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1.
J Nutr ; 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33768223

RESUMO

BACKGROUND: Although recent studies have revealed an association between the composition of the gut microbiota and obesity, whether specific gut microbiota cause obesity has not been determined. OBJECTIVES: The aim of this study is to determine the causal relationship between specific gut microbiota and abdominal obesity. Based on genome-wide association study (GWAS) summary statistics, we performed a 2-sample Mendelian randomization (MR) analysis to evaluate whether the gut microbiota affects abdominal obesity. METHODS: Gut microbiota GWAS in 1126 twin pairs (age range, 18-89 years; 89% were females) from the TwinsUK study were used as exposure data. The primary outcome tested was trunk fat mass (TFM) GWAS in 492,805 participants (age range, 40-69 years; 54% were females) from the UK Biobank. The gut microbiota were classified at family, genus, and species levels. A feature was defined as a distinct family, genus, or species. MR analysis was mainly performed by an inverse variance-weighted test or Wald ratio test, depending on the number of instrumental variables (IVs) involved. A sensitivity analysis was performed on significant results by a weighted median test and a weighted genetic risk score (GRS) analysis. RESULTS: Results of MR analyses provided evidence of a causal association between 3 microbiota features and TFM, including 1 family [Lachnosiraceae; P = 0.02; ß = 0.001 (SEE, 4.28 × 10-4)], 1 genus [Bifidobacterium; P = 5.0 × 10-9; ß = -0.08 (SEE, 0.14)], and 1 species [Prausnitzii; P = 0.03; ß = -0.007 (SEE, 0.003)]. Both the weighted median test and GRS analysis successfully validated the association of the genetically predicted family, Lachnosiraceae (Pweighted median = 0.03; PGRS = 0.004). CONCLUSIONS: Our findings provided evidence of a causal association between gut microbiota and TFM in UK adults and identified specific bacteria taxa that may regulate the fat metabolism, thus offering new direction for the treatment of obesity.

2.
Life Sci ; : 118957, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-33524421

RESUMO

The main pathological feature of atherosclerosis is lipid metabolism disorder and inflammation. Macrophages, as the most important immune cells in the body, run through the beginning and end of disease development. After macrophages overtake the atherosclerosis-susceptible area apolipoprotein low-density lipoprotein ox-LDL, they transform into foam cells that adhere to blood vessels and recruit a large number of pro-inflammatory factors to initiate the disease. Promoting the outflow of lipids in foam cells and alleviating inflammation have become the basic ideas for the study of atherosclerosis treatment strategies. The polarization of macrophages refers to the estimation of the activation of macrophages at a specific point in space and time. Determining the proportion of different macrophage phenotypes in the plaque can help identify delay or prevent disease development. However, the abnormal polarization of macrophages and the accumulation of lipid also affect the growth state of cells to some extent, thus aggravate the influence on plaque area and stability. Besides, overactive or deficient autophagy of macrophages may also lead to cell death and participate in lipid metabolism and inflammation regression. In this paper, the role of macrophages in atherosclerosis was discussed from three aspects: polarization, death, and autophagy.

3.
Pharmacol Res ; 166: 105481, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33549726

RESUMO

Cardiovascular disease (CVD) remains the major cause of death worldwide, accounting for almost 31% of the global mortality annually. Several preclinical studies have indicated that ginseng and the major bioactive ingredient (ginsenosides) can modulate several CVDs through diverse mechanisms. However, there is paucity in the translation of such experiments into clinical arena for cardiovascular ailments due to lack of conclusive specific pathways through which these activities are initiated and lack of larger, long-term well-structured clinical trials. Therefore, this review elaborates on current pharmacological effects of ginseng and ginsenosides in the cardiovascular system and provides some insights into the safety, toxicity, and synergistic effects in human trials. The review concludes that before ginseng, ginsenosides and their preparations could be utilized in the clinical treatment of CVDs, there should be more preclinical studies in larger animals (like the guinea pig, rabbit, dog, and monkey) to find the specific dosages, address the toxicity, safety and synergistic effects with other conventional drugs. This could lead to the initiation of large-scale, long-term well-structured randomized, and placebo-controlled clinical trials to test whether treatment is effective for a longer period and test the efficacy against other conventional therapies.

4.
Phytomedicine ; 82: 153406, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33422954

RESUMO

BACKGROUND: Diabetic cardiomyopathy is characterized by both systolic and diastolic dysfunction due to decreased contractility, as well as reduced compliance of the myocardium. Oxidative stress plays a significant role in diabetes mellitus and its cardiovascular complications. Salidroside, a glucoside of the phenylpropanoid tyrosol, reportedly increases the levels of the antioxidative enzymes, nuclear factor erythroid 2-related factor 2, and heme oxygenase-1 (HO-1) to counteract oxidative stress; however, the underlying mechanisms are poorly understood. PURPOSE: Here we investigate the potential cardio-protective effects of salidroside and its mechanism in a diabetic animal model. METHODS: Male db/m, db/db, and age-matched wild-type mice were treated with salidroside at low dose (0.025 mg/kg) or high dose (0.05 mg/kg) by gavage every day for 12 weeks. Cardiac function and structure were assessed by echocardiography and histopathological examination. H9C2 cardiomyocytes were exposed in vitro to advanced glycosylation end products (400 µg/ml) and treated with salidroside (0.1, 1, or 10 µM). The expression of signaling-related genes were explored by western blotting and real-time PCR. RESULTS: Salidroside treatment significantly improved diabetes-induced cardiac dysfunction, hypertrophy, and fibrosis in vivo. Mechanistically, salidroside markedly up-regulates HO-1 expression by activation of the AKT signaling pathway. CONCLUSION: Salidroside protects against cardiomyocyte apoptosis and ventricular remodeling in diabetic mice. This cardio-protective effect of salidroside is dependent on AKT signaling activation.

5.
Sci Rep ; 11(1): 291, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431926

RESUMO

The CLOVES syndrome is an overgrowth disease arising from mosaic activating somatic mutations in the PIK3CA gene. These mutations occur during fetal development producing malformation and overgrowth of a variety of tissues. It has recently been shown that treatment with low doses of a selective inhibitor of Class I PI3K catalytic subunit p110α, the protein product of the PIK3CA gene, can yield dramatic therapeutic benefits for patients with CLOVES and PROS (a spectrum of PIK3CA-related overgrowth syndromes). To assess the long-term effects of moderate loses of p110α activity, we followed development and growth of mice with heterozygous loss of p110α (Pik3ca+/-) over their entire lifetimes, paying particular attention to effects on the brain. While homozygous deletion of the Pik3ca gene is known to result in early embryonic lethality, these Pik3ca+/- mice displayed a longer lifespan compared to their wild-type littermates. These mice appeared normal, exhibited no obvious behavioral abnormalities, and no body weight changes. However, their brains showed a significant reduction in size and weight. Notably, mice featuring deletion of one allele of Pik3ca only in the brain also showed gradually reduced brain size and weight. Mechanistically, either deletion of p110α or pharmacological inhibition of p110α activity reduced neurosphere size, but not numbers, in vitro, suggesting that p110α activity is critical for neuronal stem cells. The phenotypes observed in our two genetically engineered mouse models suggest that the sustained pharmacological inhibition of the PIK3CA activity in human patients might have both beneficial and harmful effects, and future treatments may need to be deployed in a way to avoid or minimize adverse effects.

7.
Gen Physiol Biophys ; 39(6): 545-555, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33226363

RESUMO

Cardiovascular disease (CVD) states are associated with endothelial dysfunction (ED) and increased production of ROS in endothelial cells. The present study aimed to explore the protective effects of antioxidant protein peroxiredoxin 6 (PRDX6) on angiotensin II (AngII)­induced human umbilical vein endothelial cell (HUVEC) dysfunction. To investigate cell viability, levels of inflammatory molecules and proteins were assayed using the CCK-8 assay and evaluated by ELISA and Western blot. NO and ROS levels were determined by Griess assay and the fluorescent probe DCFH-DA. Cell migration capacity was assessed by Transwell assay. AngII decreased cell viability and PRDX6, upregulated the expression levels of TNF-α, IL-6, IL-1ß, LDH and MDA, stimulated ROS production, and reduced NO synthase, the expressions of eNOS, MnSOD, ICAM-1, VCAM-1, and activated the MAPK family of signaling proteins. However, the stimulatory effects of AngII on HUVECs were remarkably suppressed by PRDX6. Furthermore, mercaptosuccinate (MS; PRDX6 inhibitor) had similar effects as AngII in aggravating HUVECs damage. Conversely, these adverse events caused by AngII and MS were obviously reversed by ML3404 and SP600125. The present study indicated that PRDX6 overexpression inactivated p38 MAPK and JNK pathway through decrease AngII-induced inflammation, oxidative stress and endothelial dysfunction leading to attenuation of endothelial cell damage.

8.
Cancer Manag Res ; 12: 11085-11093, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33173341

RESUMO

Purpose: Platinum resistance is a primary barrier to improving the survival rate of ovarian cancer. The relationship between mtDNA somatic mutations and response to platinum-based chemotherapy in ovarian cancer has not been well clarified. Patients and Methods: Here, we employed the next-generation sequencing (NGS) platform to identify mtDNA mutations of the unrelated high-grade serous ovarian cancer (HGSOC) patients. Results: We identified 569 germline variants and 28 mtDNA somatic mutations, and found the platinum-sensitive relapsed HGSOC patients had more synonymous mutations while the platinum-resistant relapsed HGSOC patients had more missense mutations in the mtDNA somatic mutations. Meanwhile, we found that the HGSOC patients who harbored heteroplasmic pathogenic mtDNA somatic mutations had significantly higher prevalence of both platinum-resistance and relapse than those without (80.0% versus 16.7%, p=0.035). Additionally, we observed that the tumor tissues had significantly higher lactate-to-pyruvate (L/P) ratio than the paired nontumor tissues (p<0.001), and L/P ratio of tumors with any heteroplasmic pathogenic mtDNA mutations was significantly higher than that of the tumors free of pathogenic mtDNA mutations (p=0.025). Conclusion: Our findings indicate that these heteroplasmic pathogenic mtDNA somatic mutations may cause decreased respiratory chain activity and lead to the metabolism remodeling that seem to be beneficial for progression of both platinum-based chemotherapy resistance and relapse.

9.
Food Chem ; : 128444, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-33131958

RESUMO

In last ten years, much attention focused on tree peony fruit (TPF) for edible oil production despite other potential utilization. The present study identified and quantified 29 bioactive components by liquid chromatography-electrospray ionization-triple quadrupole-mass spectrometry (LC-ESI-QqQ-MS) targeted approach during the development of TPF. Trans-resveratrol, benzoic acid, luteolin, and methyl gallate were selected as predominant chemical markers between seeds and pods through principal component analysis (PCA) and orthogonal partial least square-discriminant analysis (OPLS-DA). Extremely high levels of paeoniflorin (1893 mg/100 g) and trans-resveratrol (1793 mg/100 g) were observed at stage 2 (S2) and S6 in seeds, respectively. Antioxidant activities determined by ABTS+•, DPPH•, and FRAP assays showed significant correlations with total phenolic content (TPC) and total flavonoid content (TFC). The strongest antibacterial effects of pod and seed against Staphylococcus aureus and Proteus vulgaris occurred at initial stages and maturation stages. TPF could be a potential source of bioactive compounds with functional properties.

10.
Oncol Lett ; 20(6): 361, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33133261

RESUMO

Phospholipid scramblase 1 (PLSCR1) serves a function in the pathogenesis and progression of various types of cancer. However, the role of PLSCR1 in human primary liver cancer remains unknown. The aim of the present study was to evaluate the expression of PLSCR1 in primary liver cancer and analyse the clinical significance. In addition, the present study detected and compared the biological behaviours of HepG2 cells with different levels of activated PLSCR1 or silenced PLSCR1. PLSCR1 expression in primary liver cancer tissue samples was examined using immunohistochemistry. Cultured HepG2 cells were infected with lentiviruses to suppress or activate PLSCR1 expression. Reverse transcription-quantitative PCR and western blotting were performed to analyse the effects of silencing or activating PLSCR1 in cell lines at the mRNA and protein levels, respectively. The effects of PLSCR1 expression on cell proliferation, adhesion, migration and invasion were subsequently determined using Cell Counting Kit 8, adhesion, and Transwell migration and invasion assays. PLSCR1 expression in primary liver cancer tissue samples was higher compared with that in adjacent non-cancerous liver tissue samples and normal tissue samples, and positively correlated with the clinical stage. PLSCR1 was effectively downregulated or overexpressed in HepG2 cells using small interfering RNA and lentivirus techniques, respectively. PLSCR1 upregulation promoted cell proliferation, invasion and migration, while PLSCR1 downregulation inhibited these effects. PLSCR1 is highly expressed in primary liver cancer and associated with the clinical stage. Downregulating the expression of PLSCR1 significantly inhibited the proliferation, adhesion, migration and invasion of cancer cells, suggesting that PLSCR1 may be a potential therapeutic target for preventing the progression of primary liver cancer.

11.
Lancet Oncol ; 21(10): 1378-1386, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002439

RESUMO

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.


Assuntos
Predisposição Genética para Doença/genética , Estilo de Vida Saudável , Neoplasias Gástricas/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Feminino , Seguimentos , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/psicologia , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/psicologia
12.
Onco Targets Ther ; 13: 9857-9863, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116571

RESUMO

Purpose: Survival of platinum-resistant ovarian cancer (PROC) patients is significantly shortened to around 12 months. Anlotinib is a new multi-target tyrosine kinase inhibitor. The goal of this study is to evaluate the efficacy and safety of anlotinib in PROC patients. Patients and Methods: PROC patients treated with anlotinib in Jiangsu Cancer Hospital between June 2018 to September 2019 were recruited. Most patients received an initial bolus of 12mg orally once daily on days 1-14 of a 21-day cycle (except one received a dose of 10mg and another one received a dose of 8mg orally once a day). The adverse events (AEs) and efficacy were analyzed by CTCAE 4.0 and RECIST 1.1. Results: Of all 15 enrolled patients, 12 patients received anlotinib as multi-line therapy and 3 patients received it as maintenance therapy. In the multi-line therapy group, eight patients received anlotinib monotherapy and four patients received anlotinib combined with chemotherapy. Ultimately, evaluation showed that one patient achieved partial response (PR), five patients achieved stable disease (SD) and one patient had progressive disease (PD) with monotherapy, yielding objective response rate (ORR) of 14.3% (95% CI=0.01-0.58) and disease control rate (DCR) of 85.7% (95% CI=0.42-0.99). One patient achieved PR, two patients achieved SD with combination therapy, yielding ORR of 33.3% (95% CI=0.02-0.87) and DCR of 100% (95% CI=0.31-1.00). Three patients with maintenance therapy were followed up for 5, 8, and 11 months, respectively. The most grade 1-2 AEs were hand-foot syndrome, nausea, and hypertension. Serious AEs (SAEs) (Grade 3-4) were observed in one patient with oral ulcer and another patient with hand-foot syndrome that were managed by dose reduction. Conclusion: Anlotinib was of promising efficacy and well tolerated in PROC patients. This is the first retrospective study about exploratory therapy for ovarian cancer patients with anlotinib.

13.
Cell Rep ; 32(13): 108196, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-32997991

RESUMO

Loss of PTEN, the negative regulator of PI3K activity, is frequent in glioblastomas (GBMs). However, the role of the two major PI3K isoforms, p110α and p110ß, in PTEN-deficient gliomagenesis remains unknown. We show that PTEN-deficient GBM largely depends on p110α for proliferation and p110ß for migration. Genetic ablation of either isoform delays tumor progression in mice, but only ablating both isoforms completely blocks GBM driven by the concurrent ablation of Pten and p53. BKM120 (buparlisib) treatment only modestly prolongs survival in mice bearing intracranial Pten/p53 null tumors due to partial pathway inhibition. BKM120 extends the survival of mice bearing intracranial tumors in which p110ß, but not p110α, has been genetically ablated in the Pten/p53 null glioma, indicating that BKM120 fails to inhibit p110ß effectively. Our study suggests that the failure of PI3K inhibitors in GBM may be due to insufficient inhibition of p110ß and indicates a need to develop brain-penetrant p110α/ß inhibitors.

14.
Bone ; : 115652, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32971307

RESUMO

Recent studies have demonstrated the important role played by gut microbiota in regulating bone development, but the evidence of such causal relationship is still sparse in human population. The aim of this study is to assess the causal relationship from gut microbiota to bone development and to identify specific causal bacteria taxa via a Mendelian randomization (MR) approach. A genome-wide association study (GWAS) summary statistic based two-sample MR analysis was performed. Summary statistics of microbiome GWAS (MGWAS) in 1126 twin pairs of the TwinsUK study was used as discovery sample, and the MGWAS in 984 Dutch participants from the LifeLines-DEEP cohort was used as replication sample. Estimated heel bone mineral density (eBMD) GWAS in 426,824 participants from the UK biobank (UKB) cohort was used as outcome. Bacteria were grouped into taxa features at both order and family levels. In the discovery sample, a total of 25 bacteria features including 9 orders and 16 families were analyzed. Fourteen features (5 orders + 9 families) were nominally significant, including 5 orders (Bacteroidales, Clostridiales, Lactobacillales, Pasteurellales and Verrucomicrobiales) and 9 families (Bacteroidaceae, Clostridiaceae, Lachnospiraceae, Mogibacteriaceae, Pasteurellaceae, Porphyromonadaceae, Streptococcaceae, Verrucomicrobiaceae and Veillonellaceae). One order Clostridiales and its child taxon, family Lachnospiraceae, were successfully replicated in the replication sample (Clostridiales Pdiscovery = 3.32 × 10-3Preplication = 7.29 × 10-3; Lachnospiraceae Pdiscovery = 0.03 Preplication = 7.29 × 10-3). Our findings provided evidence of causal relationship from microbiota to bone development, as well as identified specific bacteria taxa that regulated bone mass variation, thus providing new insights into the microbiota mediated bone development mechanism.

15.
Eur J Hum Genet ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963334

RESUMO

Osteoporosis and obesity are two severe complex diseases threatening public health worldwide. Both diseases are under strong genetic determinants as well as genetically correlated. Aiming to identify pleiotropic genes underlying obesity and osteoporosis, we performed a bivariate genome-wide association (GWA) meta-analysis of hip bone mineral density (BMD) and total body fat mass (TBFM) in 12,981 participants from seven samples, and followed by in silico replication in the UK biobank (UKB) cohort sample (N = 217,822). Combining the results from discovery meta-analysis and replication sample, we identified one novel locus, 17q21.31 (lead SNP rs12150327, NC_000017.11:g.44956910G > A, discovery bivariate P = 4.83 × 10-9, replication P = 5.75 × 10-5) at the genome-wide significance level (ɑ = 5.0 × 10-8), which may have pleiotropic effects to both hip BMD and TBFM. Functional annotations highlighted several candidate genes, including KIF18B, C1QL1, and PRPF19 that may exert pleiotropic effects to the development of both body mass and bone mass. Our findings can improve our understanding of the etiology of osteoporosis and obesity, as well as shed light on potential new therapies.

16.
Nat Prod Res ; : 1-5, 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32985239

RESUMO

This work aimed to investigate the hepatoprotective effect of total flavonoids from Glycyrrhiza uralensis. The main compounds in licorice total flavonoids (LTF) were isolated from Glycyrrhiza uralensis and their total content in LTF were more than 60%. Hepatoprotective effects of LTF were investigated in three kinds of hepatic injury mice model induced by high-fat emulsion, Chinese liquor and tetrachloromethane. Serum ALT, AST and ALP levels and hepatic MDA, TG, cholesterol, and hydroxyproline of hepatic injury mice were reduced by LTF. Simultaneously, hepatic SOD and glutathione were increased by LTF. These results suggested that LTF can repair liver tissue and reduce hepatic injury via alleviating inflammation, improving antioxidant enzyme activity and reducing oxidative stress in liver tissue and it may be a valuable natural source of hepatoprotective activity.

17.
Ann Rheum Dis ; 79(12): 1565-1571, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32868391

RESUMO

OBJECTIVES: The present study aimed to discover novel susceptibility loci associated with risk of rheumatoid arthritis (RA). METHODS: We performed a new genome-wide association study (GWAS) in Chinese subjects (1027 RA cases and 2879 controls) and further conducted an expanded meta-analysis with previous GWAS summary data and replication studies. The functional roles of the associated loci were interrogated using publicly available databases. Dual-luciferase reporter and cytokine assay were also used for exploring variant function. RESULTS: We identified five new susceptibility loci (IL12RB2, BOLL-PLCL1, CCR2, TCF7 and IQGAP1; pmeta <5.00E-08) with same effect direction in each study cohort. The sensitivity analyses showed that the genetic association of at least three loci was reliable and robust. All these lead variants are expression quantitative trait loci and overlapped with epigenetic marks in immune cells. Furthermore, genes within the five loci are genetically associated with risk of other autoimmune diseases, and genes within four loci are known functional players in autoimmunity, which supports the validity of our findings. The reporter assay showed that the risk allele of rs8030390 in IQGAP1 have significantly increased reporter activity in HEK293T cells. In addition, the cytokine assay found that the risk allele of rs244672 in TCF7 was most significantly associated with increased plasma IL-17A levels in healthy controls. Finally, identified likely causal genes in these loci significantly interacted with RA drug targets. CONCLUSION: This study identified novel RA risk loci and highlighted that comprehensive genetic study can provide important information for RA pathogenesis and drug therapy.

18.
Front Genet ; 11: 679, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32754194

RESUMO

Genome-wide association studies (GWAS) have identified several susceptibility loci for gastric cancer (GC), but the majority of identified single-nucleotide polymorphisms (SNPs) fall within the non-coding region and are likely to exert their biological function by modulating gene expression. To systematically estimate expression-associated SNPs (eSNPs) that confer genetic predisposition to GC, we evaluated the associations of 314,203 stomach tissue-specific eSNPs with GC risk in three GWAS datasets (2,631 cases and 4,373 controls). Subsequently, we conducted a gene-based analysis to calculate the cumulative effect of eSNPs through sequence kernel association combined test and Sherlock integrative analysis. At the SNP-level, we identified two novel variants (rs836545 at 7p22.1 and rs1892252 at 6p22.2) associated with GC risk. The risk allele carriers of rs836545-T and rs1892252-G exhibited higher expression levels of DAGLB (P = 3.70 × 10-18) and BTN3A2 (P = 3.20 × 10-5), respectively. Gene-based analyses identified DAGLB and FBXO43 as novel susceptibility genes for GC. DAGLB and FBXO43 were significantly overexpressed in GC tissues than in their adjacent tissues (P = 5.59 × 10-7 and P = 3.90 × 10-6, respectively), and high expression level of these two genes was associated with an unfavorable prognosis of GC patients (P = 1.30 × 10-7 and P = 7.60 × 10-3, respectively). Co-expression genes with these two novel genes in normal stomach tissues were significantly enriched in several cancer-related pathways, including P53, MAPK and TGF-beta pathways. In summary, our findings confirm the importance of eSNPs in dissecting the genetic basis of GC, and the identified eSNPs and relevant genes will provide new insight into the genetic and biological basis for the mechanism of GC development.

19.
Cancer Gene Ther ; 2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32759989

RESUMO

More than 24 regulators have been revealed to dynamically participant in N6-methyladenosine (m6A) RNA methylation, and play critical roles in tumorigenesis and development of cancers. However, their functional roles have not been comprehensively clarified in breast cancer. Here we systematically analyzed the RNA sequencing data of 24 main m6A RNA methylation regulators in 775 breast cancer patients from The Cancer Genome Atlas dataset. Consensus clustering of the 24 m6A regulators was carried out and identified two patient subgroups, RNA methylation 1/2 (RM1/2). RM1 demonstrated generally lower RNA methylation modification than that of RM2, and had significantly shorter overall survival. The hallmarks of PI3K/AKT signaling in cancer, KRAS signaling and angiogenesis were significantly enriched in RM1. Moreover, the association between m6A regulators and antitumor immune response was also investigated in this study and revealed that RM2 was associated with significantly higher expressions of HLA-A, higher numbers of tumor-infiltrating CD8+ T cells, helper T cells and activated NK cells, but lower expressions of PD-L1, PD-L2, TIM3, and CCR4 than RM1. In conclusion, the expression pattern of m6A regulators was significantly correlated with the malignancy, prognosis and antitumor immune response in breast cancer, which might serve as potential targets and biomarkers for immunotherapy.

20.
Int J Lab Hematol ; 42(6): 849-857, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32730663

RESUMO

INTRODUCTION: Decitabine-based chemotherapy regimens have shown efficacy in the treatment of elderly patients with acute myeloid leukemia (AML). However, it remains unclear whether any molecular alteration is correlated with the therapeutic effect of such treatment regimens. METHODS: Gene mutations were detected using next-generation sequencing, and their impact on survival was investigated in elderly AML patients receiving decitabine-based chemotherapy. RESULTS: A higher incidence of gene mutations was identified in elderly AML patients than in the younger cohorts. Elderly patients more frequently carried DNMT3A, IDH2, ASXL1, TET2, RUNX1, CEBPA single mutation (CEBPAsingle-mut ), and TP53 mutations. Survival analysis showed that DNMT3A, FLT3-ITD, and TP53 mutations were associated with inferior overall survival (OS) and event-free survival (EFS) in younger AML patients receiving standard treatment. However, in elderly patients treated with decitabine-based chemotherapy, FLT3-ITD, and ASXL1 mutations, but not DNMT3A and TP53 mutations, were associated with poor OS and EFS. Moreover, contrary to CEBPA double mutation (CEBPAdouble-mut ), CEBPAsingle-mut was identified as an unfavorable prognostic factor. CONCLUSION: This study comprehensively analyzed the prognostic implications of gene mutations in elderly AML patients under decitabine-based treatment modality. Identification of genetic biomarkers to predict the subgroup of elderly AML patients who can benefit from decitabine-based regimens might have an immediate clinical utility to optimize the treatment of elderly AML patients.

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