Astrocyte-derived SerpinA3N promotes neuroinflammation and epileptic seizures by activating the NF-κB signaling pathway in mice with temporal lobe epilepsy.

Impaired activation and regulation of the extinction of inflammatory cells and molecules in injured neuronal tissues are key factors in the development of epilepsy. SerpinA3N is mainly associated with the acute phase response and inflammatory response. In our current study, transcriptomics analysis, proteomics analysis, and Western blotting showed that the expression level of Serpin clade A member 3N (SerpinA3N) is significantly increased in the hippocampus of mice with kainic acid (KA)-induced temporal lobe epilepsy, and this molecule is mainly expressed in astrocytes. Notably, in vivo studies using gain- and loss-of-function approaches revealed that SerpinA3N in astrocytes promoted the release of proinflammatory factors and aggravated seizures. Mechanistically, RNA sequencing and Western blotting showed that SerpinA3N promoted KA-induced neuroinflammation by activating the NF-κB signaling pathway. In addition, co-immunoprecipitation revealed that SerpinA3N interacts with ryanodine receptor type 2 (RYR2) and promotes RYR2 phosphorylation. Overall, our study reveals a novel SerpinA3N-mediated mechanism in seizure-induced neuroinflammation and provides a new target for developing neuroinflammation-based strategies to reduce seizure-induced brain injury.

Emotional symptoms and cognitive function outcomes of subthalamic stimulation in Parkinson's disease depend on location of active contacts and the volume of tissue activated.

BACKGROUND: Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), that can improve patients' motor and non-motor symptoms. However, there are differences in the improvement of patients' emotional symptoms and cognitive function. OBJECTIVE: To investigate the impact of active contact location and the volume of tissue activated (VTA) on patients' emotional symptoms and cognitive function in STN-DBS in PD. METHODS: A total of 185 PD patients were included in this study. We evaluated them using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Hamilton Anxiety Scale (HAM-A), Hamilton Depression Scale (HAM-D), Montreal Cognitive Assessment (MoCA), and Mini-Mental State Examination (MMSE) scales at the preoperative, 1- and 12-month postoperative time points. Leads were positioned in standard space using the Lead-DBS toolbox, and VTA was calculated for analysis. RESULTS: When the lead active contact was closer to the ventral side of the STN, the patients' HAM-A improvement rate was higher, and when the active contact was closer to the anterior and dorsal sides of the STN, the patients' MoCA improvement rate was higher. Stimulation of the sensorimotor zone was more favorable to the improvement of HAM-A and HAM-D in patients. And, the stimulation of the associative zone was more favorable to the improvement of MoCA in patients. CONCLUSION: Our results provide evidence that the 12-month outcomes of cognitive function and emotional symptoms in PD patients with STN-DBS were closely related to the specific location of the active contacts in the STN and influenced by the VTA.

Characterization and prognostic significance of alternative splicing events in lower-grade diffuse gliomas.

Alternative splicing (AS) is assumed to play important roles in the progression and prognosis of cancer. Currently, the comprehensive analysis and clinical relevance of AS in lower-grade diffuse gliomas have not been systematically addressed. Here, we gathered alternative splicing data of lower-grade diffuse gliomas from SpliceSeq. Based on the Percent Spliced In (PSI) values of 515 lower-grade diffuse glioma patients from the Cancer Genome Atlas (TCGA), we performed subtype-differential AS analysis and consensus clustering to determine robust clusters of patients. A total of 48 050 AS events in 10 787 genes in lower-grade diffuse gliomas were profiled. Subtype-differential splicing analysis and functional annotation revealed that spliced genes were significantly enriched in numerous cancer-related biological phenotypes and signalling pathways. Consensus clustering using AS events identified three robust clusters of patients with distinguished pathological and prognostic features. Moreover, each cluster was also associated with distinct genomic alterations. Finally, we developed and validated an AS-related signature with Cox proportional hazards model. The signature, significantly associated with clinical and molecular features, could serve as an independent prognostic factor for lower-grade diffuse gliomas. Thus, our results indicated that AS events could discriminate molecular subtypes and have prognostic impact in lower-grade diffuse gliomas.

Molecular subtyping reveals immune alterations in IDH wild-type lower-grade diffuse glioma.

Isocitrate dehydrogenase (IDH) wild-type diffuse lower-grade glioma (LGG) is usually associated with poor outcome, but there have been disputes over its clinical outcome and classification. We present here a robust gene expression-based molecular classification of IDH wild-type diffuse LGG into two subtypes with distinct biological and clinical features. A discovery cohort of 49 IDH wild-type diffuse LGGs from the Chinese Glioma Genome Atlas (CGGA) was subjected to clustering and function analysis. Seventy-three tumors from The Cancer Genome Atlas (TCGA) were used to validate our findings. Consensus clustering of transcriptional data uncovered concordant classification of two robust and prognostically significant subtypes of IDH wild-type LGG. Subtype 1, associated with poorer outcomes, was characterized by significantly higher immune and cytolytic scores, M2 macrophages, and up-regulation of immune exhaustion markers, while Subtype 2, which had elevated lymphocytes and plasma cells, showed relatively favorable survival. Somatic alteration analysis revealed that Subtype 1 showed more frequently deleted regions, such as the locus of CDKN2A/CDKN2B, DMRTA1, C9orf53, and MTAP. Furthermore, we developed and validated a five-gene signature for better application of this acquired stratification. Our data demonstrate the biological and prognostic heterogeneity within IDH wild-type diffuse LGGs and deepen our molecular understandi-g of this tumor entity. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Siglecs, Novel Immunotherapy Targets, Potentially Enhance The Effectiveness of Existing Immune Checkpoint Inhibitors in Glioma Immunotherapy.

BACKGROUND: Inhibitors of immune checkpoints have shown little effect in clinical trials involving glioma patients. Here, we explored novel targets for use in future treatments. Previous studies showed the sialic acid-binding Ig-like lectin (Siglec) family to have a specific role in immunosuppression. We aimed to study the characteristics and immune function of Siglec family members. METHODS: Transcriptome data from 1024 glioma samples and 1551 glioma single cells were used in our study. Clinical and molecular pathology information was also included. Statistical, bioinformatical methods, and single-cell sequencing analysis were applied to investigate the role of Siglec family members. RESULTS: Siglecs-5, -7, -9, and -16 showed a significant correlation with immunosuppression in glioma. They are typically expressed in higher grade, IDH-wildtype, and mesenchymal subtype gliomas. Siglec-5, -7, and -9 had a similar immune function to TIM-3, while Siglec-16 was similar to PD-L1, suppressing tumor immunity via different mechanisms. Joint use of Siglec-inhibitors and immune checkpoint inhibitors could prolong the survival of glioma patients. CONCLUSION: Siglec-5, -7, -9, and -16 suppressed tumor immunity in different ways. Joint usage of inhibitors may be an effective means to improve the efficacy of glioma immunotherapy.

[Economic burden and related factors on inpatients with HBV-related diseases in Shandong province].

OBJECTIVE: To investigate the economic burden of patients with acute and chronic hepatitis B, cirrhosis and liver cancer caused by hepatitis B virus (HBV). METHODS: Cluster sampling was used on cases consecutively collected during the study period. Questionnaire survey was conducted and information on the expenses during hospitalization was collected from the hospital records and through interviewing those patients. RESULTS: Yearly costs related to patients with acute hepatitis B, severe hepatitis B, chronic hepatitis B, cirrhosis, hepatocellular carcinoma were 66.7, 138.1, 127.4, 151.7 and 377.2 thousand Yuan, respectively. RESULTS: from multiple linear regression model showed that the type of medical insurance scheme, annual days of hospitalization, classifications of HBV-related diseases and personal income were major influencing factors on the cost. CONCLUSION: HBV infection caused considerable burden to families and the society, indicating that HBV infection control programs would bring huge potential benefits. The reform of insurance scheme should be administrated to promote social fairness.

[Estimation on disease burden related to hepatitis B virus infection in Shandong province of China].

OBJECTIVE: To comprehensively measure the burden of hepatitis B, liver cirrhosis and liver cancer in Shandong province, using disability-adjusted life years (DALYs) to estimate the disease burden attribute to hepatitis B virus (HBV) infection. METHODS: Based on the mortality data of hepatitis B, liver cirrhosis and liver cancer derived from the third National Sampling Retrospective Survey for Causes of Death during 2004 and 2005, the incidence data of hepatitis B and the prevalence and the disability weights of liver cancer gained from the Shandong Cancer Prevalence Sampling Survey in 2007, we calculated the years of life lost (YLLs), years lived with disability (YLDs) and DALYs of three diseases following the procedures developed for the global burden of disease (GBD) study to ensure the comparability. RESULTS: The total burden for hepatitis B, liver cirrhosis and liver cancer were 211,616 (39,377 YLLs and 172,239 YLDs), 16,783 (13,497 YLLs and 3286 YLDs) and 247,795 (240,236 YLLs and 7559 YLDs) DALYs in 2005 respectively, and men were 2.19, 2.36 and 3.16 times as that for women, respectively in Shandong province. The burden for hepatitis B was mainly because of disability (81.39%). However, most burden on liver cirrhosis and liver cancer were due to premature death (80.42% and 96.95%). The burden of each patient related to hepatitis B, liver cirrhosis and liver cancer were 4.8, 13.73 and 11.11 respectively. CONCLUSION: Hepatitis B, liver cirrhosis and liver cancer caused considerable burden to the people living in Shandong province, indicating that the control of hepatitis B virus infection would bring huge potential benefits.

[Epidemiological analysis of cases with rash and fever illness after measles vaccine inoculation during 1999 to 2002 in Shandong province, China].

OBJECTIVE: To study the incidence of cases with rash and fever illness (RFIs) after measles vaccine (MV) inoculation. METHODS: During 1999 to 2002, 150 RFIs cases reported by the special measles surveillance system in Shandong province, China, were investigated and analyzed epidemiologically. RESULTS: 7 674 690 ml MV were distributed during 1999 to 2002 and the annual average incidence of RFIs cases after MV inoculation was 0.20/10 000 ml (0.2 ml per dose). There was significant difference of incidences each year (chi(2) = 10.13, P < 0.05). All RFIs cases were sporadically distributed without epidemiological links. Clinical symptoms showed that 88.67% of the 150 RFIs cases having > 38.5 degrees C fever and 75.33% of all cases appeared typical rash after 4 to 11 days (the medium was 8 days) after MV inoculation. The order of rash onset among RFIs cases was consistent with that of regular measles cases caused by wild virus. 68.67% of the RFIs cases had first MV inoculation and 94.71% were 8 to 12 month-olds. IgM sera antibody test from RFIs cases were rubella negative and 45.65% positive for measles. CONCLUSION: RFIs due to allergic reaction or measles vaccine virus infection might occur after MV inoculation. There seemed to be a correlation between RFIs incidence and the doses of MV. Measles virus genotype analysis needs to be carried out to confirm if the onset of some RFIs cases is aetiologically associated to MV vaccine virus infection.