Molecular characteristics of immunocytes infiltration in primary central nervous system lymphoma.

Background: Primary central nervous system lymphoma (PCNSL) is a rare B-cell lymphoma of central nervous system, which is often found in immunocompromised patients. The common clinical treatment of PCNSL is methotrexate (MTX) and whole brain radiation therapy. With the development of tumour immunology research, the tumour microenvironment of PCNSL is characterised by abnormal expression of different immune signature molecules and patients with PCNSL may benefit from tumour immunotherapy. Methods: In our research, RNA-seq data from 82 PCNSL patients were collated by mining the microarray data from the GEO database. All samples were classified into three types related to tumour immune response by the Cibersort algorithm and consistent clustering. Differential analysis of genes was used to uncover 2 sets of differential genes associated with tumour immunity. The ICI scores of each sample were obtained by PCA algorithm, and the relationship between ICI scores and immune checkpoint expression, immunotherapy and drug sensitivity was investigated. Genes associated with ICI scores and their functional characteristics were investigated by WGCNA analysis and PPI analysis, based on the ICI scores of each sample. Results: The tumour microenvironment in PCNSL has a greater relationship with the tumour immune response. ICI scores obtained from 375 differential genes were associated with multiple immune responses in PCNSL. PCNSL patients with higher ICI scores had a better tumour microenvironment and were sensitive to immunotherapy and some small molecule drug. This study also identified 64 genes associated with ICI scores, which may serve as important therapeutic and prognostic targets for PCNSL. Conclusion: The presence of multiple immunosuppressive responses in the tumour microenvironment of PCNSL which suggested that improving the immune function of PCNSL patients through immunotherapy and targeted therapies can be an effective treatment for PCNSL. And the ICI score and associated genes may also provide a better predictor of the clinical use of immunotherapy.

The influence of periampullary diverticula on ERCP for treatment of common bile duct stones.

In order to evaluate the effectiveness of various methods we applied to decrease the influence of periampullary diverticula (PAD) on the success rate and complications of endoscopic retrograde cholangiopancreatography (ERCP) in the treatment of common bile duct (CBD) stones, we enrolled patients with CBD stones who had been treated by ERCP in our hospital between January 2015 and December 2018. According to the presence of PAD, the patients were divided into a PAD group and a non-PAD group. The rate of complete stone removal in the first session, the rate of overall stone removal, the frequency of application of mechanical lithotripsy, and procedure-related complications, including bleeding, hyperamylasemia, pancreatitis, perforation, and infection of biliary tract were recorded. A total of 183 cases, including 72 cases in the PAD group and 111 cases in the non-PAD group were enrolled. There was no statistical difference between the two groups regarding gender (P = 0.354). However, regarding age, there was a statistical difference (P = 0.002), and the incidence of PAD increased with age. There were 5 (6.9%) cases in the PAD group and 14 (12.6%) cases in the non-PAD group where mechanical lithotripsy was applied. There were 59 (81.9%) cases in the PAD group and 102 (91.9%) cases in the non-PAD group where there was complete removal of CBD stones in the first session, and there were 68 (94.4%) cases in the PAD group and 107 (96.4%) cases in the non-PAD group where there was complete removal of all stones. In the PAD group, there were 0 cases (0%) with gastrointestinal bleeding, 0 cases (0%) with gastrointestinal perforation, 13 cases (18.1%) with post-ERCP hyperamylasemia, 3 cases (4.2%) with post-ERCP pancreatitis, and 4 cases (5.6%) with biliary tract infection. In the non-PAD group, 1 case (0.9%) had gastrointestinal bleeding, 0 cases had gastrointestinal perforation, 18 cases (16.2%) had post-ERCP hyperamylasemia, 5 cases (4.5%) had post-ERCP pancreatitis, and 11 cases (9.9%) had biliary tract infection. This retrospective study showed that there was a statistical difference between the two groups regarding complete removal of CBD stones in the first session and application of mechanical lithotripsy (both P < 0.05), but no statistical difference according to the rates of overall stone removal and the complications (P > 0.05), which means that we can reduce the influence of PAD on ERCP for treatment of common bile duct stones.

LncRNA MEG3 contributes to drug resistance in acute myeloid leukemia by positively regulating ALG9 through sponging miR-155.

INTRODUCTION: The development of drug resistance is the main obstacle for successful treatment in acute myeloid leukemia (AML). Noncoding RNAs have been implicated in biological function in AML drug resistance. Aberrant protein glycosylation is associated with AML progression. The aim of the study was to explore the potential regulatory mechanism of lncRNA MEG3/miR-155/ALG9 axis in drug resistance of AML. METHODS: QRT-PCR and Western blot were used for comparison analyses of ALG9, MEG3, and miR-155 levels. CCK-8 and colony formation assays were determined for drug sensitivity and proliferative capability of AML cells. Luciferase reporter assay was used to confirm the targets of miR-155. RESULTS: The mannosyltransferase ALG9 and MEG3 was downregulated in peripheral blood mononuclear cells (PBMCs) of M5/multidrug resistance (MDR) AML patients and adriamycin (ADR)-resistant AML cell lines, which determined a positive correlation in AML patients. Low expression of ALG9 and MEG3 predicted poor prognosis of AML patients. The altered level of ALG9 was found corresponding to the drug-resistant phenotype and sphere formation of AML cells. MiR-155 was overexpressed in M5/MDR patients and ADR-resistant AML cells, as well as inversely correlated to ALG9 expression. MEG3 was a direct target of miR-155 and could sponge miR-155 in AML cells. MEG3 interacted with miR-155 to regulate ALG9 expression, which reversed the effects of ALG9 regulation on proliferation and drug resistance in AML cells. CONCLUSION: MEG3 sponged miR-155 by competing endogenous RNA (ceRNA) mechanism, which further modulated ALG9 expression and AML procession, providing a novel therapeutic target for AML chemoresistance.

Whole exome sequencing identified a new compound heterozygous PRKN mutation in a Chinese family with early-onset Parkinson's disease.

Early-onset Parkinson's disease (EOPD) is usually caused by genetic variants and patients with EOPD develop symptoms before the age of 50, accounting for 5% Parkinson's disease (PD). Here we present a Chinese Han pedigree with clinical features of EOPD. To determine the diagnosis and pathogenic mutations of this pedigree, whole exome sequencing, Sanger sequencing and real-time quantitative PCR were performed to detect all the four family members. Our results showed that a new form of compound heterozygous mutation in the PRKN gene, consisting of heterozygous point mutation c.850G > C (p.G284R) along with exon 4 deletion, is the causative genetic factor for EOPD in this pedigree. These discoveries may have implications for genetic counseling, clinical management and developing PRKN target gene therapy strategy.

Three-hour post-ERCP amylase level: a useful indicator for early prediction of post-ERCP pancreatitis.

BACKGROUND: To evaluate the value of the 3-h post-ERCP serum amylase level for early prediction of post-ERCP pancreatitis (PEP). METHOD: A study of 206 patients performed ERCP (Encoscopic Retrograde Cholangio-Pancreatography) at a single centre was done from Jan. 2011 to Nov. 2016. The serum amylase or lipase level was measured at 3 h after ERCP. The patients with PEP were recorded. ROC curves were used to statistically analyze the data: The enrolled patients were divided into two groups according to gender, then we analyzed the data respectively. We comprehensively evaluated the predictive value of PEP by 3-h post-ERCP serum amylase level based on the results above. RESULTS: Two hundred six patients (92 males, 114 females) were enrolled. PEP occurred in 21 patients (10.19%) among them. The median time to discharge was 7 days (min = 1d, max = 13d) after the procedure. In the 206 patients, the 3-h post-ERCP pancreatic amylase level was used as the test variable, and the PEP occurrence as the state variable to plot the ROC curve. The area under the curve (AUC) was 0.816, and was statistically significant (P < 0.001). The standard error (SE) was 0.0507, the 95% confidence interval (CI) was 0.756-0.866, and the optimal cut-off value was 351 U/L (sensitivity 76.19%, specificity 83.24%, positive likelihood ratio 4.55, negative likelihood ratio 0.29, Youden index 59.43%). Of the 206 patients, there were 83 patients with both 3-h post-ERCP amylase level and lipase level detected, and the ROC curves were plotted for both serum amylase and lipase respectively. The ROC curve matched-pair testing was carried out: The areas under the ROC curves were statistically significant. (P < 0.001) The area under the ROC curve for the 3-h post-ERCP lipase was 0.778, the 95% confidence interval was 0.673-0.862, and optimal cut-off value was 1834 U/L. The area under the ROC curve for the 3-h post-ERCP serum amylase was 0.780, and the 95% confidence interval was 0.676-0.864. The optimal cut-off is 380 U/L, and there was no statistically significant difference between the two for diagnostic accuracy. According to gender, 206 patients were divided into 2 groups, and the ROC curves were drawn respectively. Based on statistical analysis, there was no statistically significant difference in the diagnostic accuracy of the two groups. In the male group, 436 U/L serum amylase provided the greatest diagnostic accuracy with sensitivity (SE) of 70.5%, specificity (SP) of 89.2%, positive predictive value (PPV) 87.5%, and negative predictive value (NPV) 78.1%. Whereas, in the female group, 357 U/L serum amylase provided the greatest diagnostic accuracy with sensitivity of 76.9%, specificity of 81.2%, positive predictive value of 80.4%, negative predictive value of 77.9%. CONCLUSIONS: 1. The 3-h post-ERCP serum amylase level is a useful measurement for predicting post-ERCP pancreatitis. 2. There was no significant difference between serum amylase and lipase 3-h post-ERCP for predicting PEP. 3. There was no statistically significant difference between male and female using the 3-h post-ERCP serum amylase level to predict PEP. For female, the optimal cut-off value was 357 U/L, whereas male 436 U/L .

Roles of VMP1 in Autophagy and ER-Membrane Contact: Potential Implications in Neurodegenerative Disorders.

Cellular communication processes are highly dynamic and mediated, at least in part, by contacts between various membrane structures. The endoplasmic reticulum (ER), the major biosynthetic organelle of the cell, establishes an extensive network with other membrane structures to regulate the transport of intracellular molecules. Vacuole membrane protein 1 (VMP1), an ER-localized metazoan-specific protein, plays important roles in the formation of autophagosomes and communication between the ER and other organelles, including mitochondria, autophagosome precursor membranes, Golgi, lipid droplets, and endosomes. Increasing evidence has indicated that autophagy and ER-membrane communication at membrane contact sites are closely related to neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. In this review, we summarize the roles of VMP1 in autophagy and ER-membrane contacts and discuss their potential implications in neurodegenerative disorders.

Piperine attenuates cognitive impairment in an experimental mouse model of sporadic Alzheimer's disease.

Piperine, the major alkaloid constituent of black pepper, has been reported to possess a wide range of pharmacological effects on the central nervous system, including antidepressant, anticonvulsant and anti-ischemic activities. In the present study, we aimed to investigate the therapeutic potential and neuroprotective mechanisms of piperine in an experimental mouse model of sporadic Alzheimer's disease (sAD) induced by intracerebroventricular (ICV) infusion of streptozotocin (STZ). STZ was infused bilaterally at a dose of 1.5 mg/kg/day on day 1 and day 3. From day 8, piperine (2.5-10 mg/kg body weight) was administered intraperitoneally once daily for 15 consecutive days. The locomotor activity and cognitive performance of mice were evaluated using open field test and Morris water maze test, respectively. On day 23, all animals were sacrificed, and the hippocampus was used for biochemical, neurochemical and neuroinflammatory determinations. Our data revealed that the ICV-STZ-infused sAD mouse showed an increased oxidative-nitrosative stress, an altered neurotransmission and an elevated neuroinflammation in hippocampus, as well as significant cognitive deficits. All these alterations can be ameliorated by piperine in a dose-dependent manner. In summary, our findings predict a therapeutic potential of piperine against cognitive deficits in sAD mouse. This effect might be due to its abilities to ameliorate oxidative-nitrosative stress, restore neurotransmission and reduce neuroinflammation.