Abstract Background Gastric cancer is one of most common malignancies in the world. Currently the prognostic prediction is entirely based on the TNM staging system. In this study, we evaluated ...whether metastatic lymph node ratio (rN) at the time of surgery would improve the prognostic prediction in conjunction with the TNM staging system. Methods This retrospective study includes 745 patients, who had been referred for surgery due to gastric cancer between 1995 and 2007 and had at least 15 lymph nodes examined at the time of surgery without preoperative treatment. Clinicopathologic features and overall survival were analyzed using univariate and multivariate modes to identify the risk factors for overall survival. Results Median overall survival of all patients analyzed is 57.8 months and 5-year overall survival is 49.5%. Tumor site, macroscopic type, pTNM stage, and rN stage are identified as independent prognostic factors. Increased positive lymph node ratio correlates with shorter survival in all patients and in each T and N stage. In stage III gastric cancer patients, rN stage shows additional prognostic value on overall survival ( p < 0.001). Conclusions rN stage is a simple and promising prognostic factor of gastric cancer after surgery in addition to the TNM stage system especially in stage III patients. But the independent prognostic value of rN stage in stage I, II and IV gastric cancer is yet to be determined.
Mutations in the gene encoding the amyloid protein precursor (APP) cause autosomal dominant Alzheimer's disease. Cleavage of APP by unidentified proteases, referred to as β- and γ-secretases, ...generates the amyloid β-peptide, the main component of the amyloid plaques found in Alzheimer's disease patients. The disease-causing mutations flank the protease cleavage sites in APP and facilitate its cleavage. Here we identify a new membrane-bound aspartyl protease (Asp2) with β-secretase activity. The Asp2 gene is expressed widely in brain and other tissues. Decreasing the expression of Asp2 in cells reduces amyloid β-peptide production and blocks the accumulation of the carboxy-terminal APP fragment that is created by β-secretase cleavage. Solubilized Asp2 protein cleaves a synthetic APP peptide substrate at the β-secretase site, and the rate of cleavage is increased tenfold by a mutation associated with early-onset Alzheimer's disease in Sweden. Thus, Asp2 is a new protein target for drugs that are designed to block the production of amyloid β-peptide peptide and the consequent formation of amyloid plaque in Alzheimer's disease.
DNA methylation (DNAm) clocks are important biomarkers of cellular aging and are associated with a variety of age-related chronic diseases and all-cause mortality. Examining the relationship between ...education and lifestyle risk factors for age-related diseases and multiple DNAm clocks can increase the understanding of how risk factors contribute to aging at the cellular level. This study explored the association between education or lifestyle risk factors for age-related diseases and the acceleration of four DNAm clocks, including intrinsic (IEAA) and extrinsic epigenetic age acceleration (EEAA), PhenoAge acceleration (PhenoAA), and GrimAge acceleration (GrimAA) in the African American participants of the Genetic Epidemiology Network of Arteriopathy. We performed both cross-sectional and longitudinal analyses. In cross-sectional analyses, gender, education, BMI, smoking, and alcohol consumption were all independently associated with GrimAA, whereas only some of them were associated with other clocks. The effect of smoking and education on GrimAA varied by gender. Longitudinal analyses suggest that age and BMI continued to increase GrimAA, and that age and current smoking continued to increase PhenoAA after controlling DNAm clocks at baseline. In conclusion, education and common lifestyle risk factors were associated with multiple DNAm clocks. However, the association with each risk factor varied by clock, which suggests that different clocks may capture adverse effects from different environmental stimuli.
The gut microbiota modifies endogenous primary bile acids (BAs) to produce exogenous secondary BAs, which may be further metabolized by cytochrome P450 enzymes (P450s). Our primary aim was to examine ...how the host adapts to the stress of microbe-derived secondary BAs by P450-mediated oxidative modifications on the steroid nucleus. Five unconjugated tri-hydroxyl BAs that were structurally and/or biologically associated with deoxycholate (DCA) were determined in human biologic samples by liquid chromatography-tandem mass spectrometry in combination with enzyme-digestion techniques. They were identified as DCA-19-ol, DCA-6
-ol, DCA-5
-ol, DCA-6
-ol, DCA-1
-ol, and DCA-4
-ol based on matching in-laboratory synthesized standards. Metabolic inhibition assays in human liver microsomes and recombinant P450 assays revealed that CYP3A4 and CYP3A7 were responsible for the regioselective oxidations of both DCA and its conjugated forms, glycodeoxycholate (GDCA) and taurodeoxycholate (TDCA). The modification of secondary BAs to tertiary BAs defines a host liver (primary BAs)-gut microbiota (secondary BAs)-host liver (tertiary BAs) axis. The regioselective oxidations of DCA, GDCA, and TDCA by CYP3A4 and CYP3A7 may help eliminate host-toxic DCA species. The 19- and 4
-hydroxylation of DCA species demonstrated outstanding CYP3A7 selectivity and may be useful as indicators of CYP3A7 activity.
Statins reduce cardiovascular morbidity and mortality in appropriately selected patients. However, statin-associated myopathy is a significant risk associated with these agents. Recently, variation ...in the SLCO1B1 gene was reported to predict simvastatin-associated myopathy. The aim of this study was to replicate association of the rs4149056 variant in SLCO1B1 with severe statin-associated myopathy in a cohort of patients using a variety of statin medications and to investigate the association with specific statin types. We identified 25 cases of severe statin-associated myopathy and 84 controls matched for age, gender, statin type and dose. The rs4149056 variant in SLCO1B1 was not significantly associated with myopathy in this group as a whole. However, when subjects were stratified by statin type, the SLCO1B1 rs4149056 genotype was significantly associated with myopathy in patients who received simvastatin, but not in patients who received atorvastatin. Our findings provide further support for a role for SLCO1B1 genotype in simvastatin-associated myopathy, and suggest that this association may be stronger for simvastatin compared with atorvastatin.
Introduction: Cigarette smoking has been associated with adverse health outcomes for mothers and children and is a major contributor to heart disease. Although cigarette smoking is known to affect ...the epigenome, few studies have been done in African American populations. In this study, we investigated the association between cigarette smoking and DNA methylation (DNAm) among African Americans from the Intergenerational Impact of Genetic and Psychological Factors on Blood Pressure Study (InterGEN), and the Genetic Epidemiology Network of Arteriopathy (GENOA).
Methods: The InterGEN study aims to examine the effects of genetic and psychological factors on blood pressure among African American women and their children. Current cigarette smoking was assessed at baseline. DNAm of saliva was assessed using the 850K EPIC Illumina BeadChip for Epigenome-Wide Association analyses. A replication study was conducted among 1100 participants in the GENOA study using the same BeadChip.
Results: After controlling for age, body mass index, population structure and cell composition, 26 epigenome-wide significant sites (FDR q < 0.05) were identified, including the AHRR and PHF14 genes associated with atherosclerosis and lung disease, respectively. Six novel CpG sites were discovered in the InterGEN sample and replicated in the GENOA sample. Genes mapped include RARA, FSIP1, ALPP, PIK3R5, KIAA0087, and MGAT3, which were largely associated with cancer development.
Conclusion: We observed significant epigenetic associations between smoking and disease-associated genes (e.g., cardiovascular disease, lung cancer). Six novel CpG sites were identified and replicated across saliva and blood samples.
To study the effect of micro ribonucleic acid (miR)-31 on rats with chronic obstructive pulmonary disease (COPD) by activating the nuclear factor-κB (NF-κB) signaling pathway.
A total of 36 ...Sprague-Dawley rats were randomly divided into normal group (n=12), model group (n=12) and miR-31 mimics group (n=12). The rats were fed normally in normal group. In model group, the COPD model was first established, followed by intervention using normal saline. In miR-31 mimics group, the COPD model was also first established, followed by intervention using miR-31 mimics. The expression of NF-κB was detected via immunohistochemistry. Protein expressions of B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax) were determined through Western blotting. Serum levels of interleukin-6 (IL-6), IL-18 and tumor necrosis factor-α (TNF-α) were measured via enzyme-linked immunosorbent assay (ELISA). Moreover, the apoptosis was examined via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and the relative expression of miR-31 was detected by means of quantitative polymerase chain reaction (qPCR).
The immunohistochemistry results showed that the positive expression of NF-κB was significantly higher in the other two groups than that in normal group (p<0.05), while it was also remarkably higher in miR-31 mimics group than that in model group (p<0.05). The results of Western blotting revealed that the relative protein expression of Bax significantly increased, while that of Bcl-2 notably declined in the other two groups compared with those in normal group (p<0.05). Similarly, the relative protein expression of Bax was upregulated, while that of Bcl-2 was distinctly reduced in miR-31 mimics group compared with those in model group (p<0.05). It was found via ELISA that the model group and miR-31 mimics group had evidently higher levels of IL-6, IL-18 and TNF-α than those in normal group (p<0.05), while miR-31 mimics group also had prominently higher levels than those in model group (p<0.05). In addition, according to the TUNEL assay, the apoptosis rate remarkably increased in the other two groups in comparison with that in normal group (p<0.05), while it remarkably rose in miR-31 mimics group compared with that in model group (p<0.05). Finally, a significantly higher expression of miR-31 was observed in the other two groups than that in normal group via qPCR (p<0.05), and such a higher expression was also found in miR-31 mimics group than that in model group (p<0.05).
MiR-31 aggravates inflammation and apoptosis in COPD rats by activating the NF-κB signaling pathway.
Abstract
Genome-wide association studies (GWAS) conducted in European ancestry (EA) have identified hundreds of single-nucleotide polymorphisms (SNPs) associated with general cognitive function ...and/or Alzheimer’s disease (AD). The association between these SNPs and cognitive function has not been fully evaluated in populations with complex genetic substructure such as South Asians. This study investigated whether SNPs identified in EA GWAS, either individually or as polygenic risk scores (PRSs), were associated with general cognitive function and 5 broad cognitive domains in 932 South Asians from the Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD). We found that SNPs identified from AD GWAS were more strongly associated with cognitive function in LASI-DAD than those from a GWAS of general cognitive function. PRSs for general cognitive function and AD explained up to 1.1% of the variability in LASI-DAD cognitive domain scores. Our study represents an important stepping stone toward better characterization of the genetic architecture of cognitive aging in the Indian/South Asian population and highlights the need for further research that may lead to the identification of new variants unique to this population.
BACKGROUND/OBJECTIVES
Genetic factors play an important role in Alzheimer's disease (AD) and cognitive aging. However, it is unclear whether risk loci identified in European ancestry (EA) populations ...have similar effects in other groups, such as South Asians.
DESIGN
We investigated the allelic distribution and cognitive associations of 56 known AD risk single‐nucleotide polymorphisms (SNPs) identified from three EA genome‐wide association studies (EA‐GWASs) in a South Asian population. Single SNP and genetic risk score (GRS) associations with measures of episodic memory were assessed.
SETTING
The Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI‐DAD).
PARTICIPANTS
A total of 906 LASI‐DAD participants from diverse states in India.
MEASUREMENTS
Participants were genotyped using the Illumina Global Screening Array and imputed with 1000G Phase 3v5. Cognitive measures included total learning and delayed word recall.
RESULTS
Although only a few SNPs were significantly associated with memory scores (P < .05), effect estimates from the EA‐GWAS and the LASI‐DAD showed moderate correlation (0.35–0.88) in the expected direction. GRSs were also associated with memory scores, although percentage variation explained was small (0.1%–0.6%).
CONCLUSIONS
Discrepancies in allele frequencies and cognitive association results suggest that genetic factors found predominantly through EA‐GWASs may play a limited role in South Asians. However, the extent of differences in the genetic architecture of AD and cognition in EA and South Asians remains uncertain. There is also a critical need to perform a more comprehensive assessment of the mutational spectrum of South Asia to identify novel genetic variants associated with AD and cognition in this population. J Am Geriatr Soc 68:S45‐S53, 2020.
The inclusive electron neutrino charged-current cross section is measured in the NOvA near detector using 8.02 x 1020 protons-on-target (POT) in the NuMI beam. The sample of GeV electron neutrino ...interactions is the largest analyzed to date and is limited by ≃ 17% systematic rather than the ≃ 7.4% statistical uncertainties. The double-differential cross section in final-state electron energy and angle is presented for the first time, together with the single-differential dependence on Q2 (squared four-momentum transfer) and energy, in the range 1 GeV ≤ Eν < 6 GeV. Detailed comparisons are made to the predictions of the GENIE, GiBUU, NEUT, and NuWro neutrino event generators. The data do not strongly favor a model over the others consistently across all three cross sections measured, though some models have especially good or poor agreement in the single differential cross section vs. Q2.
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