Identification of PP2A and S6 Kinase as Modifiers of Leucine-Rich Repeat Kinase-Induced Neurotoxicity.

Mutations in LRRK2 are currently recognized as the most common monogenetic cause of Parkinsonism. The elevation of kinase activity of LRRK2 that frequently accompanies its mutations is widely thought to contribute to its toxicity. Accordingly, many groups have developed LRRK2-specific kinase inhibitors as a potential therapeutic strategy. Given that protein phosphorylation is a reversible event, we sought to elucidate the phosphatase(s) that can reverse LRRK2-mediated phosphorylation, with the view that targeting this phosphatase(s) may similarly be beneficial. Using an unbiased RNAi phosphatase screen conducted in a Drosophila LRRK2 model, we identified PP2A as a genetic modulator of LRRK2-induced neurotoxicity. Further, we also identified ribosomal S6 kinase (S6K), a target of PP2A, as a novel regulator of LRRK2 function. Finally, we showed that modulation of PP2A or S6K activities ameliorates LRRK2-associated disease phenotype in Drosophila.

Diffusion kurtosis imaging differs between primary central nervous system lymphoma and high-grade glioma and is correlated with the diverse nuclear-to-cytoplasmic ratio: a histopathologic, biopsy-based study.

OBJECTIVES: To determine whether water kurtosis and diffusional metrics derived from diffusional kurtosis imaging (DKI) within primary central nervous system lymphomas (PCNSLs) and high-grade gliomas (HGGs) correlate with cellularity and/or nuclear-to-cytoplasmic (N/C) ratio. METHODS: Forty-four and 43 pathologically confirmed high-grade glioma and primary central nervous system lymphoma specimens between May 2013 and November 2016 were retrospectively reviewed. Diffusional metrics, kurtosis metrics, cellularity, and N/C ratios in PCNSLs and HGGs were compared using the Mann-Whitney U test (significant level, p < 0.007 [0.05/7]); Bonferroni correction). RESULTS: Mean kurtosis (MK), axial kurtosis (K//), and radial kurtosis (K⊥) in PCNSLs were 0.857 (0.693-0.924), 0.837 (0.660-0.941), and 0.834 (0.685-0.937), respectively; and 0.629 (0.524-0.716), 0.575 (0.511-0.689), and 0.675 (0.532-0.766), respectively, in HGGs (all p < 0.001). No significant differences in fractional anisotropy (FA), mean diffusion (MD), axial diffusion (λ//), and radial diffusion (λ⊥) were found between HGGs and PCNSLs. Cellularity was higher in PCNSLs than in HGGs (p = 0.125); whereas, the N/C ratio in PCNSLs was significantly higher than that in HGGs (p < 0.001). All DKI metrics (FA, MD, λ//, λ⊥, MK, K//, and K⊥) were significantly correlated with N/C ratio in PCNSLs with correlation coefficients being rho = 0.418, - 0.722, - 0.525, - 0.768, 0.704, 0.579, and 0.686, respectively. Cellularity in PCNSLs and HGGs did not correlate with any kurtosis or diffusional metrics. CONCLUSIONS: Difference of kurtosis parameters between PCNSLs and HGGs is correlated with their diverse N/C ratio. KEY POINTS: • DKI has considerable value in differentiating between PCNSLs and HGGs. • DKI can provide important information on nuclear-to-cytoplasmic ratio. • Difference of kurtosis parameters between PCNSLs and HGGs correlated well with their diverse N/C ratios.

Portal 125I seed stent implantation combined with drug-loaded microsphere embolization for the treatment of HCC: initial results in 7 patients / 介入放射学杂志

Objective To investigate the feasibility and safety of portal 125I seed stent implantation combined with doxorubicin-eluting beads transcatheter arterial chemoembolization (DEB-TACE) for the treatment of hepatocellular carcinoma (HCC) associated with main portal vein tumor thrombus (MPVTF).Methods Prospective single-arm study was designed.Seven HCC patients with MPVTT were sequentially enrolled in this study to receive treatment.Portal pressure before and after portal vein stent implantation were determined,the liver function were tested before and 1-3 days,4 days,5-7 days after portal vein stent implantation,the results and the postoperative complications were analyzed.Results All 7 patients were in BCLC-C stage,with Child-Pugh classification being A-B level.All patients were diagnosed as massive type HCC complicated by portal vein tumor thrombus.The lesions were located in hepatic left lobe (n=l) and hepatic right lobe (n=6),tumor thrombus in left branch of portal vein was seen in one patient and tumor thrombus in right branch of portal vein was found in 6 patients,MPVTT was observed in all 7 patients.Portal 125I seed stent implantation plus DEB-TACE was successfully accomplished in all 7 patients.The portal pressure before and after stent implantation was 15.3 cmH2O and 10.2 cmH2O respectively,the postoperative pressure showed an obvious reduction.After stent implantation,a transient elevation of the serum total bilirubin (TB),alanine aminotransferase (ALT) and aspartate aminotransferase (AST) could be observed,which gradually decreased in 3-4 days;the recovery of TB level was slower than that of ALT and AST levels.Two patients had concomitant myocardial damage,which was gradually recovered in 2-3 days.Conclusion For the treatment of HCC associated with MPVTT,portal 125I seed stent implantation plus DEB-TACE is safe and feasible,although its long-term curative effect needs to be further clarified.

Preliminary application of 3D printing coplanar template in treating pancreatic cancer with 125I seed implantation / 介入放射学杂志

Objective To investigate the clinical application value of 3D printing coplanar template in treating pancreatic cancer with 125I seed implantation.Methods Clinical data of 10 patients with pancreatic cancer,who received 3D printing coplanar template-guided 125I seed implantation during the period from January 2016 to June 2017,were retrospectively analyzed.According to preoperative CT scan results and treatment planning system findings,a 3D coplanar template was designed and printed,guided by which percutaneous puncture and 125I seed implantation were conducted.Dosimetric verification was performed after 125I seed implantation.Both preoperative and postoperative 90％ dose of target volume (D90),90％ target volume of prescription dose (V90),100％ target volume of prescription dose (V100) and 150％ target volume of prescription dose (V150) were calculated.The success rate of puncture location of 3D printing coplanar template-guided 125I seed implantation was calculated.The coincidence between preoperative dosimetric plan and postoperative dosimetric parameter was assessed,and the complications were recorded.Results Under the guidance of 3D coplanar template,percutaneous puncture and 125I seed implantation were successfully accomplished in all 10 patients with pancreatic cancer.The postoperative dosimetric parameter D90 was consistent with preoperative planning.No statistically significant difference in D90 existed between preoperative value and postoperative one (P＞0.05).The postoperative V90,V100 and V150 were (94.3±2.4)％,(90.4±4.1)％ and (62.1±13.4)％ respectively,which were compliance with therapeutic dosimetry requirements.Local hematoma occurred in one patient after the treatment.Conclusion 3D printing coplanar template appears to be a safe and effective guiding tool,it is very helpful for precise implantation of 125I seeds in treating pancreatic cancer,and with the help of 3D printing coplanar template the postoperative dose parameters will be able to meet the preoperative planning requirements.