Dicer Suppresses Hepatocellular Carcinoma via Interleukin-8 Pathway.

Background: Elevated level of interleukin-8 (IL-8) promotes hepatocellular carcinoma (HCC) development and contributes to poor prognosis. Previously, we have proved that Dicer inhibits HCC progression. In this study, we evaluated the potential interaction between IL-8 and Dicer as well as their influence on HCC. Methods: Hepatocellular carcinoma cells of SMMC-7721 were divided into 2 groups for subsequent analysis: pCMV-Dicer group for Dicer-overexpressing lentivirus transfected cells (pCMV-Dicer cells) and pCMV-NC group for empty lentivirus transfected cells (pCMV-NC cells). Cell Counting kit-8 (CCK8), wound healing, and transwell were used to evaluate the inhibitory effect of Dicer overexpression on proliferation, migration, and invasion of HCC cells. The level of IL-8 was measured by flow cytometry bead-based immunoassays. Male nude BALB/c mice injected with pCMV-Dicer or pCMV-NC cell suspensions was used for transplant of HCC tumor. Results: We found that the secretion of IL-8 was reduced in the medium of pCMV-Dicer cells (P = .027). Recombinant human IL-8 (rhIL-8) reversed the inhibitory effect of Dicer on proliferation (P < .01), migration (P = .003), and invasion (P = .001), whereas IL-8 inhibitor of reparixin enhanced inhibitory effect of Dicer on proliferation (P < .05), migration (P = .008), and invasion (P = .000). Lenvatinib downregulated the IL-8 level of HCC cells (P = .000) as well as promote Dicer-induced inhibition for HCC cells referring to proliferation (P < .05), migration (P = .000), and invasion (P = .000). Animal experiments also demonstrated that Dicer cooperated with lenvatinib to inhibit the growth of HCC tumors (P < .05). Conclusions: Dicer cooperated with lenvatinib to inhibit HCC growth via downregulating IL-8, and Dicer displayed its potential capability to enhance the anti-tumor effect of lenvatinib.

Risk-associated single nucleotide polymorphisms of mitochondrial D-loop mediate imbalance of cytokines and redox in rheumatoid arthritis.

BACKGROUND: We have identified rheumatoid arthritis (RA) risk-associated single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D-loop) including the major alleles of nucleotides 195T/C, 16260C/T, and 16519C/T as well as the minor alleles of nucleotides 146T/C and 150C/T previously. OBJECTIVE: We evaluated the potential relationships of these SNPs with status for oxidative stress and inflammation cytokines. METHODS: The DNA was extracted from blood samples of RA patients, and the SNPs of DNA D-loop were verified by polymerase chain reaction amplification and sequence analysis. Serum levels of inflammatory cytokines including interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-6, IL-10, and tumor necrosis factor-α (TNF-α) were determined by cytometric bead array. Plasma reactive oxygen species (ROS) levels were measured by fluorescent probe technology. RESULTS: The RA risk-related allele 16519C was significantly associated with high IFN-γ levels (100.576 ± 11.769 vs 64.268 ± 8.199, 95% confidence interval [CI] -66.317 to -6.299, P = 0.018). This allele also associated with ROS at borderline statistics level (619.295 ± 36.687 vs 526.979 ± 25.896, 95% CI -186.145 to -1.513, P = 0.054). The subsequent analysis also showed that the ROS levels were positively correlated with IFN-γ levels (R = 0.291, P = 0.002). Further analysis showed that RA patients with high C-reactive protein levels displayed a higher ROS level (P = 0.001). CONCLUSION: Our results imply that the 16519C allele of the mtDNA D-loop might promote ROS and IFN-γ levels by altering the replication and transcription of mtDNA, thereby modifying RA development. REMARK: The potential relationships of RA-associated SNPs in the mitochondrial D-loop with status for oxidative stress and inflammation were evaluated. The 16519C allele of the mtDNA D-loop might promote ROS and IFN-γ levels by altering the replication and transcription of mtDNA to modify RA development.

Are anti-PD-1-associated immune related adverse events a harbinger of favorable clinical prognosis in patients with gastric cancer?

BACKGROUND: Immune checkpoint inhibitors (ICIs) has shown remarkable benefit in the treatment of a range of cancer types, although it may initiate immune related adverse events (irAEs) in patients. Some studies have shown that there is a close relationship between the occurrence of irAEs and prognosis. In present study, we have attempted to establish whether the occurrence of irAEs after the use of anti PD-1 antibodies is associated with treatment efficacy in people with advanced gastric cancer (AGC). METHODS: This study included patients treated with the anti-PD-1 antibodies for AGC patients at The Fourth Hospital of Hebei Medical University. IrAEs were identified clinically and graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS). The analysis was performed to determine the association between irAEs and clinical outcomes. RESULT: Of the 74 AGC patients in our study, 24 developed irAEs. The DCR of the irAE displayed a trend better than that of non-irAE group but without statistical difference (41.70% VS 6.0%, p = 0.118). Median PFS in the irAE group was superior to that in the non-irAE group (176 days VS 94 days, p = 0.001). Median OS also showed this trend of difference at borderline statistical level (292 days VS 239 days, p = 0.057). Multivariate analysis also demonstrated irAE (HR = 0.269, 95%CI: 0.088 to 0.822, p = 0.021) were associated independently with the better prognosis for AGC patients. CONCLUSION: In advanced gastric cancer treated with anti PD-1 antibodies, the occourence of irAEs might contribute to the improved prognosis.

Nonsynonymous C1653T Mutation of Hepatitis B Virus X Gene Enhances Malignancy of Hepatocellular Carcinoma Cells.

Purpose: Functional analysis was performed to elucidate the mechanism by which hepatocellular carcinoma (HCC) outcome-associated mutation in the hepatitis B virus X (HBx) gene modifies the HCC process. Methods: Proliferation, invasion, migration, and apoptosis assays were performed, and changes in fibrosis, intracellular reactive oxygen species (ROS), and cytokine levels were measured. The differences between variables were evaluated by Student's t-test. Results: The influence of two previously identified nonsynonymous mutation, C1653T and T1753C, on HCC cells was assessed. With regard to HBX-induced promotion of proliferation (p < 0.01), invasion (p < 0.01) and migration (p < 0.01), the C1653T mutation displayed a significant additive effect in these assays (P < 0.05). The subsequent apoptosis assay indicated that HBX could inhibit apoptosis (P < 0.01), whereas the C1653T mutation markedly amplified this effect in HCC cells (P < 0.01). Furthermore, the tumor growth-promoting effect of HBX was confirmed in a mouse xenograft model of HCC (P < 0.05), and the C1653T mutation was observed to amplify this effect (P < 0.05). To further investigate the mechanism by which the C1653T mutation enhances malignancy in HCC cells, fibrosis, intracellular ROS, and cytokine levels were measured. The C1653T mutant increased fibrosis and intracellular ROS level, and altered monocyte chemotactic protein-1 and interleukin-18 expression in HepG2 cells. Drug sensitivity test revealed that the C1653T mutation is sensitive to apatinib treatment and that overexpression of vascular endothelial growth factor might be involved in this process. Conclusion: Our data indicate that the C1653T mutation of HBx promotes HCC malignancy by altering the levels of fibrosis, ROS, and some cytokines. This mutation could serve as a potential biomarker for screening HCC patients to determine apatinib treatment efficacy.

Mitochondrial Displacement Loop Region SNPs Modify Sjögren's Syndrome Development by Regulating Cytokines Expression in Female Patients.

Mitochondrial dysfunction could induce innate immune response with cytokines releasing to initiate Sjögren's syndrome (SS) onset. Single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D-loop) and mitochondrial DNA (mtDNA) copy number of female SS patients were evaluated for their association with SS in female patients. At the nucleotide site of 152, 16304, 16311 and 16362 in the D-loop, the frequencies for the minor alleles of 152C (p = 0.040, odds ratio [OR] = 0.504), 16304C (p = 0.045, OR = 0.406), 16311C (p = 0.045, OR = 0.406) and 16362C (p = 0.028, OR = 0.519) were significantly higher in the SS patients than those in the female controls, which indicated that 152,C, 16304C, 16311C, and 16362C allele in the D-loop of mtDNA were associated with the risk of SS. Meanwhile, the excessive SNPs were accumulated in D-loop region of SS patients (8.955 ± 2.028 versus 7.898 ± 1.987, p < 0.001, 95% confidence interval [CI]: 0.477-1.637) and mtDNA copy number increased in SS patients (1.509 ± 0.836 versus 1.221 ± 0.506, p = 0.006, 95% CI: 0.086-0.490) by a case-control analysis. The subsequent analysis showed that SS risk-related allele 16311C was associated with higher IL-2 levels (p = 0.010) at significantly statistical level whereas 152C associated with lower IL-10 levels (p = 0.058) at a borderline statistical levels. Our findings suggest that mitochondrial D-loop SNPs are predictors for SS risk, it might modify the SS development by regulating cytokine expression.

The SNPs of mitochondrial DNA displacement loop region and mitochondrial DNA copy number associated with risk of polymyositis and dermatomyositis.

Oxidative damage-induced mitochondrial dysfunction may activate muscle catabolism and autophagy pathways to initiate muscle weakening in idiopathic inflammatory myopathies (IIMs). In this study, Single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D-loop) and mitochondrial DNA (mtDNA) copy number were assessed and their association with the risk of polymyositis and dermatomyositis (PM/DM) was evaluated. Excessive D-loop SNPs (8.779 ± 1.912 vs. 7.972 ± 1.903, p = 0.004) correlated positively with mtDNA copy number (0.602 ± 0.457 vs. 0.300 ± 0.118, p < 0.001). Compared with that of the controls, the mtDNA of PM/DM patients showed D-loop SNP accumulation. In addition, the distribution frequencies of 16304C (p = 0.047) and 16519C (p = 0.043) were significantly higher in the patients with PM/DM. Subsequent analysis showed that reactive oxygen species (ROS) generation was increased in PM/DM patients compared with that in the controls (18,477.756 ± 13,574.916 vs. 14,484.191 ± 5703.097, p = 0.012). Further analysis showed that the PM/DM risk-related allele 16304C was significantly associated with lower IL-4 levels (p = 0.021), while 16519C had a trend to be associated with higher IL-2 expression (p = 0.064). The allele 16519C was associated with a positive antinuclear antibody (ANA) status in PM/DM patients (p = 0.011). Our findings suggest that mitochondrial D-loop SNPs could be potential biomarkers for PM/DM risk and these SNPs associated with cytokine expression may be involved in the development of PM/DM. Further, mtDNA copy number-mediated mitochondrial dysfunction may precede the onset of PM/DM.

Identification of sequence polymorphisms in the mitochondrial deoxyribonucleic acid displacement-loop region as risk factors for systemic lupus erythematosus.

OBJECTIVES: This study aims to evaluate the relationship between sequence polymorphisms (SNPs) in the displacement-loop (D-loop) region of mitochondrial deoxyribonucleic acid (mtDNA) and systemic lupus erythematosus (SLE) in Chinese female patients. PATIENTS AND METHODS: This cross-sectional study was conducted between May 2017 and October 2017. The mtDNA was extracted from the peripheral blood of 97 female SLE patients (mean age 40.8 years; range, 20 to 79 years) and 108 age-matched healthy controls (mean age 48.7 years; range, 22 to 78 years). The SNPs of mtDNA D-loop were verified by polymerase chain reaction amplification and sequence analysis. The allele frequencies of D-loop region were compared by the Chi-square test between SLE and control groups. RESULTS: The SNP accumulation in SLE patients was significantly higher than that in the controls (p=0.027, 95% confidence interval [CI]: 0.075, 1.210). The frequencies of the major alleles of the nucleotides 73G/A (p<0.001, odds ratio [OR]=1.241) and 195T/C (p=0.047, OR=4.318) as well as the minor allele of nucleotide 199T/C (p=0.048, OR=0.279) were significantly higher in the SLE patients than in the controls, which indicated that 73G, 195T and 199C allele in the D-loop of mtDNA were associated with the risk of SLE. Further analysis indicated that the reactive oxygen species level in the SLE patients was significantly higher than that of controls (mean fluorescence intensity ± standard deviation: 3054.333±256.099 vs. 2099.167±599.662, p=0.009, 95% CI: 321.243, 1589.091). CONCLUSION: This study indicated the SNPs in the mtDNA may associated with the risk of SLE. Analysis of SNPs in the mitochondrial D-loop may help identify individuals who are at high risk of developing SLE.

Correlation Between Immune-Related Adverse Events and Prognosis in Hepatocellular Carcinoma Patients Treated With Immune Checkpoint Inhibitors.

Background: Immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs) were associated with clinical benefit in cancer patients of melanoma, a lung cancer. In the present study, we investigated the correlation between irAE and ICI efficacy in hepatocellular carcinoma (HCC) patients. Methods: We divided the HCC patients who received the anti-PD-1 antibody into two groups as irAE group and non-irAE group according to the National Cancer Institute Common Terminology Criteria for Adverse Events ver. 4.03. The treatment efficacy of ICIs was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Result: Of the 65 HCC patients who received the anti-PD-1 antibody (monotherapy or combined with targeted medicine), median PFS in the irAE group was superior to that in the non-irAE group (302 days vs. 148 days, p = 0.004). Median OS in the irAE group was also better than that in the non-irAE group (374 days vs. 279 days, p = 0.038). Although the statistical difference for DCR in the irAE group and non-irAE group was not reached, the DCR of the irAE displayed a trend better than that of the non-irAE group (41.20% vs. 20.80%, p = 0.118). Multivariate analysis also demonstrated that the non-irAE group (HR = 6.410, 95% CI: 1.404 to 29.275) was associated independently with the poor prognosis. Conclusions: Development of irAEs was associated with clinical benefit for HCC patients who were treated with immune checkpoint inhibitors; irAE, particularly low-grade irAE, was a predictable marker for better ICI treatment efficiency in HCC patients.

Type I collagen promotes tumor progression of integrin ß1 positive gastric cancer through a BCL9L/ß-catenin signaling pathway.

The mechanism of extracellular matrix induced tumor progression is poorly understood. Based on the TCGA database and clinical tumor tissues analysis, we observed abundant type I collagen expression in tumor tissues and poor overall survival in gastric patients with high integrin ß1 (ITGB1) expression. In vitro, our study found that 3D collagen culture promoted the capability of colony formation and growth in ITGB1 positive gastric cancer, whereas limited colony growth was observed in ITGB1 negative gastric cancer, suggesting the role of ITGB1 in type I collagen associated tumor progression. Mechanistically, we demonstrated that type I collagen was capable of promoting the activation of BCL9L/ß-catenin signaling pathway through ITGB1, thereby contributing to the gastric cancer development. Subsequently, ß-catenin signals further up-regulated the expression anti-apoptosis protein BCL2, leading to the chemo-resistance in gastric cancer cells. Blockade of ß-catenin signals efficiently improved the anticancer effects of chemotherapy, providing an innovative sight for clinical gastric cancer therapy.

Antibiotics Modulate Chemotherapy Efficacy in Patients with Esophageal Cancer.

PURPOSE: Accumulating evidence suggests that microbiota dysbiosis induced by antibiotic administration plays a crucial role in regulating the efficacy and toxicity of cancer therapy. We explored the influence of antibiotic administration on the efficacy of chemotherapy in patients with esophageal cancer (EC). PATIENTS AND METHODS: EC patients were stratified into two groups: antibiotic-treated group and control group. The antibiotic-treated group included patients who received antibiotics within 60 days before or after chemotherapy initiation, and the control group included patients who did not receive antibiotics within 60 days before or after chemotherapy initiation. Progression-free survival (PFS) and overall survival (OS) curves were constructed using the Kaplan-Meier method. The Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: The rate of primary progressive disease in the antibiotic-treated group was significantly higher than that in the control group (36.58% vs 10.45%, p = 0.002) as calculated using the chi-square test. Further, antibiotic administration was associated with shorter PFS (6.7 vs 14.6 months, hazard ratio (HR): 2.545, 95% confidence interval (CI): 1.554-4.168, p < 0.001) and reduced OS (15.0 vs 21.0 months, HR: 2.007, 95% CI: 1.213-3.319, p = 0.007) in univariate analysis. Subsequent multivariate analysis indicated that antibiotic administration was a significant independent prognostic factor for PFS (HR: 2.350, 95% CI: 1.423-3.882, p = 0.001) and OS (HR: 1.900, 95% CI: 1.140-3.167, p = 0.014). CONCLUSION: Antibiotic administration was associated with reduced chemotherapy efficacy and poor prognosis in patients with EC.

A Polymorphism at the microRNA Binding Site in the 3' Untranslated Region of KRT81 Is Associated with Breast Cancer.

Single nucleotide polymorphisms in miRNA binding sites (miR-SNPs) are associated with cancer risk. We assessed the relationship between five miR-SNPs in the 3' untranslated region (3'-UTR) of RYR3 (rs1044129), KIAA0423 (rs1053667), C14orf101 (rs4901706), GOLGA7 (rs11337), and KRT81 (rs3660) and the risk of breast cancer (BC). The CC genotype of rs3660 located in the 3'-UTR of KRT81 was identified for its association with lower BC risk (odds ratio, 0.093; 95% confidence interval, 0.045-0.193; p = 0.000). Immunnochemical analysis and Renilla luciferase reporter assays indicated that the CC genotype of KRT81 was associated with lower expression of KRT81 (p < 0.05). The subsequently functional analysis showed that knockdown the KRT81 could inhibit proliferation and promote apoptosis of the MDA-MB-231 BC cells (p < 0.05) with monocyte chemotactic protein-1 (MCP-1) deregulation. Meanwhile, KRT81 overexpression could promote the proliferation and inhibit the apoptosis of MCF-7 BC cells (p < 0.05). Our data demonstrated that the KRT81 expressional change modulated by rs3660 miR-SNP could modify the carcinogenesis of BC, thereby KRT81 would be a new target for BC treatment.

Ischemic colitis caused by polycythemia vera: A case report and literature review.

Polycythemia vera (PV) is a chronic myeloproliferative disorder originating from hematopoietic stem cells and complicated by thrombosis and bleeding. This report describes a case of ischemic colitis (IC) caused by PV and includes a review of the relevant literature. The patient was a 59-year-old male with a history of PV who presented with abdominal pain and hematochezia. Colonoscopy and histopathological examination results indicated suspected ischemic bowel disease. Following experimental anticoagulant therapy for 7 days, the patient no longer experienced abdominal pain and hematochezia had resolved. Colonoscopy review showed no obvious anomalies 1 month later. These data demonstrated that PV is an uncommon cause of IC.