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Sodium taurocholate cotransporting polypeptide (NTCP) is identified as the functional receptor for HBV entry, which is responsible for upregulated HBV transcription in the HBV life cycle. Besides, NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma (HCC). Thereby, NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy. Herein, we integrated in silico screening and chemical synthesis to obtain a small-molecule NTCP inhibitor B7, which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activity in vitro. Additionally, CETSA assay, molecular docking, and MD simulation validated that B7 could bind to NTCP. Furthermore, western blot analysis demonstrated that B7 induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells. Taken together, our study identified B7 as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.

Autophagy, defined as a scavenging process of protein aggregates and damaged organelles mediated by lysosomes, plays a significant role in the quality control of macromolecules and organelles. Since protein kinases are integral to the autophagy process, it is critically important to understand the role of kinases in autophagic regulation. At present, intervention of autophagic processes by small-molecule modulators targeting specific kinases has becoming a reasonable and prevalent strategy for treating several varieties of human disease, especially cancer. In this review, we describe the role of some autophagy-related kinase targets and kinase-mediated phosphorylation mechanisms in autophagy regulation. We also summarize the small-molecule kinase inhibitors/activators of these targets, highlighting the opportunities of these new therapeutic agents., Graphical abstract This review elaborates in detail the role of some autophagy-related kinase targets and phosphorylation in autophagy regulation, and further summarizes the application of small-molecule kinase inhibitors/activators for autophagy inhibition and induction. Understanding how these autophagy-related kinases regulate autophagy machinery is critical for the potential therapeutic application of autophagy.Image 1

Immune checkpoint therapy shows impressive and durable clinical responses in cancer patients, but the genetic determinants that enable cancer cells to respond to anti-PD-1 therapy are still elusive. Herein, we identified thatNIPBLdeficiency promotes endogenous retrovirus (ERV) expression in tumour cells, which in turn inactivates CD8+ tumour-infiltrating lymphocytes (TILs) via the PD-L1/PD-1 inhibitory checkpoint pathway. Mechanistically,NIPBLdeficiency impairs DNMT1 transcription, preventing DNMT1 from suppressing ERV expression in tumour cells; ERVs stimulate PD-L1 expression by inducing the STAT2-IRF9 complex, a downstream event of double-stranded RNA (dsRNA)-MAVS-IRF3 signalling, and thereby suppress CD8 TIL-mediated immunity. An anti-PD-1 monoclonal antibody achieved remarkable therapeutic effects inNipbl-deficient syngeneic tumour models and improved host survival by eliciting an antitumour memory immune response. Cancer patients harbouring mutations of cohesin subunits and regulators plus DNMT1 had significantly better responses to anti-PD-1 therapy than their non-mutated counterparts did. Our study reveals a novel mechanism by which cohesin complex deregulation stimulates ERV expression by impairing DNMT1 expression and fosters an immunosuppressive tumour microenvironment by activating the PD-L1/PD-1 inhibitory checkpoint.

Sirtuin 3 (SIRT3) is one of the most prominent deacetylases that can regulate acetylation levels in mitochondria, which are essential for eukaryotic life and inextricably linked to the metabolism of multiple organs. Hitherto, SIRT3 has been substantiated to be involved in almost all aspects of mitochondrial metabolism and homeostasis, protecting mitochondria from a variety of damage. Accumulating evidence has recently documented that SIRT3 is associated with many types of human diseases, including age-related diseases, cancer, heart disease and metabolic diseases, indicating that SIRT3 can be a potential therapeutic target. Here we focus on summarizing the intricate mechanisms of SIRT3 in human diseases, and recent notable advances in the field of small-molecule activators or inhibitors targeting SIRT3 as well as their potential therapeutic applications for future drug discovery.

BRCA2 is crucial for repairing DNA double-strand breaks with high fidelity, and loss of BRCA2 increases the risks of developing breast and ovarian cancers. Herein, we show that BRCA2 is inactively mutated in 10% of gastric and 7% of colorectal adenocarcinomas, and that this inactivation is significantly correlated with microsatellite instability. Villin-driven Brca2 depletion promotes mouse gastrointestinal tumor formation when genome instability is increased. Whole-genome screening data showed that these BRCA2 monoallelic and biallelic mutant tumors were selectively inhibited by mitomycin C. Mechanistically, mitomycin C provoked double-strand breaks in cancer cells that often recruit wild-type BRCA2 for repair; the failure to repair double-strand breaks caused cell-cycle arrest at the S phase and p53-mediated cell apoptosis of BRCA2 monoallelic and biallelic mutant tumor cells. Our study unveils the role of BRCA2 loss in the development of gastrointestinal tumors and provides a potential therapeutic strategy to eliminate BRCA2 monoallelic and biallelic mutant tumors through mitomycin C.

Additional file 1: Figure S1. Box plots depicting the expression of 20 cancer-associated lncRNAs in PDAC and normal tissues. TCGA data was analyzed using the GEPIA website (http://gepia.cancer-pku.cn/index.html). Figure S2. Overall survival analysis of the expression of 20 cancer-associated lncRNAs in PDAC. TCGA data was analyzed using the GEPIA website (http://gepia.cancer-pku.cn/index.html). Figure S3. RNA decay curves depicting the degradation of mRNAs. 18S was used as a reference gene and no significant alterations were observed following Actinomycin D treatment. Data represent the mean ± SD of three independent experiments. Figure S4. a, RPISeq prediction parameters of Linc00337 and E2F1 binding. b, western blot analysis of Flag-E2F1 immunoprecipitation, DP1 as positive control and GAPDH as negative control. c, qRT-PCR analysis of Linc00337 and GAPDH enrichment in PANC1 cells by Lac Z and 337.

The plenoptic camera is a new camera structure which can record the intensity, color and the direction of the light by adding a microlens array in front of the image sensor. Based on some basic concepts of the focused plenoptic camera, we first analyze the imaging characteristics. Then, the design method was given. Furthermore, we establish the depth resolution model after detailed derivation. The imaging characteristics of the focused plenoptic camera with a novel structure of four types focal lengths microlens array was analyzed. The simulation results show that our designed camera has the advantages of large depth of field and high depth resolution. The method proposed in this paper can provide reference for designing plenoptic cameras for specific application scenarios.

Microarray studies revealed down-regulation of PCDH9 mRNA level in lymph node metastasis of gastric cancer compared with the primary tumors. The expression of PCDH9 protein and its clinicopathological relevance were assessed on tissue microarrays of 1072 cases of gastric cancer. Its prognostic value was further evaluated on a small cohort of 175 gastric cancers. PCDH9 was down-regulated during the development and progression of gastric cancer. The overall rates of PCDH9 expression in normal, primary tumor, nodal and hepatic metastatic tissues were 100 % (1072/1072), 48.0 % (515/1072), 20.1 % (34/169), and 5.6 % (1/18), respectively. Positive staining of PCDH9 protein was significantly reversely correlated with tumor size, tumor differentiation, tumor invasion, lymph node metastasis, and disease progression. The Cox proportional hazards model revealed that the PCDH9 was an independent prognostic factor for gastric cancer. Therefore, decreased expression of PCDH9 is frequent in human gastric cancer metastasis and PCDH9 expression is an independent prognostic factor, suggesting that PCDH9 could be a promising biomarker of this malignancy.

Pancreatic cancer is one of the most lethal cancers worldwide. CD86 (B7-2) is a costimulatory molecule on antigen-presenting cells and plays critical roles in tumor immunity. It has been reported that polymorphisms in CD86 gene can be involved in the development of various cancers. Here, we investigated the association of two CD86 polymorphisms, +1057G/A (rs1129055) and +2379G/C (rs17281995), with pancreatic cancer in the Chinese population. The two polymorphisms were identified in 369 pancreatic cancer patients and 412 healthy controls using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Data were analyzed by chi-square test and adjusted for body mass index, smoking, drinking, and diabetes status. Results showed that the frequency of the +1057A allele was significantly higher in pancreatic cancer cases than in controls (59.8 vs. 52.8 %, p = 0.021). Comparison of genotype frequencies showed that +1057GA and +1057AA genotypes were significantly increased in the pancreatic cancer group (odds ratio (OR) = 1.52; 95 % confidence interval (CI), 1.09–2.38; p = 0.026; and OR = 1.90; 95 % CI, 1.21–3.01; p = 0.007). We did not find any association between the +2379G/C polymorphism and pancreatic cancer. Analysis of haplotypes indicated that the AG (+1057, +2379) haplotype was correlated with the susceptibility to this disease (p = 0.019). These results suggest that the CD86 +1057G/A polymorphism and AG (+1057, +2379) haplotype are genetic risk factors for pancreatic cancer.

In the optimization design of contact system for the air circuit breaker (ACB), it is important to calculate the short-time withstand current. Introducing the contact bridges to describe contact spots between movable and fixed contacts, transient analysis is carried out by coupling electromagnetic field and thermal field to parallel contact systems, where nonlinear of ferromagnetic splitter plates and properties of conduct material varying with temperature are under consideration. In each time step of calculation, the cross-sectional areas of the contact bridges are changed with the contact forces by Holm formula. The proposed method could be used to analyze the short-time withstand current of ACB.