A systematic review and meta-analysis of observational studies of the association between the use of incretin-based therapies and the risk of pancreatic cancer.

BACKGROUND: Some early reports in the medical literature have raised concern about a possible increased risk of pancreatic cancer associated with the use of two broad classes of incretin-based therapies, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists. This possibility has been somewhat mitigated by the null findings meta-analyses of randomized controlled trials, but the usefulness of their findings was hampered by serious shortcomings of lack of power and representativeness. These shortcomings can typically be addressed by observational studies, but observational studies on the topic have yielded conflicting findings. A systematic review and meta-analysis of observational studies was performed to qualitatively and quantitatively appraise the totality of evidence on the association between the use of incretin-based therapies and the risk of pancreatic cancer in routine clinical practice. METHODS: The PubMed, Web of Science, Embase, and Google Scholar databases were searched. The study quality was appraised using the ROBINS-I tool and based on the presence of pharmacoepidemiology biases. A random-effects model was used to estimate the summary relative risks with corresponding CIs. RESULTS: A total of 14 studies were included. The qualitative assessment revealed that all studies had inadequate follow-up (≤5 years), 12 studies were suspected to suffer from time-lag bias (due to inappropriate choice of comparator group) to varying extent, five studies included prevalent users, five studies did not implement exposure lag period, five studies had a serious risk of bias due to confounding, and one study had a time-window bias. The quantitative assessment showed no indication of an increased risk when all studies were pooled together (RR 1.04, 95% CI 0.87, 1.24) and when the analysis was restricted to the studies with the least bias (RR 0.77, 95% CI 0.51, 1.17). However, the pooled RRs were more frequently higher in the studies with less rigorous design and analysis. Specifically, a tendency toward an increased risk was observed in the studies with (RR 1.34, 95% CI 1.04, 1.72) or possibly with (RR 1.10, 95% CI 0.89, 1.36) time-lag bias, in the studies that did not apply (RR 1.23, 95% CI 0.93, 1.63) or with potentially inadequate exposure lag period of 6 months (RR 1.13, 95% CI 0.66, 1.94), in the studies that inappropriate comparator group of a combination of unspecified (RR 1.49, 95% CI 1.25, 1.78) or non-insulin (RR 1.15, 95% CI 0.93, 1.42) antidiabetic drugs, and in the studies with serious risk of bias due to confounding (RR 1.18, 95% CI 0.56, 2.49). CONCLUSIONS: In summary, the totality of evidence from observational studies does not support the claim that the use of incretin-based therapies is associated with an increased risk of pancreatic cancer in routine clinical practice. The increased risk of pancreatic cancer observed in observational studies reflects bias resulting from suboptimal methodological approaches, which need to be avoided by future studies.

Influencing factors for hepatic fat accumulation in patients with type 2 diabetes mellitus.

BACKGROUND: Non-alcoholic fatty liver disease has become the most common chronic liver disease worldwide, which originates from the accumulation of triglyceride (TG) in the liver. Patients with type 2 diabetes mellitus (T2DM) are considered to have a predisposition to hepatic steatosis. However, the influencing factors for hepatic fat accumulation in T2DM patients remain unclear. AIM: To investigate the influencing factors for hepatic fat accumulation in T2DM patients. METHODS: We enrolled 329 T2DM patients admitted to the Endocrinology Department of the First Affiliated Hospital of Soochow University, who underwent MR mDIXON-Quant examination to quantify the hepatic fat fraction (HFF). According to body mass index (BMI), the patients were divided into normal weight, overweight, and obese groups. The differences in general statistics, biochemical parameters, islet function, and HFF were compared among the three groups. The associations between HFF and other parameters and the influences of various parameters on the severity of hepatic fat accumulation were analyzed. RESULTS: The HFF of T2DM patients gradually increased in the normal weight, overweight, and obese groups (P < 0.05). Spearman correlation analysis showed that in T2DM patients, HFF was negatively correlated with age and high-density lipoprotein cholesterol (P < 0.05), whereas it was positively correlated with BMI, waist-hip ratio, fasting plasma glucose, alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin, glutamyl transpeptidase, lactate dehydrogenase, albumin (ALB), uric acid (UA), total cholesterol, TG, low-density lipoprotein cholesterol (LDL-C), C-reactive protein, free triiodothyronine, fasting insulin, fasting C-peptide, and homeostasis model assessment of insulin resistance (P < 0.05). Multiple linear regression analysis showed significant positive influences of BMI, ALT, LDL-C, UA, and ALB on HFF in T2DM patients (P < 0.05). Binary logistic regression analysis showed that BMI, ALT, ALB, and LDL-C were independent risk factors for moderate to severe fatty liver in T2DM patients, and obesity increased the risk of being complicated with moderate to severe fatty liver by 4.03 times (P < 0.05). CONCLUSION: The HFF of T2DM patients increases with BMI. Higher BMI, ALT, ALB, and LDL-C are independent risk factors for moderate to severe fatty liver in T2DM patients.

Serum von Willebrand factor for early diagnosis of lung adenocarcinoma in patients with type 2 diabetes mellitus.

BACKGROUND: The elevation of plasma von Willebrand factor (vWF) has been proposed to be a predictor of lung cancer. Type 2 diabetes mellitus (T2DM) causes endothelial activation, resulting in the secretion of vWF. However, the role of vWF in patients with T2DM complicated with lung cancer remains unclear. AIM: To investigate the clinical value of serum vWF as a tumor marker in patients with T2DM combined with lung adenocarcinoma in situ (AIS). METHODS: This study enrolled 43 patients with T2DM combined with lung AIS (T2DM + AIS group), 43 patients with T2DM alone (T2DM group), 43 patients with lung AIS alone (AIS group), and 43 healthy volunteers (control group). The serum levels of vWF, insulin-like growth factor 1, and insulin-like growth factor binding protein 3 were determined. Multiple linear stepwise regression was performed to determine the correlations among variables. RESULTS: Serum concentration of vWF in the T2DM + AIS group was significantly higher than those in the T2DM, AIS, and control groups (P < 0.05). Serum vWF levels in the T2DM and AIS groups were significantly higher than that in the control group (P < 0.05). There was no significant difference in serum vWF level between the T2DM and AIS groups. In the T2DM + AIS group, serum vWF was independently associated and positively correlated with serum levels of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 (P < 0.05). CONCLUSION: Serum vWF level may represent a novel biomarker for the early diagnosis of lung AIS.

Foetal and childhood exposure to famine and the risks of cardiometabolic conditions in adulthood: A systematic review and meta-analysis of observational studies.

A systematic review and meta-analysis of observational studies was performed to provide a deeper understanding of the associations between foetal and childhood exposure to famine and the risks of type 2 diabetes mellitus (T2DM), metabolic syndrome, hypertension, hyperglycaemia, dyslipidaemia, obesity, overweight, coronary heart disease, stroke, and nonalcoholic fatty liver disease (NAFLD) in adulthood. Both foetal and childhood exposure to famine were positively associated with the risks of T2DM (foetal exposure: RR 1.37, 95% CI, 1.23-1.52; childhood exposure: RR 1.33, 95% CI, 1.08-1.64), metabolic syndrome (RR 1.26, 95% CI, 1.07-1.50; RR 1.24, 95% CI, 1.13-1.35), hypertension (RR 1.30, 95% CI, 1.07-1.57; RR 1.33, 95% CI, 1.02-1.74), hyperglycaemia (RR 1.27, 95% CI, 1.11-1.45; RR 1.25, 95% CI, 1.10-1.42), dyslipidaemia (RR 1.48, 95% CI, 1.33-1.66; RR 1.27, 95% CI, 1.12-1.45), obesity (RR 1.19, 95% CI, 1.02-1.39; RR 1.13, 95% CI, 1.00-1.28), overweight (RR 1.17, 95% CI, 1.07-1.29; RR 1.07, 95% CI, 1.00-1.14), coronary heart disease (RR 1.22, 95% CI, 1.00-1.51; RR 1.21, 95% CI, 1.09-1.35), and moderate-to-severe NAFLD (RR 1.66, 95% CI, 1.07-2.57; RR 1.68, 95% CI, 1.41-1.99) in adulthood. No association was observed for the risks of stroke or mild NAFLD. Adjustments for age, alcohol, smoking, body mass index, and physical activity nullified some associations. The associations were generally stronger in women than in men. In summary, foetal and childhood exposure to famine may confer greater risks of developing certain cardiometabolic conditions in adulthood, particularly in women. The extent to which risks for cardiometabolic conditions are associated with early-life famine appears to be determined by certain factors in adulthood.

Influence of physical activity at a young age and lifetime physical activity on the risks of 3 obesity-related cancers: systematic review and meta-analysis of observational studies.

CONTEXT: Excess weight has been linked to increased risks of 13 types of cancers. Physical activity is a non-nutritional modifiable lifestyle factor that is not only crucial for weight control but is also known to regulate hormones and metabolic pathways that may contribute to carcinogenesis. There is solid evidence that being physically active during middle and late adulthood lowers the risks of 3 obesity-related cancers, namely breast cancer, colon cancer, and endometrial cancer. However, the associations between physical activity at a young age (childhood, adolescence, and young adulthood; age 5 to ≤30 yr) and lifetime physical activity and the risks of breast cancer, colon cancer, and endometrial cancer are less defined. OBJECTIVE: The present systematic review and meta-analysis of observational studies was performed in accordance with the MOOSE guidelines to determine whether physical activity at a young age and lifetime physical activity may lower the risks of breast cancer, colon cancer, and endometrial cancer. DATA SOURCES: The PubMed and Web of Science databases were searched for relevant observational studies published from inception to July 2018. STUDY SELECTION: Observational studies (prospective cohort, case-cohort, nested case-control, historical cohort, and case-control) were considered relevant if they investigated the association between physical activity at a young age or lifetime physical activity and the risks of developing selected cancers. DATA EXTRACTION: A random-effects meta-analysis was performed to generate the summary relative risk (RR) with 95%CI for the highest vs the lowest category of physical activity of any type. RESULTS: Eighty publications were included in the present meta-analysis. Higher physical activity at a young age was associated with lower risks of breast cancer (RR 0.81, 95%CI 0.76, 0.87) and colon cancer (RR 0.67, 95%CI 0.50, 0.88). Similarly, lifetime physical activity was inversely associated with the risks of breast cancer (RR 0.79, 95%CI 0.72, 0.86) and colon cancer (RR 0.75, 95%CI 0.69, 0.82). For breast cancer, menopausal status did not appear to modify the observed inverse association. The benefit with respect to endometrial cancer risk reduction was only observed with higher lifetime physical activity (RR 0.77, 95%CI 0.67, 0.88), not with higher physical activity at a young age (RR 0.89, 95%CI 0.73, 1.07). CONCLUSIONS: Being physically active over a lifetime, starting from early childhood, may lower the risks of developing breast cancer, colon cancer, and endometrial cancer.

The use of metformin, insulin, sulphonylureas, and thiazolidinediones and the risk of fracture: Systematic review and meta-analysis of observational studies.

Certain glucose-lowering medications have been implicated in the risk of fracture. While there is convincing evidence from randomized controlled trials (RCTs) that thiazolidinedione use is associated with a higher risk of fracture, the effects of metformin, insulin, and sulphonylureas on the risk of fracture remain equivocal because these medications are not generally investigated in RCTs. A meta-analysis of observational studies to provide further insights into the association between the use of metformin, insulin, sulphonylureas, or thiazolidinediones and the risk of fracture was performed. PubMed and Web of Science databases were searched to identify relevant observational studies. A random effects model was used to estimate the summary relative risks (RRs) with 95% confidence intervals (CIs). The use of insulin (RR 1.49, 95% CI 1.29, 1.73; n = 23 studies), sulphonylureas (RR 1.30, 95% CI 1.18, 1.43; n = 10), and thiazolidinediones (RR 1.24, 95% CI 1.13, 1.35; n = 14) was associated with an increased risk of fracture, whereas the use of metformin was associated with a reduced risk of fracture (RR 0.86, 95% CI 0.75, 0.99; n = 12). Regarding types of thiazolidinediones, both pioglitazone (RR 1.38, 95% CI 1.23, 1.54; n = 5) and rosiglitazone (RR 1.34, 95% CI 1.14, 1.58; n = 5) were positively associated with the risk of fracture. In summary, there is compelling evidence to discourage the use of thiazolidinediones in individuals with an increased risk of fracture, whereas metformin appears to have a good safety profile for the risk of fracture. The reduced risk of fracture with metformin could possibly be due to the reduced overall risk of fracture among metformin users, as this medication is typically prescribed in the early stages of type 2 diabetes mellitus. The use of insulin or sulphonylureas may increase fracture risk; this risk is most likely attributed to an increased risk of hypoglycaemia-induced falls. Further confirmation by additional RCTs is required to determine whether the observed association between the use of metformin, insulin, or sulphonylureas and the risk of fracture is due to treatment with these medications or confounding factors.

The Neuropeptide Vasoactive Intestinal Peptide Levels in Serum are Inversely Related to Disease Severity of Postmenopausal Osteoporosis: A Cross-Sectional Study.

Background: The neuropeptide vasoactive intestinal peptide (VIP) has been identified as inhibiting osteoclastogenesis and suppressing inflammation. Objective: This study was conducted to examine serum VIP levels in postmenopausal osteoporosis (PMOP) patients and explore the correlation of serum VIP levels with disease severity of PMOP. Methods: A total of 106 postmenopausal women diagnosed as osteoporotic were enrolled in the study and 102 postmenopausal women with normal bone mineral density (BMD) were enrolled as controls. BMD at the femoral neck (FN), lumbar spine 1-4, and total hip were examined using dual-energy X-ray absorptiometry. Genant semiquantitative grading was used for vertebral morphometry and fracture. Serum VIP levels were tested using enzyme-linked immunosorbent assay. Serum inflammatory factor interleukin-1ß (IL-1ß), osteoclastic activity marker tartrate-resistant acid phosphatase 5b (TRACP-5b), and estrogen-2 (E2) were also examined. Receiver operating characteristic (ROC) analyses was performed to determine the diagnostic values of serum VIP, IL-1ß, TRCAP-5, and E2 with regard to Genant grade. Results: Our findings demonstrated a reduction in the serum level of VIP expressed in PMOP patients compared with controls. In the PMOP group, patients with lumbar fracture had significantly lower serum VIP concentrations in comparison with healthy controls. Serum VIP concentrations were positively associated with BMD at the FN, lumbar spine 1-4, and total hip. We also observed that serum VIP levels were positively correlated with E2 levels but negatively correlated with IL-1ß and TRCAP-5 levels. In addition, ROC analysis found that reduction of serum VIP in combination with elevation of TRACP-5b may serve as an indicator of a severe Genant grade. Conclusions: Attenuated serum VIP levels were linked to disease severity of PMOP and may act as a protective marker for PMOP.

Milk in the prevention and management of type 2 diabetes: The potential role of milk proteins.

Globally, diabetes mellitus is not only considered a leading cause of mortality and morbidities but has also created a substantial economic burden. There is growing evidence that foods and their components can be implemented in the prevention and management of type 2 diabetes mellitus (T2DM). Increased dairy consumption has been linked to a lower risk of T2DM. The protective role of dairy foods in the development of T2DM is thought to be largely attributable to dairy nutrients, one of them being dairy protein. There is considerable evidence that milk proteins increase the postprandial insulin response and lower the postprandial blood glucose response in both healthy subjects and patients with T2DM. The exact mechanisms by which milk proteins lower postprandial glucose levels are yet to established; however, the amino acids and bioactive peptides derived from milk proteins are thought to modify a physiological milieu, which includes delayed gastric emptying and the enhancement of incretin and insulin responses, consequently leading to lower postprandial glucose levels. The present review will focus on providing a clear presentation of the potential implementation of milk proteins as a dietary supplement in the prevention and management of T2DM by summarizing the relevant supporting evidence for this particular topic.

The influence of maternal body mass index, maternal diabetes mellitus, and maternal smoking during pregnancy on the risk of childhood-onset type 1 diabetes mellitus in the offspring: Systematic review and meta-analysis of observational studies.

There is emerging evidence that events occurring before and shortly after birth may be important in determining the risk of childhood-onset type 1 diabetes mellitus (T1DM). We aimed to summarize and synthesize the associations between maternal body mass index (BMI), maternal diabetes mellitus (DM), and maternal smoking during pregnancy and the risk of childhood-onset T1DM in the offspring by performing a systematic review and meta-analysis of observational studies. A random effects model was used to generate the summary risk estimates. The PubMed and Web of Science databases were searched to identify relevant observational studies. Twenty one observational studies were included in the present meta-analysis. Compared with offspring of mothers with normal weight, offspring of women with overweight or obesity were at an increased risk of developing childhood-onset T1DM (overweight: relative risk [RR] 1.09, 95% confidence interval [CI], 1.03-1.15; obesity: RR 1.25, 95% CI, 1.16-1.34; per 5 kg m-2 increase in BMI: RR 1.10, 95% CI, 1.06-1.13). No association was found for maternal underweight (RR 0.92, 95% CI, 0.75-1.13). Maternal DM was associated with an increased risk of childhood-onset T1DM (RR 3.26, 95% CI, 2.84-3.74). Regarding the type of maternal DM, the greatest risk of T1DM in the offspring appeared to be conferred by maternal T1DM (RR 4.46, 95% CI, 2.89-6.89), followed by maternal gestational diabetes mellitus (RR 1.66, 95% CI, 1.16-2.36), and lastly by maternal type 2 diabetes mellitus (RR 1.11, 95% CI, 0.69-1.80). Additional analysis of studies comparing maternal versus paternal T1DM within the same population revealed that offspring of fathers with T1DM had a 1.5 times higher risk of developing childhood-onset T1DM than offspring of mothers with T1DM (RR 9.58, 95% CI, 6.33-14.48 vs. RR 6.24, 95% CI, 5.52-7.07). Furthermore, a reduced risk of childhood-onset T1DM was observed in infants born to mothers who smoked during pregnancy compared with infants born to mothers who did not smoke during pregnancy (RR 0.79, 95% CI, 0.71-0.87). In summary, our findings add further evidence that early-life events or environmental factors may play a role in modulating infants' risk of developing T1DM later in life.

Anthropometric factors and non-Hodgkin's lymphoma risk: systematic review and meta-analysis of prospective studies.

The associations between anthropometric factors and non-Hodgkin's lymphoma (NHL) risk remain inconclusive. A meta-analysis was performed to clarify these associations. PubMed and Web of Science were searched for relevant prospective observational studies. A random-effects model was used to generate the summary relative risks (RRs) with 95% confidence intervals (CIs). A total of 22 prospective cohort studies, with over 20,000 NHL cases, were included in the present meta-analysis. The summary RRs of NHL risk were 1.06 (95% CI 1.03, 1.09) for each 5 kg/m2 increase in body mass index (BMI), 1.11 (95% CI 1.07, 1.16) for each 5 kg/m2 increase in BMI in early adulthood (age 18-21 years), 1.05 (95% CI 1.01, 1.09) for each 10 kg increase in weight, 1.21 (95% CI 1.15, 1.28) for each 10 kg increase in weight in early adulthood (age 18-21 years), and 1.13 (95% CI 1.10, 1.17) for each 10 cm increase in height. No association was found for waist circumference (WC) and waist-to-hip ratio. By subtypes, all anthropometric factors (but not WC) were associated with an increased risk of diffuse large B-cell lymphoma. Chronic lymphocytic leukemia/small lymphocytic lymphoma was positively associated with BMI in early adulthood and with height, whereas follicular lymphoma was only positively associated with height. In summary, BMI and weight in early adulthood may be more relevant to NHL development than current BMI and weight. These findings emphasize the importance of maintaining a healthy weight throughout the life-course, starting from early life, for NHL prevention. Increased NHL risk with taller stature, which may reflect cumulative exposure to hormones/growth factors and nutrition status in early life, further supports the relevance of early life exposure in the etiology of NHL.

Effects of FGF-23-mediated ERK/MAPK signaling pathway on parathyroid hormone secretion of parathyroid cells in rats with secondary hyperparathyroidism.

This study is supposed to investigate the effect of FGF-23 on parathyroid hormone (PTH) secretion through ERK/MAPK signaling pathway in secondary hyperparathyroidism (SHPT) rat model. Thirty rats were equally served as the normal and SHPT groups. After transfection, parathyroid cells was assigned into blank, NC, pcDNA3.1-FGF-23, siRNA-FGF-23, U0126, and siRNA-FGF-23 + U0126 groups. The serum levels of Calcium (Ca), Phosphorus (P), alkaline phosphatase (ALP), and PTH were detected. HE and immunohistochemical (IHC) staining were used for the histopathological changes and the FGF-23, EKR1/2, and pEKR1/2 expressions. qRT-PCR and Western blotting were performed to determine the mRNA and protein expression of FGF-23, PTH, MAPK, EKR1/2, and Klotho. The proliferation, apoptosis, and cell cycle were all measured for parathyroid cells by CCK-8 assay, TUNEL staining and Flow cytometry. Compared with the normal group, the SHPT group showed increased serum levels PTH, P, ALP, and FGF-23 and mRNA and protein expressions of FGF-23 and PTH, whereas declined Ca and p-ERK1/2 expression, mRNA and protein expression of Klotho, cell apoptosis rate was reduced. Furthermore, compared to the blank and NC groups, the pcDNA3.1-FGF-23 and U0126 groups had a decreased mRNA expression of Klotho, protein expression of EKR1/2 and Klotho, and cell apoptosis rate was down-regulated, whereas the RNA and protein expressions of FGF-23 and PTH were up-regulated, and cell proliferation was elevated. The opposite results were observed in the siRNA-FGF-23 group. Our study demonstrated that FGF-23 could inhibit signaling transduction of ERK/MAPK pathway and accelerate the secretion of PTH in rats with SHPT.

The protective effect of asiatic acid on podocytes in the kidney of diabetic rats.

The essential ingredient of Centella asiatic is asiatic acid (AA). There are a lot of biological activities in AA, such as anti-oxidant, anti-diabetic. However, so far, there have been no reports on the underlying protective mechanism of AA on podocytes. In this research, we observed the morphological changes of podocytes in diabetic rats by optics microscope and transmission electron microscopy and the protective effect of AA. Additionally, we investigated the expressions of nephrin, desmin and p-JNK, JNK in podocytes of diabetic rats and the influence of AA on podocytes and JNK signaling pathway. The results showed that AA could reduce renal function and urinary albumin. It could attenuate abnormal pathological findings of podocytes in kidney tissue of diabetic rats. Besides, treatment with AA could significantly improve the expression of nephrin and decrease expression of desmin. The ratio of p-JNK protein to JNK protein in podocytes was reduced considerably by AA. With the treatment dose of AA increased, the renal protective effect of AA was gradually improved. These results indicate that asiatic acid has a significant protective effect on diabetic nephropathy. Potential mechanisms include inhibiting the production of oxidants effectively, protection of podocytes, and suppression of the JNK signaling pathway activation. Therefore, there is an excellent prospect of using AA to treat diabetic nephropathy.

Body fatness at an early age and risk of colorectal cancer.

While there is convincing evidence that excess body fatness in adulthood is positively associated with colorectal cancer risk, the association between body fatness at an early age (≤30 years) and the risk of colorectal cancer has been equivocal. The present meta-analysis was performed to clarify this association. PubMed and Web of Science databases were searched for relevant studies that investigated this association. The risk estimates from each study were transformed into a continuous variable for each 5 kg/m2 increase in body mass index (BMI). A random effects model was used to calculate the summary relative risks (RRs) with 95% confidence intervals (CIs). A total of 15 observational studies (13 cohort studies and two case-control studies) were included in this meta-analysis. Each 5 kg/m2 increase in BMI was significantly associated with a 13% (RR 1.13, 95% CI 1.08, 1.19), 17% (RR 1.17, 95% CI 1.09, 1.25) and 8% (RR 1.08, 95% CI 1.04, 1.11) higher risk of colorectal cancer overall, in men, and in women, respectively. Substantial heterogeneity was observed across studies. Based on the anatomic subsite, each 5 kg/m2 increase in BMI was significantly associated with a 14% (RR 1.14, 95% CI 1.07, 1.22) higher risk of colon cancer, whereas no association (RR 1.03, 95% CI 0.95, 1.13) was observed with rectal cancer. In summary, body fatness at an early age may affect colon cancer risk later in life. Prevention of overweight and obesity in young individuals should be emphasized to prevent early-onset colon cancer attributed to excess body fatness.

Abdominal obesity and gastroesophageal cancer risk: systematic review and meta-analysis of prospective studies.

To systematically and quantitatively review the relation of abdominal obesity, as measured by waist circumference (WC) and waist to hip ratio (WHR), to total gastroesophageal cancer, gastric cancer (GC), and esophageal cancer. PubMed and Web of Science databases were searched for studies assessing the association between abdominal obesity and gastroesophageal cancer (GC and/or esophageal cancer) up to August 2016. A random-effect model was used to calculate the summary relative risks (RRs) and 95% confidence intervals (CIs). Seven prospective cohort studies - one publication included two separate cohorts - from six publications were included in the final analysis. A total of 2130 gastroesophageal cancer cases diagnosed amongst 913182 participants. Higher WC and WHR were significantly associated with increased risk of total gastroesophageal cancer (WC: RR 1.68, 95% CI: 1.38, 2.04; WHR: RR 1.49, 95% CI: 1.19, 1.88), GC (WC: RR 1.48, 95% CI: 1.24, 1.78; WHR: 1.33, 95% CI: 1.04, 1.70), and esophageal cancer (WC: RR 2.06, 95% CI: 1.30, 3.24; WHR: RR 1.99, 95% CI: 1.05, 3.75).Findings from our subgroup analyses showed non-significant positive associations between gastric non-cardia adenocarcinoma (GNCA) and both measures of abdominal adiposity, while gastric cardia adenocarcinoma (GCA) was positively associated with WC but not with WHR. On analysis restricted to studies that adjusted for body mass index (BMI), WC was positively associated with GC and esophageal cancer, whereas WHR was positively associated with risk of GC only. Although limited, the findings from our meta-analysis suggest the potential role of abdominal obesity in the etiology of gastric and esophageal cancers.

Blood pressure and kidney cancer risk: meta-analysis of prospective studies.

BACKGROUND: Globally, kidney cancer is the twelfth most common cancer, accounting for 337 860 cases recorded in 2012. By 2020, this number has been estimated to reach 412 929 or increase by 22%. Over the past few decades, a number of prospective studies have investigated the association between blood pressure (BP) and risk of kidney cancer, using either recorded BP levels or reported hypertension as the principal exposure variable. However, the relation of BP to kidney cancer remains incompletely understood, and the data on sex-specific differences in risk estimates have been inconsistent. METHOD: PubMed and Web of Science databases were searched for studies assessing the association between BP and kidney cancer through July 2016. The summary relative risk with 95% confidence intervals was calculated using a random-effects model. RESULT: A total of 18 prospective studies with 8097 kidney cancer cases from 3 628 479 participants were included in our meta-analysis. History of hypertension was associated with 67% increased risk of kidney cancer. Significant heterogeneity and evidence of publication bias were observed. However, the results remain unchanged after introducing the trim and fill method to correct the publication bias. Accordingly, each 10-mmHg increase in SBP and DBP was associated with 10 and 22% increased risk of kidney cancer. CONCLUSION: Collectively, the present meta-analysis of 18 prospective studies provides further support for a positive association between hypertension and kidney cancer risk.

Thyroid nodule sizes influence the diagnostic performance of TIRADS and ultrasound patterns of 2015 ATA guidelines: a multicenter retrospective study.

To evaluate the impact of thyroid nodule sizes on the diagnostic performance of thyroid imaging reporting and data system (TIRADS) and ultrasound patterns of 2015 American Thyroid Association (ATA) guidelines. Total 734 patients with 962 thyroid nodules were recruited in this retrospective study. All nodules were divided into three groups according to the maximal diameter (d < 10 mm, d = 10-20 mm and d > 20 mm). The ultrasound images were categorized based on TIRADS and ATA ultrasound patterns, respectively. A total of 931 (96.8%) and 906 (94.2%) patterns met the criteria for TIRADS and ATA ultrasound patterns. The AUC (0.849) and sensitivity (85.3%) of TIRADS were highest in d = 10-20 mm group. However, ATA had highest AUC (0.839) and specificity (89.8%) in d > 20 mm group. ATA ultrasound patterns had higher specificity (P = 0.04), while TI-RADS had higher sensitivity (P = 0.02). In nodules d > 20 mm, the specificity of ATA patterns was higher than TIRADS (P = 0.003). Our results indicated that nodule sizes may influence the diagnostic performance of TIRADS and ATA ultrasound patterns. The ATA patterns may yield higher specificity than TIRADS, especially in nodules larger than 20 mm.

Calcium intake and breast cancer risk: meta-analysis of prospective cohort studies.

Findings from observational studies have suggested a possible relation between Ca and breast cancer risk. However, the results of these studies are inconclusive, and the dose-response relationship between Ca intake and risk of breast cancer remains to be determined. A meta-analysis of prospective studies was conducted to address these issues. PubMed and Embase databases were searched for relevant studies concerning the association between Ca intake and breast cancer up to March 2016. The summary relative risks (RR) with 95 % CI were calculated with a random-effects model. The final analysis included eleven prospective cohort studies involving 26 606 cases and 872 895 participants. The overall RR of breast cancer for high v. low intake of Ca was 0·92 (95 % CI 0·85, 0·99), with moderate heterogeneity (P=0·026, I 2=44·2 %). In the subgroup analysis, the inverse association appeared stronger for premenopausal breast cancer (RR 0·75; 95 % CI 0·59, 0·96) than for postmenopausal breast cancer (RR 0·94; 95 % CI 0·87, 1·01). Dose-response analysis revealed that each 300 mg/d increase in Ca intake was associated with 2 % (RR 0·98; 95 % CI 0·96, 0·99), 8 % (RR 0·92; 95 % CI 0·87, 0·98) and 2 % (RR 0·98; 95 % CI 0·97, 0·99) reduction in the risk of total, premenopausal and postmenopausal breast cancer, respectively. Our findings suggest an inverse dose-response association between Ca intake and risk of breast cancer.

Enhancement of CD4(+) T cell response and survival via coexpressed OX40/OX40L in Graves' disease.

OX40/OX40L pathway plays a very important role in the antigen priming T cells and effector T cells. In the present study, we aimed to examine the involvement of OX40/OX40L pathway in the activation of autoreactive T cells in patients with Grave's disease (GD). We found that OX40 and OX40L were constitutively coexpressed on peripheral CD4(+) T cells from GD patients using flow cytometry analysis. The levels of OX40 and OX40L coexpression on CD4(+) T cells were shown to be correlated with TRAbs. Cell proliferation assay showed that blocking OX40/OX40L signal inhibited T cell proliferation and survival, which suggested that OX40/OX40L could enhance CD4(+) T cell proliferation and maintain their long-term survival in GD by self-enhancing loop of T cell activation independent of APCs. Confocal microscopy and coimmunoprecipitation analysis further revealed that OX40 and OX40L formed a functional complex, which may facilitate signal transduction from OX40L to OX40 and contribute to the pathogenesis of GD.

Identifying at-risk foot among hospitalized patients with type 2 diabetes: A cross-sectional study in one Chinese tertiary hospital.

OBJECTIVE: To investigate the prevalence of diabetic at-risk foot and its associated factors. METHODS: A total of 838 hospitalized patients with type 2 diabetes were screened for at-risk foot. Neural and vascular disorders were evaluated by assessing vibration perception thresholds and ankle brachial indexes (ABIs). After excluding 12 patients with abnormally high ABIs, remaining individuals with neural and/or vascular disorder were identified as at-risk patients and further classified into three subtypes: isolated neural disorder, isolated vascular disorder and mixed disorder. Potential associated factors were examined using Logistic regression models. RESULTS: In the final sample of 826 individuals, the prevalence of diabetic at-risk foot was 30.6%. Among all at-risk patients, isolated neural disorders (69.6%) were more common than mixed (16.2%) or isolated vascular disorders (14.2%). Isolated neural and vascular disorders shared specific risk factors, including age per 20-year increment (odds ratio [95% CI], 3.73 [2.59-5.37] and 4.01 [1.98-8.11]), diabetic duration ≥10 years (1.69 [1.13-2.54] and 3.29 [1.49-7.24]) and systolic blood pressure ≥140 mmHg (1.96 [1.31-2.93] and 2.90 [1.38-6.10]) respectively. In addition, isolated neural disorders were associated with a heavy smoking history (95%CI 2.69 [1.15-6.31]), increased high-sensitivity C-reactive protein levels (95%CI 1.30 [1.04-1.62]) and mild obesity (95%CI 0.49 [0.20-1.24]). Isolated vascular disorders were linked with decreased high density lipoprotein (HDL) cholesterol levels (95%CI 3.42 [1.31-8.96]) and increased triglycerides levels (95%CI 2.74 [1.26-5.97]). CONCLUSIONS: Diabetic at-risk foot is epidemic among hospitalized patients with type 2 diabetes. Aging, long-term diabetes, hypertension, smoking, inflammatory response and dyslipidemia may be associated with the prevalence of diabetic at-risk foot.

[Expression of human PD-1Deltaex3 and primary study of its biological activity].

AIM: To express human PD-1Deltaex3(DeltaPD-1) gene in eukaryotic expressing vector and identify the biological activity of the recombinant protein. METHODS: The target gene encoding full length human PD-1(PD-1) was cloned by RT-PCR, then two fragments of PD-1Deltaex3 gene were amplified and assembled by TP-PCR, PD-1Deltaex3 gene was obtained. Then the two genes PD-1 and DeltaPD-1 were inserted into the eukaryotic expressing vector pIRES2-EGFP respectively to construct the recombinant vectors pIRES2-EGFP/PD-1 and pIRES2-EGFP/DeltaPD-1. The recombinants were transfected into 293T cells with Lipofect2000 Reagent. The membrane PD-1 protein on the transfected cell surface was detected by flow cytometry. The expression of soluble PD-1 was also analysised by Western blot. The combination of DeltaPD-1 protein to the ligands of PD-1, PD-L1 and PD-L2, were determined by indirect immunofluorescence assay. RESULTS: The results of enzyme digestion of recombinant vectors and DNA sequencing showed the two genes PD-1 and PD-1Deltaex3 were inserted correctly into plasmid pIRES2-EGFP, the two recombinant vectors were constructed successfully. Flow cytometry and Western blot revealed that 293T cells transfected with vector pIRES2-EGFP/PD-1 could express PD-1 protein on the cell surface but no soluble PD-1 in the supernatant of transfected cells, on the contrary, 293T cells transfected with vector pIRES2-EGFP/DeltaPD-1 could express soluble PD-1 in the culture supernatant but no membrane PD-1. Indirect immunofluorescence assay indicated the DeltaPD-1 protein could bind to the two ligands of PD-1 on the cells surface. CONCLUSION: The recombinant eukaryotic expressing vector containing PD-1Deltaex3 was constructed successfully, and the PD-1Deltaex3 gene could encode a soluble form of PD-1 protein. DeltaPD-1 protein remained the biological activity as PD-1. This study provides the initial material for further study of PD-1Deltaex3 in PD-1/PD-L signaling pathway.