Summary
Epidemiologic evidence has shown inconsistent findings regarding the relationships between abdominal fatness, as measured by waist circumferences (WC) or waist‐to‐hip ratio (WHR), and risks ...of pre‐ and postmenopausal breast cancer (BC). A dose–response meta‐analysis of prospective studies was conducted to address these issues. Potentially eligible studies were identified by searching PubMed and EMBASE databases, and by carefully reviewing the bibliographies of retrieved publications and related reviews. The summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random‐effects model. When the most fully adjusted RRs were combined, both WC (14 studies, RR per 10‐cm increase = 1.06, 95% CI: 1.04–1.09, I2 = 29.9%) and WHR (15 studies, RR per 0.1‐unit increase = 1.07, 95% CI: 1.01–1.14, I2 = 52.9%) were significantly positively associated with postmenopausal BC, but neither WC (eight studies, RR per 10‐cm increase = 1.05, 95% CI: 0.99–1.10, I2 = 0%) nor WHR (11 studies, RR per 0.1‐unit increase = 1.07, 95% CI: 0.95–1.21, I2 = 59.7%) were associated with premenopausal BC. The WHR‐postmenopausal BC association lost statistical significance after correcting publication bias (RR per 0.1‐unit increase = 1.06, 95% CI: 0.99–1.13). When considering BMI‐adjusted RRs, WC was associated with both pre‐ (five studies, RR per 10‐cm increase = 1.09, 95% CI: 1.02–1.16, I2 = 0%) and postmenopausal BC (seven studies, RR per 10‐cm increase = 1.05, 95% CI: 1.02–1.08, I2 = 6.3%), whereas WHR was not associated with either pre‐ (seven studies, RR per 0.1‐unit increase = 1.12, 95% CI: 0.94–1.34, I2 = 70.9%) or postmenopausal BC (eight studies, RR per 0.1‐unit increase = 1.05, 95% CI: 0.98–1.13, I2 = 57.3%). Among non‐current (former or never) users of hormone replacement therapy, the summary RR per 10‐cm increase of postmenopausal BC associated with WC was 1.08 (95% CI: 1.03–1.05, I2 = 69.2%, seven studies; BMI‐adjusted RR = 1.05, 95% CI: 1.02–1.09, I2 = 22.8%, four studies). This meta‐analysis indicates that central obesity measured by WC, but not by WHR, is associated with modestly increased risks of both pre‐ and postmenopausal BC independent of general obesity.
Summary
In the present meta-analysis, reductions in the risk of hip fracture with milk consumption were only observed among American adults, but not among Scandinavian adults, possibly because milk ...products are more commonly fortified with vitamin D in the former population than in Scandinavian countries. The reduction in the risk of hip fracture was also observed with yogurt consumption, which is often associated with healthy lifestyles and dietary patterns that contribute to improved bone health.
Introduction
Although dairy products contain bone-beneficial nutrients, the association between dairy consumption and the risk of hip fracture remains equivocal. Fueling this uncertainty, the elevated risk of hip fracture in association with milk consumption was observed in a cohort of Swedish women. A systematic review and meta-analysis of prospective cohort studies was performed to critically evaluate the association, or lack thereof, between dairy consumption (milk, yogurt, and cheese) and the risk of hip fracture.
Methods
A random effects model was used to generate the summary relative risks (RRs) with their 95% confidence intervals (CIs) for the associations of interest.
Results
In the meta-analysis of the highest versus lowest category of consumption, higher consumption of yogurt (RR 0.78, 95% CI 0.68, 0.90), but not milk (RR 0.86, 95% CI 0.73, 1.02) or cheese (RR 0.85, 95% CI 0.66, 1.08), was associated with a lower risk of hip fracture. For milk, the reduced risk of fracture with higher milk consumption was observed in the USA (RR 0.75, 95% CI 0.65, 0.87), but not in Scandinavian countries (RR 1.00, 95% CI 0.85, 1.17). These findings were further supported by the fact that American studies (RR 0.93, 95% CI 0.88, 0.98; per 1 glass/day), but not Scandinavian studies (RR 1.01, 95% CI 0.95, 1.07; per 1 glass/day), demonstrated a linear association between milk consumption and the risk of hip fracture.
Conclusions
The cumulative evidence from prospective cohort studies reassuringly suggests that the risk of hip fracture may not be elevated among people who consume milk, yogurt, and cheese, and that a greater consumption of milk or yogurt may even be associated with a lower risk of hip fracture depending on the factors that may differ across the population of interest.
Individuals with diabetes mellitus (DM) have an increased risk of fracture. Glycemic control is crucial to the management of DM, but there are concerns pertaining to hypoglycemia development in the ...course of glycemic control target achievement. The extent to which glycemic control may affect the risk of fracture remains less defined. Hypoglycemia-induced falls have been suggested to contribute to an elevated risk of fracture in DM patients. In this meta-analysis of observational studies, we aimed to investigate the relative contribution of glycemic control, as measured by glycated hemoglobin (HbA1c), and hypoglycemia to the risk of fracture in DM. The PubMed and Web of Science databases were searched for relevant studies. A random-effects model was used to generate summary relative risks (RRs) and 95% confidence intervals (CIs). Both increased HbA1c levels (RR
per 1% increase
1.08, 95% CI 1.03, 1.14;
n
studies
= 10) and hypoglycemia (RR 1.52, 95% CI 1.23, 1.88;
n
studies
= 8) were associated with an increased risk of fracture. The association between HbA1c levels and the risk of fracture was somewhat nonlinear, with a noticeably increased risk observed at an HbA1c level ≥ 8%. The positive associations of HbA1c levels and hypoglycemia with the risk of fracture did not reach statistical significance in the studies that adjusted for insulin use, hypoglycemia, or falls for the former and in those that adjusted for falls for the latter. In summary, both increased HbA1c levels and hypoglycemia may increase the risk of fracture in patients with DM. The positive association between HbA1c levels and the risk of fracture appears to be, in part, explained by hypoglycemia-induced falls, possibly due to insulin use. The avoidance of hypoglycemia in the course of achieving good glycemic control through the careful selection of glucose-lowering medications may contribute to fracture prevention by reducing the risk of falls related to treatment-induced hypoglycemia.
Milk intake is widely recommended for a healthy diet. Epidemiological studies have suggested that the consumption of dairy products may be associated with a reduction in type 2 diabetes mellitus ...(T2DM). A meta-analysis was conducted to elucidate the association between dairy products consumption and T2DM.
A systematical literature search was done through the Medline database and seven related cohort studies were identified. The adjusted relative risks (RRs) with the highest and the lowest categories from each study were extracted to calculate the combined RR. A least-square trend estimation was applied to assess the dose-response relationships.
A combined RR of 0.86 (95% confidence interval (CI), 0.79-0.92) was revealed on T2DM risk associated to dairy intake, with little evidence of heterogeneity. For subgroup analysis, a combined RR was 0.82 (95% CI, 0.74-0.90), 1.00 (95% CI, 0.89-1.10), 0.95 (95% CI, 0.86-1.05) and 0.83 (95% CI, 0.74-0.93) for the intake of low-fat dairy, high-fat dairy, whole milk and yogurt, respectively. Dose-response analysis showed that T2DM risk could be reduced 5% for total dairy products and 10% for low-fat dairy products.
An inverse association of daily intake of dairy products, especially low-fat dairy, with T2DM was revealed, indicating a beneficial effect of dairy consumption in the prevention of T2DM development.
Mutations in the genes encoding isocitrate dehydrogenase, IDH1 and IDH2, have been reported in gliomas, myeloid leukemias, chondrosarcomas and thyroid cancer. We discovered IDH1 and IDH2 mutations in ...34 of 326 (10%) intrahepatic cholangiocarcinomas. Tumor with mutations in IDH1 or IDH2 had lower 5-hydroxymethylcytosine and higher 5-methylcytosine levels, as well as increased dimethylation of histone H3 lysine 79 (H3K79). Mutations in IDH1 or IDH2 were associated with longer overall survival (P=0.028) and were independently associated with a longer time to tumor recurrence after intrahepatic cholangiocarcinoma resection in multivariate analysis (P=0.021). IDH1 and IDH2 mutations were significantly associated with increased levels of p53 in intrahepatic cholangiocarcinomas, but no mutations in the p53 gene were found, suggesting that mutations in IDH1 and IDH2 may cause a stress that leads to p53 activation. We identified 2309 genes that were significantly hypermethylated in 19 cholangiocarcinomas with mutations in IDH1 or IDH2, compared with cholangiocarcinomas without these mutations. Hypermethylated CpG sites were significantly enriched in CpG shores and upstream of transcription start sites, suggesting a global regulation of transcriptional potential. Half of the hypermethylated genes overlapped with DNA hypermethylation in IDH1-mutant gliobastomas, suggesting the existence of a common set of genes whose expression may be affected by mutations in IDH1 or IDH2 in different types of tumors.
The heterogeneous breast cancers can be classified into different subtypes according to their histopathological characteristics and molecular signatures. Foxa1 expression is linked with luminal ...breast cancer (LBC) with good prognosis, whereas Twist1 expression is associated with basal-like breast cancer (BLBC) with poor prognosis owing to its role in promoting epithelial-to-mesenchymal transition (EMT), invasiveness and metastasis. However, the regulatory and functional relationships between Twist1 and Foxa1 in breast cancer progression are unknown. In this study, we demonstrate that in the estrogen receptor (ERα)-positive LBC cells Twist1 silences Foxa1 expression, which has an essential role in relieving Foxa1-arrested migration, invasion and metastasis of breast cancer cells. Mechanistically, Twist1 binds to Foxa1 proximal promoter and recruits the NuRD transcriptional repressor complex to de-acetylate H3K9 and repress RNA polymerase II recruitment. Twist1 also silences Foxa1 promoter by inhibiting AP-1 recruitment. Twist1 expression in MCF7 cells silenced Foxa1 expression, which was concurrent with the induction of EMT, migration, invasion and metastasis of these cells. Importantly, restored Foxa1 expression in these cells largely inhibited Twist1-promoted migration, invasion and metastasis. Restored Foxa1 expression did not change the Twist1-induced mesenchymal cellular morphology and the expression of Twist1-regulated E-cadherin, β-catenin, vimentin and Slug, but it partially rescued Twist1-silenced ERα and cytokeratin 8 expression and reduced Twist1-induced integrin α5, integrin β1 and MMP9 expression. In a xenografted mouse model, restored Foxa1 also increased Twist1-repressed LBC markers and decreased Twist1-induced BLBC markers. Furthermore, Twist1 expression is negatively correlated with Foxa1 in the human breast tumors. The tumors with high Twist1 and low Foxa1 expressions are associated with poor distant metastasis-free survival. These results demonstrate that Twist1's silencing effect on Foxa1 expression is largely responsible for Twist1-induced migration, invasion and metastasis, but less responsible for Twist1-induced mesenchymal morphogenesis and expression of certain EMT markers.
Chronic stress has a crucial role in the development of psychiatric diseases, such as anxiety and depression. Dysfunction of the medial prefrontal cortex (mPFC) has been linked to the cognitive and ...emotional deficits induced by stress. However, little is known about the molecular and cellular determinants in mPFC for stress-associated mental disorders. Here we show that chronic restraint stress induces the selective loss of p11 (also known as annexin II light chain, S100A10), a multifunctional protein binding to 5-HT receptors, in layer II/III neurons of the prelimbic cortex (PrL), as well as depression-like behaviors, both of which are reversed by selective serotonin reuptake inhibitors (SSRIs) and the tricyclic class of antidepressant (TCA) agents. In layer II/III of the PrL, p11 is highly concentrated in dopamine D2 receptor-expressing (D2
) glutamatergic neurons. Viral expression of p11 in D2
PrL neurons alleviates the depression-like behaviors exhibited by genetically manipulated mice with D2
neuron-specific or global deletion of p11. In stressed animals, overexpression of p11 in D2
PrL neurons rescues depression-like behaviors by restoring glutamatergic transmission. Our results have identified p11 as a key molecule in a specific cell type that regulates stress-induced depression, which provides a framework for the development of new strategies to treat stress-associated mental illnesses.
This meta‐analysis aimed to assess the gender‐specific differences in the relationship between circulating leptin levels and risk of type 2 diabetes. Published prospective studies that reported the ...association of leptin levels with risk of type 2 diabetes for a certain gender or those that reported gender‐specific associations were considered. Dose‐response relationships were assessed by the generalized least squares trend estimation and summary relative risks (RRs) with 95% confidence interval (CI) were computed with the random‐effects model. Stratified and sensitivity analyses were also performed to investigate potential sources of heterogeneity. Overall, 11 prospective studies were identified. The summary RR for an increment in leptin levels of 1‐log ng mL⁻¹ was 1.37 (95% CI, 1.13–1.66) for men and 0.96 (95% CI, 0.90–1.03) for women. The differences between genders were statistically significant (P for interaction = 0.006). Subgroup and sensitivity analyses generally confirmed the robustness of these findings. Furthermore, the increased risk in men appeared non‐linear, with a tendency to plateau at high levels (P for non‐linearity = 0.03). Little evidence of publication bias was found. Collectively, higher leptin levels were found to be associated with elevated risk of type 2 diabetes in men but not in women.
Objectives
The vicious cycle of dynapenia and abdominal obesity may have synergistic detrimental impacts on health. We aim to investigate the prospective association between dynapenic abdominal ...obesity and the risk of heart disease among middle-aged and older adults.
Design
A prospective cohort study.
Setting
English Longitudinal Study of Ageing, 2002–2019.
Participants
A total of 4734 participants aged 50 years and older were included.
Measurements
Individuals were divided into non-dynapenia/non-abdominal obesity (ND/NAO), non-dynapenia/abdominal obesity (ND/AO), dynapenia/non-abdominal obesity (D/NAO), and dynapenia/abdominal obesity (D/AO) according to grip strength and waist circumference at baseline. The Cox proportional hazards models were used to obtain the hazard ratios (HRs) of incident heart disease associated with dynapenia and abdominal obesity after adjusting for potential confounding factors.
Results
During a median follow-up of 9.5 years, 1040 cases of heart disease were recorded. Compared with ND/NAO group, the multivariable HRs were 1.05 (0.92, 1.21) for ND/AO group, 1.31 (0.96, 1.81) for D/NAO group, and 1.39 (1.03, 1.88) for D/AO group. The significant association of D/AO with incident heart disease was detected in women but not in men HR = 1.55 (1.07, 2.24) and 1.06 (0.60, 1.88), respectively. Among middle-aged adults, significant associations of D/NAO and D/AO with incident heart disease were observed HR = 2.46 (1.42, 4.29) and 1.74 (1.02, 2.97), respectively.
Conclusion
Both D/NAO and D/AO might increase the risk of developing heart disease, highlighting the importance of dynapenia and obesity early screening for heart disease prevention.
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