Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study.

BACKGROUND: TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes. METHODS: In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18-75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103. RESULTS: A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, n = 12 per group) or placebo (n = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 µg*h/mL, and AUC0-inf ranged from 159 to 340 µg*h/mL. TG103 had a half-life of 110-116 h, with a median Tmax of 36-48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with p < 0.05 for all comparisons with placebo. CONCLUSIONS: In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

Antioxidants-related nuclear factor erythroid 2-related factor 2 gene variants associated with HBV-related liver disease.

BACKGROUND: Accumulating evidence demonstrated that nuclear factor erythroid 2-related factor 2 (NRF2) expression plays a crucial role in the proliferation, invasion and metastasis of hepatocellular carcinoma (HCC). However, research on the effect of NRF2 genetic polymorphism on the development of chronic hepatitis B (CHB), HBV-related liver cirrhosis (LC) and HCC is still missing. METHODS: A total of 673 individuals were included in the study and classified into four groups: 110 CHB cases, 86 LC cases, 260 HCC cases, and 217 healthy controls. ​The polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing method were used to detect rs6721961 and rs6726395 polymorphisms. RESULTS: Patients carrying the T allele in rs6721961 were at a higher risk of HCC than individuals with the G allele compared to CHB patients (OR = 1.561, 95%CI: 1.003-2.430, P = 0.048). The statistically significant differences were also found in the rs6721961 GT genotype (OR = 2.298, 95% CI: 1.282-4.119, P = 0.005) and dominant model (OR = 2.039, 95% CI: 1.184-0.510, P = 0.010). Subgroup analysis also detected a significant association between the rs6721961 T allele and the development of HCC in older subjects (≥ 50 years) (OR = 2.148, 95% CI: 1.208-3.818, P = 0.009). Statistical analysis results indicated that subjects carrying haplotype G-A had a lower risk of HCC (OR = 0.700, 95% CI: 0.508-0.965, P = 0.028). CONCLUSIONS: For the first time, our findings provide evidence that the NRF2 gene rs6721961 variation is a potential genetic marker of susceptibility to HCC.

Baseline Data and HLA Alleles and Haplotypes Diversity and Panel Reactive Antibody in Kidney Transplant Candidates in Southwest China.

BACKGROUND: To investigate the baseline data characteristic, human leukocyte antigen (HLA) polymorphisms, and panel reactive antibody (PRA) in end-stage kidney disease (ESKD) patients awaiting kidney transplantation in Southwest China. METHODS: HLA genotyping was performed using the real-time PCR sequence-specific primer. PRA was detected by enzyme-linked immunosorbent assay. The patients' medical records were extracted from the hospital information database. RESULTS: A total of 281 kidney transplant candidates with ESKD were analyzed. The average age was 35.7 ± 13.8 years. There were 61.6% patients had hypertension, 40.2% patients had dialysis ≥ 3 times per week, 47.3% patients had moderate or severe anemia, 30.2% patients with albumin < 35 g/L, 49.1% patients had serum ferritin < 200 ng/mL, 40.5% patients had serum calcium in target range (2.23 - 2.80 mmol/L), 43.4% patients had serum phosphate in target range (1.45 - 2.10 mmol/L), and 93.6% patients with parathyroid hormone > 88.00 pg/mL. In total, 15 HLA-A, 28 HLA-B, 15 HLA-DRB1, and 8 HLA-DQB1 allelic groups were identified. The most frequent alleles for each locus were HLA-A*02 (33.63%), HLA-B*46 (14.41%), HLA-DRB1*15 (21.89%), and HLA-DQB1*05 (39.50%). The most frequent haplotypes were HLA-A*33-B*58-DRB1*17-DQB1*02. A total of 9.60% of patients tested positive for PRAs - Class I or Class II. CONCLUSIONS: The data from this study provide some new insights into baseline data, the distribution of HLA polymorphisms, and PRA results in the population of Southwest China. This is of great significance in this region, and indeed in the country as a whole, in comparison with other populations and in the process of organ transplant allocation.

Asymmetric C1 Extension of Aldehydes through Biocatalytic Cascades for Stereodivergent Synthesis of Mandelic Acids.

The development of mild, efficient, and enantioselective methods for preparing chiral building blocks from simple, renewable carbon units has been a long-term goal of the sustainable chemical industry. Mandelate derivatives are valuable pharmaceutical intermediates and chiral resolving agents, but their manufacture relies heavily on highly toxic cyanide. Herein, we report (S)-4-hydroxymandelate synthase (HmaS)-centered biocatalytic cascades for the synthesis of mandelates from benzaldehydes and glycine. We show that HmaS can be engineered to perform R-selective hydroxylation by single-point mutation, empowering the stereodivergent synthesis of both (S)- and (R)-mandelate derivatives. These biocatalytic cascades enabled the production of various mandelate derivatives with high atom economy as well as excellent yields (up to 98 %) and ee values (up to >99 %). This methodology offers an effective cyanide-free technology for greener and sustainable production of mandelate derivatives.

Versatile Biocatalytic C(sp3 )-H Oxyfunctionalization for the Site- Selective and Stereodivergent Synthesis of α- and ß-Hydroxy Acids.

C(sp3 )-H oxyfunctionalization, the insertion of an O-atom into C(sp3 )-H bonds, streamlines the synthesis of complex molecules from easily accessible precursors and represents one of the most challenging tasks in organic chemistry with regard to site and stereoselectivity. Biocatalytic C(sp3 )-H oxyfunctionalization has the potential to overcome limitations inherent to small-molecule-mediated approaches by delivering catalyst-controlled selectivity. Through enzyme repurposing and activity profiling of natural variants, we have developed a subfamily of α-ketoglutarate-dependent iron dioxygenases that catalyze the site- and stereodivergent oxyfunctionalization of secondary and tertiary C(sp3 )-H bonds, providing concise synthetic routes towards four types of 92 α- and ß-hydroxy acids with high efficiency and selectivity. This method provides a biocatalytic approach for the production of valuable but synthetically challenging chiral hydroxy acid building blocks.

Association between WNT-1-inducible signaling pathway protein-1 (WISP1) genetic polymorphisms and the risk of gastric cancer in Guangxi Chinese.

BACKGROUND: WNT1-inducible signaling pathway protein 1 (WISP1) is a member of the CCN protein family and a downstream target of ß-catenin. Aberrant WISP1 expression may be involved in carcinogenesis. To date, no studies have investigated the association between single-nucleotide polymorphisms (SNPs) of WISP1 and gastric cancer. Therefore, we conducted this study to explore their relationship. METHODS: Polymerase chain reaction-restriction fragment length polymorphism assay was used to analyze three SNPs of WISP1 in 204 gastric cancer patients and 227 controls. RESULTS: Overall, we could not identify a significant association between WISP1 SNPs and gastric cancer risk. However, the subgroup analysis demonstrated that the presence of the rs7843546 T allele was associated with a significantly decreased risk of gastric cancer in those of Han Chinese ethnicity (CT vs. CC: OR = 0.33, 95%CI 0.14-0.78; TT vs. CC: OR = 0.29, 95%CI 0.11-0.76; CT + TT vs. CC: OR = 0.32, 95%CI 0.14-0.74). In addition, patients with the rs7843546 TT genotype display a 0.34-fold lower risk of developing stage I/II gastric cancer than those with the CC genotype Furthermore, individuals ≥ 50 years old who carried the rs10956697 AC genotype had a significantly decreased risk of gastric cancer (OR = 0.58, 95%CI 0.35-0.98). Smokers with the rs10956697 AC and AC + AA genotypes exhibited a 0.28-fold lower and 0.32-fold lower risk of gastric cancer, respectively. CONCLUSIONS: The WISP1 SNPs rs7843546 and rs10956697 were, for the first time, found to reduce susceptibility to gastric cancer in various subgroups of Guangxi Chinese.

Identification and characterization of a subpopulation of CD133+ cancer stem-like cells derived from SK-UT-1 cells.

BACKGROUND: Uterine leiomyosarcoma (ULMS) is a malignant tumor found in the smooth muscle lining the walls of the uterus. Cancer stem cells (CSCs) are responsible for metastasis, drug resistance, and relapse of cancer, resulting in treatment failure. However, little is known about CSCs and their associated-markers in ULMS. We aimed to characterize and identify a subpopulation of CD133+ cancer stem-like cells derived from SK-UT-1 cell line. METHODS: SK-UT-1 cells were sphere-forming cultured in vitro. We also sorted the CD133+ cells derived from SK-UT-1 cell line by immunomagnetic beads. CD133+ subpopulation and apoptotic cells were detected by flow cytometry. Self-renewal and anchorage-independent growth capabilities were examined using sphere and colony formation assays. The tumorigenicity of the fourth-passage spheres and parental SK-UT-1 cells was used by mouse xenograft model in vivo. Cell proliferation ability and sensitivity to doxorubicin (DXR) were assessed by CCK-8 assay. Cell migration and invasion were tested by wound healing assay or Transwell migration and invasion assays. Expressions of CSC-related marker were analyzed by Western blotting. RESULTS: The fourth-passage spheres were defined as a CD133+ cell population, which was accompanied by increase of sphere and colony forming rate, migration and invasion abilities, as well as drug-resistant properties in vitro. Moreover, the fourth-passage spheres showed a stronger tumorigenic potential in vivo. CD133+ cell population sorted from SK-UT-1 line showed an increased ability in sphere and colony formation, proliferation, migration, invasion, resistance to apoptosis after treatment with doxorubicin (DXR) compared with CD133- cell population. The expression levels of CSCs-related markers (e.g., CD44, ALDH1,BMI1, and Nanog), were significantly elevated in CD133+ cells compared with those in CD133- cells. CONCLUSIONS: Collectively, our findings indicated that CD133 may be a significant marker for cancer stem-like cells, and it may be a potential therapeutic target for human ULMS.

HBV promotes the recruitment of IL-17 secreting T cells via chemokines CCL22 and CCL17.

BACKGROUND AND AIMS: Little is known about the mechanisms of IL-17 secreting T cells accumulation in HBV-transfected livers. Here, we investigated the role of the chemokines CCL17, CCL20 and CCL22 in this process. METHODS: Peripheral blood and liver tissues were obtained from 30 chronic hepatitis B (CHB) patients and 15 healthy volunteers and were evaluated by flow cytometric analysis and immunohistochemistry. Chemokine production by monocyte-derived dendritic cells (MoDCs) cocultured with HBV-transfected or untransfected Huh7 cells was measured by quantitative real-time PCR and enzyme-linked immunosorbent assay. The chemotactic activity of the culture supernatants was also tested. RESULTS: The proportions of IL-17 secreting CD4 (Th17) and CD8 (Tc17) T cells were both increased in liver and peripheral blood mononuclear cells of CHB patients compared to those in HVs. CHB patients showed higher intrahepatic levels of CCL17 mRNA, CCL22 mRNA, CCR6 mRNA and CCR4 mRNA than HVs. The expression of CCR6 and CCR4 on the surface of Th17 and Tc17 cells in CHB patients was also significantly higher than that in HVs. Significant correlations existed between the CCR4/CCR6 levels and both the alanine transaminase levels and HBV DNA loads. Contact between MoDCs and pBlue-HBV-transfected Huh7 cells induced the expression of CCL17 and CCL22 dependent on the dose of HBV DNA. However, CCL20 expression was lower in CHB patients than in HVs. Transwell experiments showed that upregulation of CCL17 and CCL22 enhanced the migration of IL-17 secreting T cells. CONCLUSIONS: Contact of HBV-transfected cells with MoDCs induces CCL17 and CCL22 chemokine production, which may favour the recruitment of Th17 and Tc17 cells to liver tissue in CHB. Our results reveal the mechanism of IL-17 secreting T cells recruitment to liver tissue and thus provide new immunotherapy targets for CHB patients.

Effect of RAGE gene polymorphisms and circulating sRAGE levels on susceptibility to gastric cancer: a case-control study.

BACKGROUND: To investigate the influence of polymorphisms in the receptor for advanced glycation end products (RAGE) gene and circulating soluble RAGE (sRAGE) levels on susceptibility to gastric cancer, and identify whether these polymorphisms were correlated with serum sRAGE levels. METHODS: We performed a hospital-based case-control study involving 200 gastric cancer patients and 207 cancer-free controls. Four well-characterized RAGE genetic polymorphisms, namely, rs1800624, rs1800625, rs184003, and rs2070600 were genotyped by PCR-RFLP. RESULTS: The rs2070600 AG genotype might play a predominant role in the development of gastric cancer (adjusted OR 1.62, 95% CI 1.03-2.58). In contrast, the rs184003 GT genotype represented significantly reduced risk for gastric cancer (adjusted OR 0.62, 95% CI 0.39-0.99). Subgroup analysis demonstrated that rs2070600 AG variant genotype enhanced the gastric cancer risk among nonsmokers (OR 1.71, 95% CI 1.01-2.91), nondrinkers (OR 1.75, 95% CI 1.03-2.97), and patients with tumor stage III (OR 2.00, 95% CI 1.13-3.56). The average sRAGE levels in the gastric cancer patients were significantly decreased compared with those of the healthy controls. Subjects carrying the rs2070600 AG genotype had a decreased ability to produce sRAGE. Subjects carrying the rs184003 T variant allele had an increased ability to sRAGE. CONCLUSIONS: These findings suggested that the variant genotypes of rs184003 and rs2070600 in the RAGE gene exhibit significant associations with gastric cancer risk and circulating sRAGE levels inverse change simultaneously, leading to a marked causal estimate between lowered sRAGE levels and increased gastric cancer risk.

P-glycoprotein gene MDR1 polymorphisms and susceptibility to systemic lupus erythematosus in Guangxi population: a case-control study.

The multidrug resistance 1 gene (MDR1) encodes for P-glycoprotein (P-gp), which plays a pathophysiological role in the development of autoimmune diseases, including systemic lupus erythematosus (SLE). Herein, we aimed to investigate the relationship between MDR1 gene polymorphisms and SLE susceptibility in the Chinese Guangxi population. The genotypes of rs1128503 and rs1045642 in MDR1 gene were analyzed using the polymerase chain reaction-restriction fragment length polymorphism method in 283 SLE patients and 247 healthy controls from Guangxi. Direct sequencing method was used to verify the results. Binary logistic regression analyses adjusting for gender and age indicated that subjects carrying the rs1128503 T-allele and TT genotype were at increased risk of SLE when compared to carriers of the C allele and CC genotype, with adjusted ORs of 1.36 (95% CI 1.07-1.74; P = 0.014) and 1.77 (95% CI 1.08-2.88; P = 0.022), respectively. In addition, the risk allele T had a recessive effect (OR 1.49, 95% CI 1.04-2.14, P = 0.029). Subgroup analyses revealed effect modification by age for the presence of the rs1128503 T allele, yielding a significant positive association with SLE in older (≥40 years) subjects (T vs. C allele: OR 1.41, 95% CI 1.01-1.96; P = 0.041; TT vs. CC genotype: OR 1.74, 95% CI 1.07-2.79; P = 0.021). For the first time, we demonstrated that MDR1 rs1128503 polymorphisms were associated with SLE susceptibility in Chinese Guangxi population.

PIN1 genetic polymorphisms and the susceptibility of HBV-related hepatocellular carcinoma in a Guangxi population.

Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (PIN1) plays a critical role in different signaling pathways, cell cycle progression and proliferation, and gene expression, and it has been found to overexpress in many tumor tissues. Recently, researchers have found that PIN1 gene polymorphisms may alter the function of protein and be associated with the risk of cancer. The present study analyzed three common polymorphisms in promoter regions (rs2233678 and rs2233679) and in exon2 (rs2233682) of the PIN1 gene in 254 patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and 235 healthy controls in a Guangxi study population to determine whether any relationship exists between the polymorphisms and the risk of HBV-related HCC. The results revealed that the rs2233679 TT genotype was associated with increased risk of HCC with HBV infection [odds ratio (OR) = 2.04, 95 % confidence interval (95 % CI) = 1.13-3.69, p = 0.019]. This association was stronger in men than in women (OR = 2.17, 95 % CI = 1.09-4.34, p = 0.028) as well as in men 50 years of age and older (OR = 3.91, 95 % CI = 1.29-11.80, p = 0.016); moreover, for alcohol drinkers, being a carrier of the PIN1 rs2233679 CT genotype had a moderately increased risk of HCC (OR = 3.98, 95 % CI = 1.02-15.57, p = 0.047). In contrast, people carrying the rs2233682 GA genotype and A alleles were 0.23 times more likely to develop HCC (OR = 0.23, 95 % CI = 0.06-0.87, p = 0.031 and OR = 0.23, 95 % CI = 0.06-0.87, p = 0.030). No such associations were found in the PIN1 rs2233678 polymorphisms between the HBV-related HCC cases and the controls. In addition, the haplotype GCA was found to be a high protection factor for HCC with HBV infection (OR = 0.14, 95 % CI = 0.03-0.62, p = 0.003). In conclusion, this study's findings suggest that the PIN1 rs2233679 TT genotype, the rs2233682GA genotype, and A alleles might be associated with the HBV-related HCC in a Guangxi study population.

Association of the NQO1 C609T polymorphism with Alzheimer's disease in Chinese populations: a meta-analysis.

Several molecular genetics studies have investigated the association of NQO1 C609T polymorphism with Alzheimer's disease (AD) susceptibility in Chinese populations; however, the findings are inconclusive. To investigate the association, we performed the present meta-analysis of 5 case-control studies (including 735 AD cases and 828 controls). We searched literature from PubMed, Embase, HuGNet and CNKI databases for eligible articles that evaluated the association between NQO1 C609T polymorphism and AD risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of the association. Overall, C609T polymorphism was significantly associated with an increased AD risk (homozygote: OR = 1.87, 95% CI = 1.39-2.51, P = 0.000; heterozygote: OR = 1.93, 95% CI = 1.22-3.06, P = 0.019; dominant: OR = 1.97, 95% CI = 1.25-3.12, P = 0.004). When stratified by source of control, significant results were observed in subjects of population-based (PB), whereas no increased risk was observed among the hospital-based (HB). When stratified by APOEϵ4 carrier status, no effect of the NQO1 C609T polymorphism was seen in subjects of APOEϵ4 carriers and APOEϵ4 non-carriers. In conclusion, our results showed that NQO1 C609T polymorphism increases the risk of AD in Chinese populations. Larger studies with different ethnic populations are required to validate our findings.

Association between IL-18 polymorphisms, serum levels, and HBV-related hepatocellular carcinoma in a Chinese population: a retrospective case-control study.

BACKGROUND: Interleukin (IL)-18 gene polymorphisms have been found to play multiple roles in various diseases. However, studies focused on its involvement in hepatocellular carcinoma (HCC) remains controversial, and no much study has taken IL-18 serum levels into consideration. This study investigates the association between IL-18 polymorphisms and risk of hepatitis B virus-related HCC and their impact on serum IL-18 serum levels. METHODS: A total of 153 patients and 165 healthy controls were enrolled in this study. Polymorphisms at positions -607C/A and -137G/C in the IL-18 gene were determined using the polymerase chain reaction-restriction fragment length polymorphism method. Serum IL-18 levels were determined with an ELISA kit. RESULTS: No relationship was found between the -607C/A polymorphism and an individual's susceptibility to HCC. For the -137G/C polymorphism, the GC genotype and C allele were found to be significantly associated with decreased HCC risk (OR 0.506, 95% CI 0.290-0.882, P = 0.016 and OR 0.520, 95% CI 0.332-0.814, P = 0.004, respectively). The A(-607)C(-137) haplotype was also associated with a significant decreased risk of HCC (OR 0.495, 95% CI 0.294-0.834, P = 0.007). Serum IL-18 levels were found to be significantly lower in HCC patients compared to the control group in both the overall population and subjects with the different SNPs. Further, no association was found between serum IL-18 levels and the different genotypes within the same SNP. CONCLUSION: These findings suggest that the -137G/C SNP in IL-18 may be a protective factor against HCC. Nevertheless, none of the studied SNPs was associated with the expression of IL-18.

Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis.

BACKGROUND: It has been postulated that non-steroidal anti-inflammatory drugs (NSAIDs) use leads to decreased prostate cancer (PCa) risk. In recent years, NSAIDs' role in PCa development has been extensively studied; however, there is not yet a definitive answer. Moreover, the epidemiological results for NSAIDs' effect on PCa-specific mortality have been inconsistent. Therefore, we performed a meta-analysis to examine the controversy. METHODS: We performed a literature database search and included all published studies conducted in the general population exposed to any NSAID, extracting an odds ratio (OR) or a hazard ratio (HR) with 95% confidence intervals (95% CIs) that compared the incidence of PCa or PCa-specific mortality with non-exposure. We derived a pooled OR or HR using random or fixed effects models, as appropriate. Subgroup analyses were also performed. RESULTS: Thirty-nine studies (20 case-control and 19 cohort studies) were included in this analysis. Thirty-one studies were available concerning NSAID use and PCa incidence and eight studies on PCa-specific mortality. Compared to non-use, aspirin use was statistically significantly associated with PCa incidence risk, and the association was slightly stronger for advanced PCa than for total PCa (OR = 0.92, 95% CI = 0.87 to 0.97 for total PCa; OR = 0.81, 95% CI = 0.73 to 0.89 for advanced PCa). Aspirin use seems also to be associated with a modest reduction in PCa-specific mortality (HR = 0.86, 95% CI = 0.78 to 0.96 for total PCa; OR = 0.81, 95% CI = 0.71 to 0.92 for advanced PCa). Generally, the pooled effects for any NSAIDs, NA-NSAIDs and cyclooxygenase-2 inhibitors demonstrated no adverse or beneficial effects on PCa development or PCa-specific mortality, but the results were not consistent. The effect estimates did not vary markedly when stratified by study design and study quality but varied by geographic region. Furthermore, long-term aspirin use (≥ 4 years) was also significantly associated with reduced PCa incidence (OR = 0.88, 95% CI 0.79 to 0.99). CONCLUSIONS: The present meta-analysis provides support for the hypothesis that aspirin use is inversely related to PCa incidence and PCa-specific mortality. The effect estimates, varying by geographic region, deserve further investigation.

Association between statin use and colorectal cancer risk: a meta-analysis of 42 studies.

PURPOSE: There is a long-standing debate about whether statins have chemopreventive properties against colorectal cancer (CRC), but the results remain inconclusive. We therefore present a meta-analysis to investigate the association between statin use and risk of CRC. METHODS: A comprehensive literature search was undertaken through July 2013 looking for eligible studies. Pooled relative risk (RR) estimates and 95 % confidence intervals (CIs) were used to calculate estimated effect. RESULTS: Forty-two studies [18 case-control studies, 13 cohort studies, and 11 randomized controlled trials (RCTs)] were included in this analysis. Overall, statin use was associated with a modest reduction in the risk of CRC (RR = 0.90, 95 % CI 0.86-0.95). When the analyses were stratified into subgroups, a significant decreased association of CRC risk was observed in observational studies (RR = 0.89, 95 % CI 0.84-0.95), rectal cancer (RR = 0.81, 95 % CI 0.66-0.99), and lipophilic statin (RR = 0.88, 95 % CI 0.85-0.93), but not in RCTs (RR = 0.96, 95 % CI 0.85-1.08), colon cancer, and hydrophilic statin. However, long-term statin use (≥5 years) did not significantly affect the risk of CRC (RR = 0.96, 95 % CI 0.90-1.03). Cumulative meta-analysis showed that statin use significantly reduces the risk of CRC, which has been available between 2007 and 2013. CONCLUSIONS: Our results suggest that statin use is associated with a modest reduced risk of CRC; apparent associations were found for lipophilic statin use. However, long-term statin use did not appear to significantly affect the risk of CRC.

Kidney stones and cardiovascular risk: a meta-analysis of cohort studies.

BACKGROUND: Recent epidemiologic evidence suggests an association between kidney stones and incident cardiovascular disease after adjusting for other cardiovascular risk factors, but results are inconsistent. STUDY DESIGN: Meta-analysis of cohort studies. SETTING & POPULATION: Patients with kidney stones. SELECTION CRITERIA FOR STUDIES: Cohort studies with data for kidney stones and cardiovascular morbidity identified in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and conference proceedings through February 27, 2014. PREDICTOR: Kidney stones as determined by physician diagnosis, clinical coding, or self-reported scales. OUTCOMES: Cardiovascular disease, coronary heart disease (CHD), and stroke. RESULTS: 6 cohort studies that contained 49,597 patients with kidney stones and 3,558,053 controls, with 133,589 cardiovascular events, were included. Pooled results suggested that kidney stones were associated with an increased adjusted risk estimate for CHD (HR, 1.19; 95% CI, 1.05-1.35; P=0.05; n=6 cohorts) and stroke (HR, 1.40; 95% CI, 1.20-1.64; P<0.001; n=3 cohorts). In particular, kidney stones conferred HRs of 1.29 (95% CI, 1.10-1.52; n=6 cohorts) and 1.31 (95% CI, 1.05-1.65; n=4 cohorts) for myocardial infarction and coronary revascularization, respectively. Moreover, the pooled female cohorts showed a statistically significant association (HR, 1.49; 95% CI, 1.21-1.82; n=4 cohorts), whereas the male cohorts showed no association (HR, 1.15; 95% CI, 0.89-1.50; n=2 cohorts). LIMITATIONS: Results may be limited by substantial heterogeneity, likelihood of residual confounding, and paucity of studies that separately evaluated for effect modification by sex. CONCLUSIONS: Kidney stones were associated with increased cardiovascular risk, including the risk for incident CHD or stroke. There is some suggestion that the risk may be higher in women than men. Further prospective studies are needed to determine whether the association is sex specific.

Meta-analysis: eating frequency and risk of colorectal cancer.

Eating frequency has been implicated in the risk of colorectal cancer (CRC) in several epidemiological studies with contradictory and inconclusive findings. We performed a meta-analysis to evaluate their relationship. The pooled relative risk (RR) with 95% confidence interval (CI) was calculated to estimate the effects. A total of 15 eligible studies with 141,431 subjects and 11,248 cases were retrieved after a comprehensive search of the PubMed, Cochrane Library, and Web of Science databases up to October 2013. The overall meta-analysis revealed no strong significant association between eating frequency and risk of CRC in different eating occasion categories (1 meal/day): RR = 1.01, 95% CI 0.94-1.09, P = 0.709; 3 vs. <3 daily meals: RR = 1.17, 95% CI 0.93-1.46; 4 vs. <3 daily meals: RR = 1.13, 95% CI 0.92-1.38; ≥ 5 vs. <3 daily meals: RR = 0.95, 95% CI 0.61-1.47; 4 vs. ≤ 3 daily meals: RR = 1.18, 95% CI 0.92-1.51; and 1-2 vs. 3 or 4 daily meals: RR = 0.82, 95% CI 0.63-1.06). However, modest evidence of an increased risk of CRC in case-control studies (RR = 1.30; 95% CI, 1.11-1.52) and ≥ 5 vs. ≤ 3 meals group (RR = 1.30; 95% CI, 1.11-1.52) was observed. Our meta-analysis results do not support the hypothesis that eating frequency strongly reduced or increased the risk of CRC. Clinical randomized trials are required to evaluate this relationship further.

Prognostic significance of dickkopf-1 overexpression in solid tumors: a meta-analysis.

The prognostic significance of dickkopf-1 (DKK1) overexpression in solid tumors remains inconclusive. We performed a meta-analysis to evaluate the impact of DKK1 overexpression in solid tumors on patients' overall survival (OS) and disease-free survival (DFS). The pooled hazard ratio (HR) with 95 % confidence interval (CI) was used to estimate the effects. Thirteen studies were included for meta-analysis; four that evaluated hepatocellular carcinoma (HCC), two each that evaluated ovarian carcinoma, esophageal carcinoma, and lung cancer, and one each that evaluated other cancers, namely gastric cancer, breast cancer, urothelial carcinoma, and colorectal cancer. Twelve studies were evaluable for OS and six for DFS. Our analysis results indicated that DKK1 overexpression predicted poor OS (HR = 1.68, 95% CI 1.36-2.08; P < 0.001) and DFS (HR = 1.65, 95% CI 1.37-1.99; P < 0.001). Subgroup analyses showed that DKK1 overexpression was significantly related with poor OS in HCC patients (HR = 1.65; P < 0.001), ovarian carcinoma patients (HR = 2.63; P = 0.045), and other cancers patients (HR = 1.51; P = 0.021). Further, DKK1 overexpression was significantly related with poor DFS in HCC patients (HR = 1.53; P < 0.001) and other cancers patients (HR = 2.02; P < 0.001). This meta-analysis showed that DKK1 may be a novel prognostic marker in solid tumors in Asian patients; it could potentially help to further stratify patients for clinical treatment. More, well-designed studies from Western countries are needed to confirm this finding.

Association of p53 codon 72 polymorphism with prostate cancer: an update meta-analysis.

Many studies have been conducted to explore the association between p53 codon 72 polymorphism and prostate cancer (PCa). However, the results remain inconsistent. Therefore, we performed a large meta-analysis of relevant studies to determine a more precise estimation of this relationship. Systematic searches of the electronic databases PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI) up to October 2013 were performed. Fixed or random-effects meta-analytical models were used to calculate the summary odds ratio (OR) and corresponding 95% confidence intervals (CIs). Meta-regression, Galbraith plots, subgroup analysis, and sensitivity analysis were also performed. The study included 17 case-control studies involving 2,371 PCa cases and 2,854 controls. Our results showed that the p53 codon 72 polymorphism was not associated with PCa risk in all genetic models in the overall populations. When limiting the meta-analysis to the studies conforming to Hardy-Weinberg equilibrium, the pooled analyses showed a significant association between p53 codon 72 polymorphism and PCa in a Caucasian population in co-dominant model Pro/Pro vs. Arg/Arg (OR = 1.57, 95% CI = 1.08-2.28, P = 0.017) and recessive model Pro/Pro vs. (Arg/Pro + Arg/Arg) (OR = 1.60, 95% CI = 1.12-2.27, P = 0.009). In subgroup analysis stratified by PCa stages and Gleason grades, a slight but significant association was found when advanced PCa was compared with localized PCa only in recessive model Pro/Pro vs. (Arg/Pro + Arg/Arg) (OR = 1.51, 95% CI = 1.02-2.23, P = 0.039). This meta-analysis suggested that the Pro/Pro genotype of p53 codon 72 polymorphism was associated with increased prostate cancer risk, especially among Caucasians.

Effect of statin on risk of gynecologic cancers: a meta-analysis of observational studies and randomized controlled trials.

Objective. Epidemiologic and clinical findings are inconsistent concerning the risk for gynecologic cancers associated with statin use. We conducted a detailed meta-analysis of all relevant original studies to evaluate the effects of statin on the risk of gynecologic cancers. Methods. We searched PubMed, Embase, and Cochrane library databases up to February 2014 looking for eligible studies. Summary relative risk (RR) estimates and 95% confidence intervals (CIs) were used to calculate the risk using random-effects models. Results. A total of 14 (4 randomized controlled trials, 5 cohorts, and 5 case-control) studies, involving 12,904 gynecologic cancer cases, contributed to the analysis. Pooled results indicated a non-significant decrease of total gynecologic cancer risk among statin users (RR=0.89; 95% CI, 0.78-1.01). Stratified analyses across cancer site revealed a modest protective effect of statin on ovarian cancer (RR=0.79; 95% CI, 0.64-0.98), while no association was found for endometrial cancer (RR=0.90; 95% CI, 0.75-1.07). The effect of statin use against cervical cancer and vulvar cancer is not conclusive. Furthermore, long-term statin use (>5years use) did not significantly affect the risk of endometrial cancer (RR=0.69; 95% CI, 0.44-1.10), but had an obvious decrease on the risk of ovarian cancer (RR=0.48; 95% CI, 0.28-0.80). Conclusions. Our results suggest that statin use was inversely associated with ovarian cancer risk, and the association was stronger for long-term statin use (>5years). The evidence for a protective effect of statin use against other gynecologic cancers is suggestive but not conclusive, which deserves further investigation.