Rs3746444 T>C locus in miR-499 increases the susceptibility to hepatocellular carcinoma: A meta-analysis 14812 subjects.

BACKGROUND: Recently, many investigations have suggested that the rs3746444 T>C locus in the microRNA (miR)-499 gene may contribute to the occurrence of cancer. However, reports on the association between rs3746444 and hepatocellular carcinoma (HCC) are conflicting. AIM: To further understand and explore the potential correlation between the single-nucleotide polymorphism of rs3746444 and the incidence of HCC. METHODS: In this meta-analysis, we obtained electronic literature by searching the PubMed, Embase and Chinese BioMedical Disc databases (through May 20, 2022). All eligible case-control, prospective cohort or nested case-control studies with sufficient data for calculating the odds ratios with their 95% confidence intervals were included. RESULTS: Ultimately, a total of 17 independent studies were included. We identified that rs3746444 was associated with the development of HCC (C vs T: P = 0.019 and CC/CT vs TT: P = 0.016). In Asian individuals, rs3746444 was associated with susceptibility to HCC (C vs T: P = 0.013 and CC/CT vs TT: P = 0.016). In addition, this study identified that the miR-499 rs3746444 locus was associated with susceptibility to HCC in the normal/healthy control subgroup (C vs T: P = 0.034 and CC/CT vs TT: P = 0.024). CONCLUSION: In summary, this meta-analysis highlights that rs3746444 in the miR-499 gene is involved in the occurrence of HCC, especially in Asian individuals.

Louki Zupa decoction attenuates the airway inflammation in acute asthma mice induced by ovalbumin through IL-33/ST2-NF-κB/GSK3ß/mTOR signalling pathway.

CONTEXT: Asthma is a common respiratory system disease. Louki Zupa decoction (LKZP), a traditional Chinese medicine, presents a promising efficacy against lung diseases. OBJECTIVE: To investigate the pathogenic mechanism of asthma and reveal the intervention mechanism of LKZP. MATERIALS AND METHODS: Forty-eight female Balb/c mice were randomly divided into 6 groups: normal control group (NC), ovalbumin (OVA)/saline asthma model group, OVA/LL group, OVA/LM group, OVA/LH group and OVA/DEX group (n = 8 per group). The asthmatic mice were modelled through intraperitoneal injecting and neutralizing OVA. LKZP decoction was administrated by gavage at the challenge stage for seven consecutive days (2.1, 4.2 and 8.4 g/kg/day). We investigated the change in lung function, airway inflammation, mucus secretion and TH-1/TH-2-related cytokines. We further verify the activated status of the IL-33/ST2/NF-κB/GSK3ß/mTOR signalling pathway. RESULTS: LKZP was proved to improve asthmatic symptoms, as evidenced by the down-regulated airway resistance by 36%, 58% and 53% (p < 0.01, p < 0.001 vs. OVA/saline group), up-regulated lung compliance by 102%, 114% and 111%, decreased airway inflammation and mucus secretion by 33%, 40% and 33% (p < 0.001 vs. OVA/saline group). Moreover, the content of cytokines in BALF related to airway allergy (such as IgE) and T helper 1/T helper 2 cells (like IL-2, IL-4, IL-5, IL-13, TNF-α and IFN-γ), were also markedly reduced by 13-65% on LKZP intervention groups compared with model group. Mechanistic research revealed that the IL-33/ST2-NF-κB/GSK3ß/mTOR signalling pathway was activated in the OVA/saline group and LKZP significantly down-regulated this pathway. DISCUSSION AND CONCLUSION: LKZP improves lung function, airway inflammation, mucus secretion and correct immune imbalance by intervening with the IL-33/ST2-NF-κB/GSK3ß/mTOR signalling pathway, presenting a promising therapeutic choice for asthma.

Investigation of Leptin and its receptor (LEPR) for single nucleotide polymorphisms in colorectal cancer: a case-control study involving 2,306 subjects.

Single nucleotide polymorphisms (SNPs) in the genes coding for leptin (LEP) and its receptor (LEPR) might regulate energy balance and be implicated in the development of colorectal cancer (CRC). In the present investigation, 1,003 CRC cases and 1,303 matched controls was compared. Five functional SNPs in LEP and LEPR genes were chosen to evaluate the correlation of these chosen SNPs with CRC susceptibility. We used the SNPscanTM genotyping assay to genotype LEP and LEPR SNPs. A significantly decreased risk of CRC was found to be associated with the LEPR rs6588147 polymorphism (GA vs. GG: crude P=0.007 and GA/AA vs. GG: crude P=0.018). With adjustments for risk factors (e.g. age, gender, drinking, BMI and smoking), these associations were not changed. In subgroup analyses, the association of LEP rs2167270 with a decreased risk of CRC was found in the ≥61 years old subgroup. For LEPR rs1137100, the association of this SNP with an increased susceptibility of CRC was found in the BMI <24 kg/m2 subgroup. In subgroup analyses for LEPR rs6588147, we identified that this locus also decreased the susceptibility of CRC in the male subgroup, <61 years old subgroup, never smoking subgroup and never drinking subgroup. For LEPR rs1137101, the relationship of this polymorphism with a decreased susceptibility to CRC was found in the never drinking subgroup. In summary, the present study highlights that LEPR rs6588147, rs1137101 and LEP rs2167270 may decrease the risk of CRC. However, LEPR rs1137100 is associated with susceptibility to CRC. Further case-control studies with larger sample sizes should be conducted to validate our findings.

Isotope dilution LC/ESI--MS-MS quantitation of urinary 1,4-bis(N-acetyl-S-cysteinyl)-2-butanone in mice and rats as the biomarker of 1-chloro-2-hydroxy-3-butene, an in vitro metabolite of 1,3-butadiene.

1-Chloro-2-hydroxy-3-butene (CHB) is a possible metabolite of 1,3-butadiene, a carcinogenic air pollutant. To demonstrate its formation in vivo, it is desirable to develop a practical biomarker and the corresponding analysis method. CHB can undergo alcohol dehydrogenase- and cytochromes P450 enzymes (P450)-mediated oxidation to yield 1-chloro-3-buten-2-one (CBO), which readily forms glutathione conjugates. We hypothesized that CBO-derived mercapturic acids, which are the expected biotransformed products of CBO-glutathione conjugates, could be used as CHB biomarkers. Thus, in the present study, we investigated the in vivo biotransformation of CHB into CBO-derived mercapturic acids. Because the reaction of CBO with N-acetyl-l-cysteine yields two products, 1,4-bis(N-acetyl-S-cysteinyl)-2-butanone (NC1) and 1-chloro-4-(N-acetyl-S-cysteinyl)-2-butanone (NC2), we first developed an isotope dilution LC/ESI--MS-MS method to quantitate urinary NC1 and NC2, and then determined their concentrations in urine of C57BL/6 mice and Sprague-Dawley rats administered CHB. Since no NC2 was detected in samples, the LC/ESI--MS-MS method was optimized specifically for NC1. NC1 was enriched through solid phase extraction with the recovery being 75-82%. The limits of detection and quantitation were 6.8 and 34 fmol/0.1 mL for mouse urine, and 4.5 and 7.1 fmol/0.1 mL for rat urine, respectively. In urine of animals before CHB administration, no NC1 was detected; in mice administered CHB at 10 and 30 mg/kg, and rats at 5 and 15 mg/kg, NC1 was detected and its concentrations in urine from animals given higher doses were 3-6 fold higher than those given lower doses. Moreover, the NC1 concentrations in urine during 0-8 h were 4-6 fold and 10-11 fold higher than those during 8-24 h for mice and rats, respectively. The results demonstrated that CHB could be in vivo biotransformed into NC1, which could be used as a practical CHB biomarker.

PPARG rs3856806 C>T Polymorphism Increased the Risk of Colorectal Cancer: A Case-Control Study in Eastern Chinese Han Population.

Purpose: Functional variants in the peroxisome proliferator-activated receptor gamma (PPARG) and PPARG co-activator 1 (PPARGC1) family (e.g., PPARGC1A and PPARGC1B) genes were predicted to confer susceptibility to colorectal cancer (CRC). The aim of the present study was to explore the relationship between PPARG, PPARGC1A, PPARGC1B polymorphism and the risk of CRC. Patients and methods: We conducted a case-control study with 1,003 CRC cases and 1,303 controls. We selected the PPARG rs3856806 C>T, PPARGC1A rs2970847 C>T, rs8192678 C>T, rs3736265 G>A and PPARGC1B rs7732671 G>C and rs17572019 G>A SNPs to assess the relationship between PPARG, PPARGC1A, PPARGC1B their variants and risk of CRC. Results: We found that the PPARG rs3856806 C>T polymorphism increased the risk of CRC (TT vs. CC: adjusted OR, 1.59, 95% CI 1.08-2.35, P = 0.020; TT/CT vs. CC: adjusted OR, 1.26; 95% CI 1.06-1.49; P = 0.009 and TT vs. CC/CT: adjusted OR, 1.54; 95% CI 1.05-2.26; P = 0.028), even after a Bonferroni correction test. The stratified analysis revealed that the PPARG rs3856806 C>T polymorphism also increased the risk of CRC, especially in male, ≥61 years old, never smoking, never drinking, BMI ≥ 24 kg/m2, colon cancer and rectum cancer subgroups. Conclusion: Our findings highlight that the PPARG rs3856806 C>T polymorphism may increase the risk of CRC. In the future larger sample size case-control studies with a detailed functional assessment are needed to further determine the relationship of the PPARG rs3856806 C>T polymorphism with CRC risk.

Efficacy of paclitaxel-based doublet regimens combining with intraperitoneal chemotherapy for advanced gastric cancer with peritoneal metastasis.

We aim to evaluate the efficacy and safety of paclitaxel-based doublet intravenous chemotherapy (IVC) with and without intraperitoneal chemotherapy (IPC) as the first-line treatment in advanced gastric cancer (AGC) with peritoneal metastasis (PM). 173 AGC patients with peritoneal metastasis were enrolled. All patients received paclitaxel-based doublet systemic chemotherapy Among them, 117 patients received IVC+IPC and 56 patients received IVC alone. The median OS of patients in the IP+ group was longer than the IP- group, however, there was no statistical difference between the two groups (11.1 months vs. 10.1 months, P = 0.072). In the multivariate analysis, the ECOG PS and IVC±IPC were independent prognostic factors for PFS and OS. There were no significant differences in the incidence of grade 3 and 4 toxicity between the IP+(DDP), IP+(FUDR) and IP- groups. Paclitaxel-based doublet regimens combining with IPC is effective, feasible and tolerated in AGC patients with PM.

B-cell Lymphoma 2 rs17757541 C>G polymorphism was associated with an increased risk of gastric cardiac adenocarcinoma in a Chinese population.

AIM: Apoptosis has been considered as a fundamental component in cancer pathogenesis, and related genetic factors might play an important role in gastric cardiac adenocarcinoma (GCA) genesis. METHODS: We conducted a hospital based case-control study to evaluate the genetic effects of functional single nucleotide polymorphisms (SNPs): BCL2 rs17757541 C>G, BCL2 rs12454712 T>C, FAS rs2234767 G>A, FASL/FASLG rs763110 C>T, ERBB2 rs1136201 A>G and VEGFR2/KDR rs11941492 C>T on the development of GCA. A total of 243 GCA cases and 476 controls were recruited for the study and genotypes were determined using a custom-by-design 48-Plex SNPscanTM Kit. RESULTS: The BCL2 rs17757541 C>G polymorphism was associated with increased risk of GCA. However, there was no significant associations with the other five SNPs. Stratified analyses indicated a significantly increased risk of GCA associated with the BCL2 rs17757541 C>G polymorphism among males, older patients and those with a history of smoking or drinking. CONCLUSION: These findings indicated that the functional polymorphism BCL2 rs17757541 C>G might contribute to GCA susceptibility. However, our results were limited by small sample size. Future larger studies are required to confirm our current findings.

Molecular evolution of Japanese encephalitis virus isolates from swine in Oita, Japan during 1980-2009.

In order to identify the patterns of genetic change of Japanese encephalitis virus (JEV) strains circulating in Oita, the complete envelope (E) gene has been sequenced for 35 isolates from swine in a 30-year span. Based on nucleotide and deduced amino acid sequences, the genetic variation was examined, phylogeny was estimated and selection pressures were also analyzed. This study demonstrated that the major genotype (G) of JEV isolates had shifted from GIII to GI in the mid-1990s in Oita. The intensities of selection acting on the Oita GIII and GI strains were found to be almost same. It suggests that the intensity of selection might not be the reason for such a genotype shift observed in Oita. Pairwise comparisons revealed the high conservation of the E gene at the protein level. Compared with the Oita GIII strains, all the Oita GI strains shared four amino acid changes at E129 (T-M), E222 (A-S), E327 (S-T) and E366 (A-S). Among all 70 JEV isolates involved in this paper, the GI strains shared only one amino acid change at E222 (A-S) in comparison with the GIII strains. No strong evidence for positive selection was found, the JEV evolution has generally been subject to strong purifying selection, but one ongoing evolutionary pathway was found to be under relaxed purifying selection in Oita. This study is a localized example of JEV molecular evolution in nature.

Molecular epidemiology of dengue virus serotypes 2 and 3 in Paraguay during 2001-2006: the association of viral clade introductions with shifting serotype dominance.

To determine the genetic variability of dengue viruses (DENVs) in Paraguay, the complete envelope gene was sequenced for 4 DENV-2 and 22 DENV-3 strains isolated from 2001 to 2006. The sequence data were used in Bayesian phylogenetic analyses, which revealed that Paraguayan DENV-2 strains fell into two distinct clades within the American/Asian genotype, thus suggesting that the introduction of a new DENV-2 clade was likely associated with the shift of dominant serotype from DENV-3 to DENV-2 in 2005 and might have caused an outbreak of DENV-2. This study also indicated that DENV-3 strains fell into genotype III, of which, several 2006 isolates varied from the remaining isolates in their tree locations. The introduction of this new clade was likely associated with the shift of dominant serotype from DENV-2 to DENV-3 in 2006 and might have caused an epidemic of DENV-3. More data are needed to test this hypothesis.

Molecular basis for adaptation of a chimeric dengue type-4/Japanese encephalitis virus to Vero cells.

The premembrane and envelope (E) genes of a full-length cDNA clone of the dengue type-4 (DEN4) virus 814669 strain were replaced with those of the Japanese encephalitis (JE) virus JaOH0566 strain. The in vitro-synthesized RNA transcripts prepared from chimeric cDNA were used to transfect mosquito C6/36 cells. A viable chimeric virus (designated DEN4/JE) was recovered. Unexpectedly, DEN4/JE exhibited restricted growth in Vero cells. After a serial passage in Vero cells, the Vero-adapted chimeras were obtained (two clones, designated Strain I and Strain II, respectively). The entire genomes of DEN4/JE, Strain I, and Strain II were sequenced and compared. There were multiple mutations, but amino acid substitutions occurred only in E and nonstructural (NS) protein NS4B. Our findings in this study indicate that the 5' nontranslated region, E, and NS4B may be involved in Vero cell adaptation in this chimeric system.