Efficacy and safety of janagliflozin as add-on therapy to metformin in Chinese patients with type 2 diabetes inadequately controlled with metformin alone: A multicentre, randomized, double-blind, placebo-controlled, phase 3 trial.

AIM: To evaluate the efficacy and safety of janagliflozin in Chinese patients with type 2 diabetes (T2D) inadequately controlled with metformin monotherapy. MATERIALS AND METHODS: This multicentre phase 3 trial included a 24-week, randomized, double-blind, placebo-controlled period, followed by a 28-week extension period. Patients (N = 421) with HbA1c of 7.0% or higher and 10.5% or less were randomized (1:1:1) to receive once-daily placebo, janagliflozin 25 or 50 mg. After the 24-week treatment period, patients on placebo were re-randomized (1:1) to janagliflozin 25 or 50 mg for the additional 28-week treatment, whereas patients on janagliflozin maintained the same therapy. The primary endpoint was the change from baseline in HbA1c to week 24. RESULTS: At week 24, the placebo-adjusted least squares mean changes of HbA1c were -0.58% and -0.58% with janagliflozin 25 and 50 mg, respectively (P < .0001 for both). The proportion of patients achieving HbA1c less than 7.0% was higher with janagliflozin 25 and 50 mg compared with placebo (41.8%, 41.7% and 28.0%, respectively). Both janagliflozin doses provided significant reductions in fasting plasma glucose, 2-hour postprandial glucose, body weight and systolic blood pressure, and improvements in high-density lipoprotein cholesterol and insulin sensitivity compared with placebo (P < .05 for all). The trends in improvement of these variables were retained during the 28-week extension period. No severe hypoglycaemia occurred throughout the whole 52-week treatment. CONCLUSIONS: Janagliflozin 25 or 50 mg once-daily added to metformin therapy significantly improved glycaemic control, reduced body weight and systolic blood pressure, improved high-density lipoprotein cholesterol and insulin sensitivity, and was generally well-tolerated by Chinese T2D patients who had poor glycaemic control with metformin monotherapy.

Overexpression of RYBP inhibits proliferation, invasion, and chemoresistance to cisplatin in anaplastic thyroid cancer cells via the EGFR pathway.

Ring1 and YY1 binding protein (RYBP), a new member of the polycomb group protein family, has been reported to play an important role in various biological processes. Recently, more and more studies have demonstrated an implication of RYBP in cancer development. However, the specific role of RYBP in anaplastic thyroid cancer (ATC) remains unknown. In this study, we investigated for the first time the expression pattern and biological functions of RYBP in ATC. We showed that RYBP was lowly expressed in ATC tissues and cell lines. We also found that overexpression of RYBP inhibited ATC cell proliferation, invasion, and cisplatin resistance. Furthermore, we observed that upregulation of RYBP decreased the phosphorylation of EGFR and ERK1/2 in ATC cells. Taken together, our data indicated that RYBP might be considered as a promising therapeutic target for the treatment of ATC.

A Ferroptosis-Related Signature Robustly Predicts Clinical Outcomes and Associates With Immune Microenvironment for Thyroid Cancer.

Objective: This study aimed to construct a prognostic ferroptosis-related signature for thyroid cancer and probe into the association with tumor immune microenvironment. Methods: Based on the expression profiles of ferroptosis-related genes, a LASSO cox regression model was established for thyroid cancer. Kaplan-Meier survival analysis was presented between high and low risk groups. The predictive performance was assessed by ROC. The predictive independency was validated via multivariate cox regression analysis and stratified analysis. A nomogram was established and verified by calibration curves. The enriched signaling pathways were predicted via GSEA. The association between the signature and immune cell infiltration was analyzed by CIBERSORT. The ferroptosis-related genes were validated in thyroid cancer tissues by immunohistochemistry and RT-qPCR. Results: A ferroptosis-related eight gene model was established for predicting the prognosis of thyroid cancer. Patients with high risk score indicated a poorer prognosis than those with low risk score (p = 1.186e-03). The AUCs for 1-, 2-, and 3-year survival were 0.887, 0.890, and 0.840, respectively. Following adjusting other prognostic factors, the model could independently predict the prognosis (p = 0.015, HR: 1.870, 95%CI: 1.132-3.090). A nomogram combining the signature and age was constructed. The nomogram-predicted probability of 1-, 3-, and 5-year survival approached the actual survival time. Several ferroptosis-related pathways were enriched in the high-risk group. The signature was distinctly associated with the immune cell infiltration. After validation, the eight genes were abnormally expressed between thyroid cancer and control tissues. Conclusion: Our findings established a prognostic ferroptosis-related signature that was associated with the immune microenvironment for thyroid cancer.

Comparative risk of new-onset diabetes mellitus for antihypertensive drugs in elderly: A Bayesian network meta-analysis.

There is no study to compare different class of antihypertensive drugs on new-onset diabetes mellitus (NOD) in elderly. We aimed to investigate the risk of antihypertensive drugs on NOD in elderly patients. The databases were retrieved in an orderly manner from the dates of their establishment to October, 2018, including Medline, Embase, Clinical Trials, and the Cochrane Database, to collect randomized controlled trials (RCTs) of different antihypertensive drugs in elderly patients (age > 60 years). Then, a network meta-analysis was conducted using R and Stata 12.0 softwares. A total of 14 RCTs involving 74 042 patients were included. The relative risk of NOD mellitus associated with six classes of antihypertensive drugs was analyzed, including placebo, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics, and ß blockers. Patients with ACEIs or ARBs appeared to have significantly reduced risk of NOD compare with placebo: ACEIs (OR = 0.49, 95% CrI 0.28-0.85), ARBs (OR = 0.37, 95% CrI 0.26-0.52), while CCBs, diuretics, and ß blockers appeared to have not significantly reduced risk of NOD mellitus compare with placebo: CCBs (OR = 1.10, 95% CrI 0.85-1.60), diuretics (OR = 1.40, 95% CrI 0.92-2.50), ß blockers (OR = 1.40, 95% CrI 0.93-2.10). The SUCRA of placebo, ACEIs, ARBs, CCBs, diuretics, and ß blockers was, respectively, 65.3%, 69.3%, 92.3%, 44.1%, 12.1%, and 16.5%. According to the evidence, ARBs have an advantage over the other treatments in reducing the risk of NOD in elderly patients.

Influence of Nutritional Status on the Absorption of Polyphyllin I, an Anticancer Candidate from Paris polyphylla in Rats.

BACKGROUND AND OBJECTIVES: Protein-calorie malnutrition (PCM) is one of the most suffered complications in cancer patients. Polyphyllin I (PPI), a saponin isolated from rhizome of Paris polyphylla, is a potential candidate in cancer therapy. In this study, the influence of nutritional status on the absorption of PPI in rats was explored after oral administration. METHODS: PCM rats, namely mal-nourished (MN) rats, were induced from well-nourished (WN) rats by caloric restriction protocol. Intestinal absorption of PPI in WN and MN rats was evaluated by pharmacokinetic and intestinal perfusion methods. The potential mechanisms between two groups were investigated on the basis of intestinal permeability, intestinal efflux and PPI's depletions in vivo. The intestinal permeability was analyzed by determining the concentration of paracellular marker transport in serum and the expression of junction proteins in intestine. The intestinal efflux was evaluated through comparing the protein level of P-glycoprotein (P-gp) in intestine, and the depletions of PPI and/or generation of its metabolites in liver and intestines were analyzed by liquid chromatography triple quadrupole mass spectrometry (LC-MS/MS) method. RESULTS: Compared to WN rats, the oral systemic exposure of PPI was significantly increased in MN rats, evidenced by significant enhancement of maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0-60h) by more than 2.51- and 3.71-folds as well as terminal elimination half-life (t1/2) prolonged from to 7.3 to 14.1 h. Further studies revealed that the potential mechanism might be associated with combined contribution of improved intestinal absorption and depressed deglycosylation of PPI in MN rats. Furthermore, enhanced intestinal absorption of PPI was benefited from increased intestinal permeability and decreased intestinal efflux in MN rats. Meanwhile, the former manifested as increased transport of paracellular marker and decreased junction proteins levels, while the later evidenced by reduced P-gp expression. CONCLUSIONS: The oral exposure of PPI was enhanced in MN rats, which suggested that nutritional status alters the absorption of PPI, and thus the dosage of PPI should be modified during the treatment of cancer patient with PCM.

Risk of depressive symptoms associated with impaired glucose metabolism, newly diagnosed diabetes, and previously diagnosed diabetes: a meta-analysis of prospective cohort studies.

AIMS: Patients with diabetes had a higher risk of developing depressive symptoms. Little is known about the risk of depressive symptoms associated with different glucose metabolism status. We performed a meta-analysis of prospective cohort studies to investigate the risk of depressive symptoms among individuals with impaired glucose metabolism (IGM), newly diagnosed diabetes (NDM), and previously diagnosed diabetes (PDM), compared with those with normal glucose metabolism (NGM), and further examined the influence of diabetes-related comorbidities on the association. METHODS: PubMed and EMBASE were searched for relevant studies through 5 September 2015. The random-effects model was used to calculated overall relative risk (RR) and confidence interval (CI). Three separated meta-analyses were conducted by estimating the risk of depressive symptoms among people with IGM, NDM, and PDM, with NGM as a common reference category. Secondary analyses were conducted to examine whether adjustment for diabetes-related comorbidities affected the association. RESULTS: Five prospective cohort studies were included in the analyses, with a total of 18,051 participants involved. People with IGM (RR = 1.08, 95 % CI 0.84-1.38) and NDM (RR = 1.07, 95 % CI 0.74-1.55) were not associated with risk of developing depressive symptoms, whereas patients with PDM were associated with a modest increased risk of depressive symptoms (RR = 1.29, 95 % CI 1.03-1.63), after adjustment for demographic/socioeconomic factors. The risk of depressive symptoms associated with PDM was attenuated to be non-significant after pooling RRs that were adjusted for diabetes-related comorbidities. CONCLUSIONS: Our meta-analysis suggested people with PDM, but not IGM or NDM had an increased risk of developing depressive symptoms, and the risk was partially explained by diabetes-related comorbidities. Our findings indicated that routine diabetes care should put more emphasis on psychological problems of diabetic patients with complications.