulates NK cell activation and that modulation of GSK-3β function could be used to enhance NK cell activation. [ABSTRACT FROM AUTHOR]

The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention. [Display omitted] • Longitudinal proteogenomic analysis reveals increased neuronal state at recurrence • Neuronal transition associates with activation of WNT/PCP pathway and BRAF kinase • Resistance to therapy via neuronal transition is recapitulated in GBM PDX models • BRAF kinase inhibition impairs the neuronal transition of GBM at recurrence Kim et al. reveal that glioblastoma develops therapeutic resistance through a neuronal transition caused by changes in the WNT/PCP pathway and BRAF kinase, as shown by extensive proteogenomic analysis. Notably, inhibiting BRAF kinase disrupts this lethal transformation, offering potential therapeutic avenues. [ABSTRACT FROM AUTHOR]

Among them, 18 patients underwent totally L-PD in 2D laparoscopic setting and 25 patients underwent totally L-PD in 3D laparoscopic setting. Two patients in 2D group(11%) required conversion to open surgery because of severe pancreatitis and continuous tumor invasion of bile duct. The conversion to open PD was required in one patient with tumor invasion to the superior mesenteric vein in 3D group(4%). [Extracted from the article]

Choledochoduodenostomy(CD) or hepaticoduodenostomy(HD) was thought to increase the risk of postoperative complication such as cholangitis, pancreatitis, duodenal fistula, so-called sump syndrome, by most of surgeons. A 71-year-old-man who previously had underwent total gastrectomy with Roux-en-Y esophagojejunostomy and jejunojejunostomy due to gastric cancer 18 years ago visited our department and he presented with recurrent pyogenic cholangitis caused by common bile duct(CBD) stones. [Extracted from the article]