简介：AbstractWith the increasing use of immune checkpoint inhibitors (ICI) including anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) in cancers, ICI-induced type 1 diabetes has been reported throughout the world. In this review, we aim to summarize the characteristics of this disease and discuss the mechanism of it. As an immune-related adverse event, type 1 diabetes developed after the administration of anti-PD-1 or anti-PD-ligand 1 (PD-L1) in the combination with or without anti-CTLA-4. It usually presented with acute onset, and 62.1% of the reported cases had diabetic ketoacidosis. Only a third of them had positive autoantibodies associated with type 1 diabetes. Susceptible HLA genotypes might be associated. T-cell-stimulation by blocking of the interaction of PD-1 and PD-L1 in pancreatic β cells was the main mechanism involved in the pathology. Insulin was the only effective treatment of ICI-induced type 1 diabetes. In conclusions, ICI-induced type 1 diabetes is a potentially life-threating adverse event after the immunotherapy of cancers. Screening and early recognition is important. Further investigation of the mechanism may help to better understand the pathology of type 1 diabetes.

简介：全球互联网安全领域首屈一指的CheckPoint软件技术有限公司日前宣布推出一款新的安全加速模块（SecurityAccelerationModuIe），旨在满足客户对高性能和低延迟环境的独特需求。安全加速模块采用CheckPoint先进的SecurityCore技术，实现业界性能最高的双架单元防火墙。

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简介：Melanomaisthedeadliestformofskincancerandhasanincidencethatisrisingfasterthananyothersolidtumor.Metastaticmelanomatreatmenthasconsiderablyprogressedinthepastfiveyearswiththeintroductionoftargetedtherapy(BRAFandMEKinhibitors)andimmunecheckpointblockade(anti-CTLA4,anti-PD-1,andanti-PD-L1).However,eachtreatmentmodalityhaslimitations.Treatmentwithtargetedtherapyhasbeenassociatedwithahighresponserate,butwithshort-termresponses.Conversely,treatmentwithimmunecheckpointblockadehasalowerresponserate,butwithlongtermresponses.Targetedtherapyaffectsantitumorimmunity,andsynergymayexistwhentargetedtherapyiscombinedwithimmunotherapy.Thisarticlepresentsabriefreviewoftherationaleandevidenceforthepotentialsynergybetweentargetedtherapyandimmunecheckpointblockade.Challengesanddirectionsforfuturestudiesarealsoproposed.

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简介：AbstractBackground:Glioma is the most common and fatal type of nerve neoplasm in the central nervous system. Several biomarkers have been considered for prognosis prediction, which is not accurate enough. We aimed to carry out a gene signature related to the expression of immune checkpoints which was enough for its performance in prediction.Methods:Gene expression of immune checkpoints in TGGA database was filtrated. The 5 selected genes underwent verification by COX and Lasso-COX regression. Next, the selected genes were included to build a novel signature for further analysis.Results:Patients were sub-grouped into high and low risk according to the novel signature. Immune response, clinicopathologic characters, and survival showed significant differences between those 2 groups. Terms including "naive," "effector," and "IL-4" were screened out by GSEA. The results showed strong relevance between the signature and immune response.Conclusions:We constructed a gene signature with 5 immune checkpoints. The signature predicted survival effectively. The novel signature performed more functional than previous biomarkers.

简介：AbstractIn recent years, the research of immune checkpoint inhibitors has made a great breakthrough in lung cancer treatment. Currently, a variety of immune checkpoint inhibitors have been applied into clinical practice, including antibodies targeting the programmed cell death-1, programmed cell death-ligand 1, and cytotoxic T-lymphocyte antigen 4, and so on. However, not all patients can benefit from the treatment. Abnormal antigen presentation, functional gene mutation, tumor microenvironment, and other factors can lead to primary or secondary resistance. In this paper, we reviewed the molecular mechanism of immune checkpoint inhibitor resistance and various combination strategies to overcome resistance, in order to expand the beneficial population and enable precision medicine.

简介：Immunecheckpointinhibitorsareincreasinglydrawingmuchattentioninthetherapeuticdevelopmentforcancertreatment.However,manycancerpatientsdonotrespondtotreatmentswithimmunecheckpointinhibitors,partlybecauseofthelackoftumor-infiltratingeffectorTcells.CancervaccinesmayprimepatientsfortreatmentswithimmunecheckpointinhibitorsbyinducingeffectorT-cellinfiltrationintothetumorsandimmunecheckpointsignals.Thecombinationofcancervaccineandanimmunecheckpointinhibitormayfunctionsynergisticallytoinducemoreeffectiveantitumorimmuneresponses,andclinicaltrialstotestthecombinationarecurrentlyongoing.

简介：AbstractImmune checkpoint inhibitors (ICIs) are widely used in lung cancer therapy due to their effectiveness and minimal side effects. However, only a few lung cancer patients benefit from ICI therapy, driving the need to develop alternative biomarkers. Programmed death-ligand 1 (PD-L1) molecules expressed in tumor cells and immune cells play a key role in the immune checkpoint pathway. Therefore, PD-L1 expression is a prognostic biomarker in evaluating the effectiveness of programmed death-1 (PD-1)/PD-L1 inhibitors. Nevertheless, adverse predictive outcomes suggest that other factors are implicated in the response. In this review, we present a detailed introduction of existing biomarkers concerning tumor abnormality and host immunity. PD-L1 expression, tumor mutation burden, neoantigens, specific gene mutations, circulating tumor DNA, human leukocyte antigen class I, tumor microenvironment, peripheral inflammatory cells, and microbiome are discussed in detail. To sum up, this review provides information on the current application and future prospects of ICI biomarkers.

简介：全球互联网安全领域首屈一指的CheckPoint软件技术有限公司宣布，现在客户可通过AmazonWebService获得CheckPoint的安全网关。企业通过它可以在云上实现高安全性，或采用CheckPoint防火墙、入侵防护、应用控制（ApplicationControl）、URL过滤等刀片来获得全面保护。只需几个简单的步骤，客户就可以轻松地将CheckPoint虚拟设备，即面云中，从而激活保护功能以防止网络攻击和数据破坏，同时在动态的云计算环境中启用安全的连接。

简介：AbstractBackground:Age-related macular degeneration (AMD) is the leading cause of vision loss worldwide. However, the mechanisms involved in the development and progression of AMD are poorly delineated. We aimed to explore the critical genes involved in the progression of AMD.Methods:The differentially expressed genes (DEGs) in AMD retinal pigment epithelial (RPE)/choroid tissues were identified using the microarray datasets GSE99248 and GSE125564, which were downloaded from the gene expression omnibus database. The overlapping DEGs from the two datasets were screened to identify DEG-related biological pathways using gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. The hub genes were identified from these DEGs through protein-protein interaction network analyses. The expression levels of hub genes were evaluated by quantitative real-time polymerase chain reaction following the induction of senescence in ARPE-19 with FK866. Following the identification of AMD-related key genes, the potential small molecule compounds targeting the key genes were predicted by PharmacoDB. Finally, a microRNA-gene interaction network was constructed.Results:Microarray analyses identified 174 DEGs in the AMD RPE compared to the healthy RPE samples. These DEGs were primarily enriched in the pathways involved in the regulation of DNA replication, cell cycle, and proteasome-mediated protein polyubiquitination. Among the top ten hub genes, HSP90AA1, CHEK1, PSMA4, PSMD4, and PSMD8 were upregulated in the senescent ARPE-19 cells. Additionally, the drugs targeting HSP90AA1, CHEK1, and PSMA4 were identified. We hypothesize that Hsa-miR-16-5p might target four out of the five key DEGs in the AMD RPE.Conclusions:Based on our findings, HSP90AA1 is likely to be a central gene controlling the DNA replication and proteasome-mediated polyubiquitination during the RPE senescence observed in the progression of AMD. Targeting HSP90AA1, CHEK1, PSMA4, PSMD4, and/or PSMD8 genes through specific miRNAs or small molecules might potentially alleviate the progression of AMD through attenuating RPE senescence.

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简介：AbstractBackground:Response to immune checkpoint inhibitors (ICIs) is affected by multiple factors. This study aimed to explore whether sites of metastasis are associated with clinical outcomes of ICIs in advanced non-small-cell lung cancer (NSCLC) patients.Methods:The data of NSCLC patients with high programmed death-ligand 1 expression and good performance status receiving first-line ICIs monotherapy from Guangdong Provincial People’s Hospital between May 2019 and July 2020 were retrospectively analyzed. Metastatic sites included liver, bone, brain, adrenal gland, pleura, and contralateral lung. Progression-free survival (PFS) and overall survival (OS) were compared between different metastatic sites and metastatic burden by the Kaplan-Meier method. Organ-specific disease control rate (OSDCR) of different individual metastatic sites was evaluated.Results:Forty NSCLC patients meeting the criteria were identified. The presence of liver metastasis was significantly associated with shorter PFS (3.1 vs. 15.5 months, P = 0.0005) and OS (11.1 months vs. not reached, P = 0.0016). Besides, patients with bone metastasis tend to get shorter PFS (4.2 vs. 15.5 months, P = 0.0532) rather than OS (P = 0.6086). Moreover, the application of local treatment could numerically prolong PFS in patients with brain metastasis (15.5 vs. 4.3 months, P = 0.1894). More metastatic organs involved were associated with inferior PFS (P = 0.0052) but not OS (P = 0.0791). The presence of liver metastasis or bone metastasis was associated with more metastatic organs (Phi[φ]: 0.516, P = 0.001). The highest OSDCR was observed in lung (15/17), and the lowest in the liver (1/4).Conclusions:Metastases in different anatomical locations may be associated with different clinical outcomes and local tumor response to ICIs in NSCLC. ICIs monotherapy shows limited efficacy in patients with liver and bone metastasis, thus patients with this type of metastasis might require more aggressive combination strategies.

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