Association between Whole Grain Intake and Chronic Kidney Disease.

BACKGROUND: The relationship between whole grain intake and chronic kidney disease (CKD) remains uncertain. OBJECTIVE: This study aimed to evaluate the association between whole grain intake and risk of CKD in Chinese adults. METHODS: The present cross-sectional study used data from the China Health and Nutrition Survey conducted in 2009. Whole grain intake was measured using 3 consecutive 24-h dietary recalls and a household food inventory. A multivariable logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for risk of CKD. In addition, a restricted cubic spline was used to investigate the dose‒response relationship between whole grain and risk of CKD. RESULTS: A total of 6747 participants were included, 728 of whom had CKD. Compared with those in the lowest whole grain intake group, those in the higher grain intake group had an inverse association with risk of CKD (Q2: adjusted OR 0.70, 95% CI: 0.54, 0.89; Q3: adjusted OR 0.54, 95% CI: 0.42, 0.69; and Q4: adjusted OR 0.29, 95% CI: 0.21, 0.41). The association between whole grain intake and CKD seems to be stronger for individuals who were male (P for interaction = 0.008) or smokers (P for interaction = 0.013). In addition, the restricted cubic spline suggested an obvious L-shaped correlation. CONCLUSIONS: Increased whole grain intake was associated with a decreased risk of CKD in Chinese adults.

Efficacy and safety of tirzepatide in people with type 2 diabetes by baseline body mass index: An exploratory subgroup analysis of SURPASS-AP-Combo.

AIMS: To assess the efficacy and safety of tirzepatide versus insulin glargine in people with type 2 diabetes (T2D) by baseline body mass index (BMI). MATERIALS AND METHODS: Participants with T2D from the Phase 3 SURPASS-AP-Combo trial (NCT04093752) were categorized into three BMI subgroups (normal weight [<25 kg/m2 ], overweight [≥25 and <30 kg/m2 ], and obese [≥30 kg/m2 ]) according to World Health Organization criteria. Exploratory outcomes including glycaemic control, body weight, cardiometabolic risk, and safety were compared among three tirzepatide doses (5, 10 or 15 mg) and insulin glargine. RESULTS: Of 907 participants, 235 (25.9%) had a BMI <25 kg/m2 , 458 (50.5%) a BMI ≥25 to <30 kg/m2 , and 214 (23.6%) a BMI ≥30 kg/m2 at baseline. At Week 40, all tirzepatide doses led to a greater reduction in mean glycated haemoglobin (HbA1c; -2.0% to -2.8% vs. -0.8% to -1.0%, respectively) and percent change in body weight (-5.5% to -10.8% vs. 1.0% to 2.5%, respectively) versus insulin glargine, across the BMI subgroups. Compared with insulin glargine, a higher proportion of tirzepatide-treated participants achieved treatment goals for HbA1c and body weight reduction. Improvements in other cardiometabolic indicators were also observed with tirzepatide across all the BMI subgroups. The safety profile of tirzepatide was similar across all subgroups by BMI. The most frequent adverse events with tirzepatide were gastrointestinal-related events and decreased appetite, with relatively few events leading to treatment discontinuation. CONCLUSIONS: In participants with T2D, regardless of baseline BMI, treatment with tirzepatide resulted in statistically significant and clinically meaningful glycaemic reductions and body weight reductions compared with insulin glargine, with a safety profile consistent with previous reports.

Correlation Between N-Demethyl Imatinib Trough Concentration and Serious Adverse Reactions in Patients with Gastrointestinal Stromal Tumors: A Retrospective Cohort Study.

BACKGROUND: Imatinib is the first-line treatment for gastrointestinal stromal tumors; however, the clinical prognosis and adverse reactions of patients vary owing to individualized discrepancies in plasma exposure. METHODS: To determine the safe interval for steady-state plasma trough concentrations (C min ) of imatinib and its active metabolite, N-demethyl imatinib (NDI), 328 plasma samples from 273 patients treated with imatinib were retrospectively analyzed. Imatinib C min and NDI C min were tested, and adverse reactions were recorded. The association between imatinib C min , NDI C min , and serious adverse reactions was evaluated. RESULTS: The C min range of imatinib was 209.5-4950.0 ng/mL, with the mean value and SD of 1491.8 ± 731.4 ng/mL. The C min range of NDI was 80.0-2390.0 ng/mL with the mean value and SD of 610.8 ± 281.5 ng/mL. NDI C min was positively correlated with imatinib C min , whereas the ratio of NDI C min to imatinib C min (NDI C min /imatinib C min ) was negatively correlated with imatinib C min . Univariate logistic regression analysis demonstrated that the treatment objective, daily dose, imatinib C min , NDI C min , and imatinib C min + NDI C min were significantly associated with serious adverse reactions. Multivariate logistic regression analysis showed that NDI C min was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. CONCLUSIONS: NDI C min was an independent risk factor for serious adverse reactions, with a threshold of 665 ng/mL. Monitoring NDI C min was beneficial for the rational application of imatinib and individualized treatment of patients with gastrointestinal stromal tumors.

Associations between whole grains intake and new-onset hypertension: a prospective cohort study.

IMPORTANCE: Epidemiological evidences regarding the association between whole grain intake and the risk of new-onset hypertension are still controversial. OBJECTIVE: We aimed to investigate the relationship between whole grain intake and new-onset hypertension and examine possible effect modifiers in the general population. METHODS: A total of 10,973 participants without hypertension from the China Health and Nutrition Survey were enrolled, with follow-up beginning in 1997 and ending in 2015. Whole grain intake was assessed by 3 consecutive 24-h dietary recalls combined with a household food inventory. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression model after adjusting for potential risk factors. RESULTS: During a median follow-up of 7.0 years, 3,733 participants developed new-onset hypertension. The adjusted HRs (95% CIs) were as follows: for quartile 2 (HR: 0.52; 95% CI: 0.47-0.57), quartile 3 (HR: 0.46; 95% CI: 0.42-0.51), and quartile 4 (HR: 0.35; 95% CI: 0.31-0.38), compared with quartile 1. Different types of whole grain types, including wheat (adjusted HR, 0.35; 95% CI, 0.32-0.39), maize (adjusted HR, 0.50; 95% CI, 0.42-0.59), and millet (adjusted HR, 0.38; 95% CI, 0.30-0.48), showed significant associations with a reduced risk of hypertension. The association between whole grain intake and new-onset hypertension was stronger in individuals with older age (P for interaction < 0.001) and higher BMI (P for interaction < 0.001). CONCLUSION: Higher consumption of whole grains was significantly associated with a lower risk of new-onset hypertension. This study provides further evidence supporting the importance of increasing whole grain intake for hypertension prevention among Chinese adults.

Long-term air pollutants exposure and respiratory mortality: A large prospective cohort study.

Ambient air pollution is a major global health concern. Yet, no study has thoroughly assessed its link to respiratory mortality. Our research evaluated the combined and individual effects of air pollutants on respiratory mortality risks based on the UK Biobank. A total of 366,478 participants were studied. A Cox proportional hazards model was used to estimate the respiratory mortality risk from combined long-term exposure to five pollutants, summarized as a weighted air pollution score. During a median of 13.6 years of follow-up, 6113 deaths due to respiratory diseases were recorded. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of respiratory diseases were 2.64 (2.05-3.39), 1.62 (1.23-2.12), 2.06 (1.73-2.45), 1.20 (1.16-1.25), and 1.07 (1.05-1.08) per 10 µg/m3 increase in PM2.5, PM2.5-10, PM10, NO2, and NOx, respectively. The air pollution score showed a dose-response association with an elevated respiratory mortality risk. The highest versus lowest quartile air pollution score was linked to a 44% increase in respiratory mortality risk (HR 1.44, 95% CI: 1.33-1.57), with consistent findings in subgroup and sensitivity analyses. Long-term individual and joint air-pollutant exposure showed a dose-response association with an increased respiratory mortality risk, highlighting the importance of a comprehensive air-pollutant assessment to protect public health.

Norvancomycin plasma concentration monitoring in hemodialysis patients with end stage kidney disease: A retrospective cohort study.

Blood concentration monitoring plays an important role in the rational use of norvancomycin. However, the reference interval for the norvancomycin plasma concentration in the treatment of infections in hemodialysis patients with end stage kidney disease is undefined. To determine the safe and effective interval for the norvancomycin plasma trough concentration, 39 patients treated with hemodialysis and norvancomycin were analyzed retrospectively. The norvancomycin plasma concentration before hemodialysis was tested as the trough concentration. The associations of the norvancomycin trough concentration with efficacy and adverse reactions were evaluated. No norvancomycin concentration above 20 µg/mL was detected. The trough concentration, but not the dose, had a significant effect on the anti-infectious efficacy. Compared with the low norvancomycin trough concentration group (<9.30 µg/mL), the high concentration group (9.30-20.0 µg/mL) had improved efficacy (OR = 15.45, p < 0.01) with similar side effects (OR = 0.5417, p = 0.4069). It is beneficial to maintain the norvancomycin trough concentration at 9.30-20.0 µg/mL to achieve a good anti-infectious effect in hemodialysis patients with end stage kidney disease. Plasma concentration monitoring provides a data basis for the individual treatment of infections with norvancomycin in hemodialysis patients.

Immunogenicity of LY2963016 insulin glargine and Lantus® insulin glargine in Chinese patients with type 1 or type 2 diabetes mellitus.

AIMS: To evaluate the immunogenicity of LY2963016 insulin glargine (LY IGlar) versus originator insulin glargine (IGlar [Lantus®]) in Chinese patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: ABES and ABET were prospective, randomized, active control, open-label, phase III studies, which enrolled Chinese patients with T1DM (N = 272) and T2DM (N = 536), respectively. Using data from these trials, immunogenicity of LY IGlar and IGlar was evaluated by comparing the proportion of patients with detectable anti-insulin glargine antibodies and the median antibody levels (percent binding) between the treatment groups. The incidence of anti-insulin antibodies and treatment-emergent antibody response (TEAR) were compared using Fisher's exact test or Pearson's chi-squared test. Levels of anti-insulin antibodies were compared using the Wilcoxon rank-sum test. We also evaluated the relationship between antibody formation or TEAR and clinical outcomes using analysis of covariance, negative binomial regression, or partial correlations. RESULTS: There were no significant treatment differences in the incidence of detectable anti-insulin antibodies, median antibody levels or TEAR, overall or at Week 24 with last observation carried forward, and median antibody levels were low (<5%) after 24 weeks of treatment, in patients with T1DM or T2DM. Levels of anti-insulin antibodies and development of TEAR were not associated with efficacy (glycated haemoglobin, insulin dose [U/kg/d] and hypoglycaemia) or safety outcomes. CONCLUSIONS: The immunogenicity profiles of LY IGlar and IGlar are similar, with low levels of anti-insulin antibodies observed for both insulins. No association was observed between antibody levels or TEAR status and clinical outcomes.

Efficacy and safety of LY2963016 insulin glargine versus insulin glargine (Lantus) in Chinese adults with type 2 diabetes: A phase III, randomized, open-label, controlled trial.

AIM: To compare the efficacy and safety of LY2963016 insulin glargine (LY IGlar) with insulin glargine (Lantus; IGlar) combined with oral antihyperglycaemic medications (OAMs) in insulin-naive Chinese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In this phase III, open-label trial, adult patients with T2D receiving two or more OAMs at stable doses for 12 weeks or longer, with HbA1c of 7.0% or more and 11.0% or less, were randomized (2:1) to receive once-daily LY IGlar or IGlar for 24 weeks. The primary outcome was non-inferiority of LY IGlar to IGlar at a 0.4% margin, and a gated secondary endpoint tested non-inferiority of IGlar to LY IGlar (-0.4% margin), assessed by least squares (LS) mean change in HbA1c from baseline to 24 weeks. RESULTS: Patients assigned to LY IGlar (n = 359) and IGlar (n = 177) achieved similar and significant reductions (p < .001) in HbA1c from baseline. LY IGlar was non-inferior to IGlar for change in HbA1c from baseline to week 24 (-1.27% vs. -1.23%; LS mean difference: -0.05% [95% CI, -0.19% to 0.10%]) and IGlar was non-inferior to LY IGlar. The study therefore showed equivalence of LY IGlar and IGlar for the primary endpoint. At week 24, there were no between-group differences in the proportion of patients achieving an HbA1c of less than 7.0%, seven-point self-measured blood glucose, insulin dose or weight gain. Adverse events, allergic reactions, hypoglycaemia and insulin antibodies were similar in the two groups. CONCLUSIONS: Once-daily LY IGlar and IGlar, combined with OAMs, provide effective and similar glycaemic control with comparable safety profiles in insulin-naive Chinese patients with T2D.

A mammary repopulating cell population characterized in mammary anlagen reveals essential mammary stroma for morphogenesis.

The cells with mammary repopulating capability can achieve mammary gland morphogenesis in a suitable cellular microenvironment. Using cell surface markers of CD24, CD29 and CD49f, mouse mammary repopulating unit (MRU) has been identified in adult mammary epithelium and late embryonic mammary bud epithelium. However, embryonic MRU remains to be fully characterized at earlier mammary anlagen stage. Here we isolated discrete populations of E14.5 mouse mammary anlagen cells. Only Lin(-)CD24(med)CD29(+) cell population was predicted as E14.5 MRU by examining their capacities of forming mammosphere and repopulating cleared mammary fat pad in vivo. However, when we characterized gene expressions of this E14.5 cell population by comparing with adult mouse MRU (Lin(-)CD24(+)CD29(hi)), the gene profiling of these two cell populations exhibited great differences. Real-time PCR and immunostaining assays uncovered that E14.5 Lin(-)CD24(med)CD29(+) cell population was a heterogeneous stroma-enriched cell population. Then, limiting dilutions and single-cell assays also confirmed that E14.5 Lin(-)CD24(med)CD29(+) cell population possessed low proportion of stem cells. In summary, heterogeneous Lin(-)CD24(med)CD29(+) cell population exhibited mammary repopulating ability in E14.5 mammary anlagen, implying that only suitable mammary stroma could enable mammary gland morphogenesis, which relied on the interaction between rare stem cells and microenvironment.

Characterization of tirzepatide-treated patients achieving different glycemic control levels in SURPASS-AP-Combo.

OBJECTIVE: The study objective was to characterize subgroups of Asia-Pacific patients with type 2 diabetes who achieved different glycated hemoglobin (HbA1c) targets on tirzepatide treatment. METHODS: This was a post hoc analysis of the SURPASS AP-Combo study. Baseline characteristics, changes in metabolic markers, and safety were compared between tirzepatide-treated patients achieving HbA1c <7.0% (<53 mmol/mol) and those achieving ≥7.0% (≥53 mmol/mol) at week 40. Among patients achieving HbA1c <7.0% (<53 mmol/mol), further comparisons were conducted among subgroups achieving HbA1c <5.7% (<39 mmol/mol), 5.7% to 6.5% (39 to 48 mmol/mol), and >6.5% to <7.0% (>48 to <53 mmol/mol). RESULTS: Five hundred ninety-eight patients on tirzepatide treatment without rescue medication were included (56.9% male; mean age: 53.1 years; mean baseline HbA1c: 8.7% [71.6 mmol/mol]). Patients achieving HbA1c <7.0% (<53 mmol/mol) versus ≥7.0% (≥53 mmol/mol) were slightly younger with a shorter disease duration and lower HbA1c at baseline, and they had greater improvements in HbA1c, fasting serum glucose, body weight, BMI, waist circumference, waist-height ratio, diastolic blood pressure, lipids, and self-monitored blood glucose at week 40. Patients achieving HbA1c <5.7% (<39 mmol/mol) versus those achieving 5.7% to 6.5% (39 to 48 mmol/mol) and those achieving >6.5% to <7.0% (>48 to <53 mmol/mol) were much younger, had much lower HbA1c, and had further improvements in metabolic markers. Tirzepatide treatment was well tolerated irrespective of the HbA1c level achieved, with a low incidence of hypoglycemic events. CONCLUSIONS: These findings may help to inform clinical decisions in Asia-Pacific patients with type 2 diabetes.

Efficacy and Safety of Tirzepatide in Patients with Type 2 Diabetes: Analysis of SURPASS-AP-Combo by Different Subgroups.

INTRODUCTION: Tirzepatide is a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist. In the SURPASS-AP-Combo trial, once-weekly tirzepatide was associated with improved glycemic control and weight loss versus insulin glargine and was generally well tolerated in an Asia-Pacific, predominately Chinese, population with type 2 diabetes (T2D). This post hoc subgroup analysis of SURPASS-AP-Combo assessed the potential influence of patient baseline characteristics on the efficacy and safety of tirzepatide. METHODS: Changes from baseline to week 40 in HbA1c, body weight, fasting serum glucose (FSG), and daily glucose average from self-measured blood glucose profiles were analyzed by potential influential factors including age (< 65, ≥ 65 years), sex, baseline HbA1c (≤ 8.5, > 8.5%), body mass index (BMI) (< 25, ≥ 25 kg/m2), body weight (< 75, ≥ 75 kg), duration of diabetes (< 10, ≥ 10 years), and concomitant oral antihyperglycemic medications (metformin, metformin plus sulphonylurea). Gastrointestinal adverse events and hypoglycemia were also evaluated. RESULTS: At week 40, all tirzepatide doses were associated with reduced HbA1c, body weight, FSG, and daily glucose average from baseline in all subgroups. Greater HbA1c reductions were achieved in patients with higher baseline HbA1c across all tirzepatide doses, higher body weight with 10 mg and younger age with 15 mg tirzepatide. Greater reductions in body weight were observed in patients with higher body weight across all tirzepatide doses, lower baseline HbA1c with 5 mg and higher BMI with 5 mg tirzepatide. CONCLUSIONS: In this post hoc analysis, tirzepatide was associated with reduced blood glucose and body weight in a predominantly Chinese population with T2D across different subgroups, consistent with previous reports for tirzepatide. CLINICAL TRIAL REGISTRATION: NCT04093752.

Pharmacokinetic Interaction Between Imatinib and Metformin in Rats.

BACKGROUND AND OBJECTIVE: Imatinib is primarily transported into the liver by organic cation transporter 1 (OCT1), organic anion transporting polypeptide 1B3 (OATP1B3), and novel organic cation transporter 2 (OCTN2), which is the first step in the metabolic and elimination of imatinib. Patients taking imatinib may concurrently take metformin, a substrate for OCT1. Drug-drug interactions (DDI) may occur between imatinib and metformin, affecting the clinical efficacy of imatinib. This experiment aimed to investigate the pharmacokinetic effects of metformin on imatinib and its active metabolism of N-desmethyl imatinib in rats. METHODS: Twenty healthy Sprague-Dawley rats were selected and randomly divided into control and experimental groups (10 rats per group). The control group was orally administered imatinib (30 mg/kg) for 14 days, and the experimental group was orally co-administered imatinib (30 mg/kg) and metformin (200 mg/kg) for 14 days. The plasma concentrations of imatinib and N-desmethyl imatinib in rats were determined by ultra-performance liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by DAS2.0 software. RESULTS: After single-dose co-administration of imatinib and metformin on day 1, the AUC0-24 (area under the plasma concentration-time curve) and Cmax (maximum concentration) of imatinib and the MRT (mean residence time) and Cmax of N-desmethyl imatinib in the experimental group were significantly decreased compared with the control group (P < 0.05). After multiple-dose co-administration of imatinib and metformin for 14 days, the AUC0-24 and Cmax of both imatinib and N-desmethyl imatinib were significantly decreased in the experimental group (P < 0.05). CONCLUSION: With both single and multiple co-administration doses, metformin significantly changed the pharmacokinetic parameters of imatinib and N-desmethyl imatinib. The results suggest that care should be taken when metformin and imatinib are co-administered.

Causal Association between Circulating Metabolites and Dementia: A Mendelian Randomization Study.

The causal association of circulating metabolites with dementia remains uncertain. We assessed the causal association of circulating metabolites with dementia utilizing Mendelian randomization (MR) methods. We performed univariable MR analysis to evaluate the associations of 486 metabolites with dementia, Alzheimer's disease (AD), and vascular dementia (VaD) risk. For secondary validation, we replicated the analyses using an additional dataset with 123 metabolites. We observed 118 metabolites relevant to the risk of dementia, 59 of which were lipids, supporting the crucial role of lipids in dementia pathogenesis. After Bonferroni adjustment, we identified nine traits of HDL particles as potential causal mediators of dementia. Regarding dementia subtypes, protective effects were observed for epiandrosterone sulfate on AD (OR = 0.60, 95% CI: 0.48-0.75) and glycoproteins on VaD (OR = 0.89, 95% CI: 0.83-0.95). Bayesian model averaging MR (MR-BMA) analysis was further conducted to prioritize the predominant metabolites for dementia risk, which highlighted the mean diameter of HDL particles and the concentration of very large HDL particles as the predominant protective factors against dementia. Moreover, pathway analysis identified 17 significant and 2 shared metabolic pathways. These findings provide support for the identification of promising predictive biomarkers and therapeutic targets for dementia.

Associations of Regular Internet Usage with All-Cause and Cause-Specific Mortality: A Prospective Cohort Study.

OBJECTIVES: The impact of internet usage on mortality is not widely known. This study intended to investigate the associations between regular internet usage and the risks of all-cause and cause-specific mortality, while also ascertaining potential factors that may modify these correlations. DESIGN: A community-based prospective cohort study. SETTING AND PARTICIPANTS: The study included 21,481 individuals [mean (SD) age, 64.1 (11.0) years] from the Health and Retirement Study, with data collected between 2006 and 2020. METHODS: The Cox proportional hazards regression model was used to evaluate the associations between regular internet usage and the risks of all-cause and cause-specific mortality, adjusting for demographic factors, lifestyle behaviors, and other potential confounding factors. Moreover, we explored the association between daily hours of internet usage and the risk of outcomes. RESULTS: Regular internet usage was significantly associated with a lower risk of all-cause mortality (hazard ratio, 0.78; 95% CI, 0.74-0.83) and cardiovascular mortality (hazard ratio, 0.72; 95% CI, 0.64-0.82). No significant interaction effects were observed for age, sex, regular exercise, or current alcohol consumption (all P interactions > .05). Additionally, estimations for daily hours of usage indicated a U-shaped relationship with all-cause mortality. Adults who used 2.1 to 4 hours per day had the lowest risk; however, not all estimations showed their significance on account of the limited sample size. CONCLUSIONS AND IMPLICATIONS: Regular internet usage was associated with a lower risk of all-cause and cardiovascular mortality, which may prompt consideration of the beneficial impact of internet usage on lifespan.

Investigating Causal Associations between the Gut Microbiota and Dementia: A Mendelian Randomization Study.

Background: The causal association of specific gut microbiota with dementia remains incompletely understood. We aimed to access the causal relationships in which one or more gut microbiota account for dementia. Method: Using data from the MiBioGen and FinnGen consortia, we employed multiple Mendelian randomization (MR) approaches including two-sample MR (TSMR), multivariable MR (MVMR), and Bayesian model averaging MR to comprehensively evaluate the causal associations between 119 genera and dementia, and to prioritize the predominant bacterium. Result: We identified 21 genera that had causal effects on dementia and suggested Barnesiella (OR = 0.827, 95%CI = 0.722-0.948, marginal inclusion probability [MIP] = 0.464; model-averaged causal estimate [MACE] = -0.068) and Allisonella (OR = 0.770, 95%CI = 0.693-0.855, MIP = 0.898, MACE = -0.204) as the predominant genera for AD and all-cause dementia. Conclusions: These findings confirm the causal relationships between specific gut microbiota and dementia, highlighting the necessity of multiple MR approaches in gut microbiota analysis, and provides promising genera as potential novel biomarkers for dementia risk.

c-Src regulates cell cycle proteins expression through protein kinase B/glycogen synthase kinase 3 beta and extracellular signal-regulated kinases 1/2 pathways in MCF-7 cells.

We have demonstrated that c-Src suppression inhibited the epithelial to mesenchymal transition in human breast cancer cells. Here, we investigated the role of c-Src on the cell cycle progression using siRNAs and small molecule inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2). Western blot analysis demonstrated the down-regulation of cyclin D1 and cyclin E and up-regulation of p27 Kip1 after c-Src suppression by PP2. Incubation of cells in the presence of PP2 significantly blocked the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK3ß). Specific pharmacological inhibitors of MEK1/2/ERK1/2 and phosphatidylinositide 3-kinase/AKT pathways were used to demonstrate the relationship between the signal cascade and cell cycle proteins expression. The expression of cyclin D1 and cyclin E were decreased after inhibition of ERK1/2 or AKT activity, whereas the p27 Kip1 expression was increased. In addition, knockdown of c-Src by siRNAs reduced cell proliferation and phosphorylation of ERK1/2, AKT, and GSK3ß. After c-Src depletion by siRNAs, we observed significant down-regulation of cyclin D1 and cyclin E, and up-regulation of p27 Kip1. These results suggest that c-Src suppression by PP2 or siRNAs may regulate the progression of cell cycle through AKT/GSK3ß and ERK1/2 pathways.

Tirzepatide versus insulin glargine as second-line or third-line therapy in type 2 diabetes in the Asia-Pacific region: the SURPASS-AP-Combo trial.

Tirzepatide is a once-weekly GIP/GLP-1 receptor agonist. In this phase 3, randomized, open-label trial, insulin-naive adults (≥18 years of age) with type 2 diabetes (T2D) uncontrolled on metformin (with or without a sulphonylurea) were randomized 1:1:1:1 to weekly tirzepatide 5 mg, 10 mg or 15 mg or daily insulin glargine at 66 hospitals in China, South Korea, Australia and India. The primary endpoint was non-inferiority of mean change in hemoglobin A1c (HbA1c) from baseline to week 40 after treatment with 10 mg and 15 mg of tirzepatide. Key secondary endpoints included non-inferiority and superiority of all tirzepatide doses in HbA1c reduction, proportions of patients achieving HbA1c < 7.0% and weight loss at week 40. A total of 917 patients (763 (83.2%) in China) were randomized to tirzepatide 5 mg (n = 230), 10 mg (n = 228) or 15 mg (n = 229) or insulin glargine (n = 230). All doses of tirzepatide were non-inferior and superior to insulin glargine for least squares mean (s.e.) reduction in HbA1c from baseline to week 40: tirzepatide 5 mg, 10 mg and 15 mg, -2.24% (0.07), -2.44% (0.07) and -2.49% (0.07), respectively, and insulin glargine, -0.95% (0.07), with a treatment difference ranging from -1.29% to -1.54% (all P < 0.001). Proportions of patients achieving HbA1c < 7.0% at week 40 were greater in tirzepatide 5-mg (75.4%), 10-mg (86.0%) and 15-mg (84.4%) groups compared to insulin glargine (23.7%) (all P < 0.001). All tirzepatide doses led to superior body weight reduction at week 40: tirzepatide 5 mg, 10 mg and 15 mg, -5.0 kg (-6.5%), -7.0 kg (-9.3%) and -7.2 kg (-9.4%), respectively, compared to insulin glargine, 1.5 kg (+2.1%) (all P < 0.001). The most common adverse events with tirzepatide were mild to moderate decreased appetite, diarrhea and nausea. No severe hypoglycemia was reported. Tirzepatide demonstrated superior reductions in HbA1c versus insulin glargine in an Asia-Pacific, predominately Chinese, population with T2D and was generally well tolerated. ClinicalTrials.gov registration: NCT04093752 .

Development, validation, and application of an UPLC-MS/MS method for vancomycin, norvancomycin, methotrexate, paclitaxel, and imatinib analysis in human plasma.

BACKGROUND: Vancomycin, norvancomycin, methotrexate, paclitaxel, and imatinib are five commonly used drugs which are all recommended to therapeutic drug monitoring in clinical settings. However, the blood concentration monitoring of these drugs and the interpretations of the test results are limited to some extent due to the differences of testing instruments and testing methods. METHODS: We established an ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method for simultaneous quantification of vancomycin, norvancomycin, methotrexate, paclitaxel, and imatinib in human plasma. The method was validated according to the guideline for bioanalytical method validation and applied in clinical therapy. RESULTS: The calibration ranges of vancomycin, norvancomycin, methotrexate, paclitaxel, and imatinib were 0.5-100 µg/mL, 0.5-100 µg/mL, 5-1000 ng/mL, 10-2000 ng/mL, and 5-500 ng/mL, respectively. Inaccuracy and imprecision of every drug were less than 15%. The internal standard normalized recovery rates of vancomycin and norvancomycin were about 45%, while which of methotrexate, paclitaxel, and imatinib were almost 100%. No obvious carryover effect was observed. Samples were stable for at least 24 h in the automatic sampler, 72 h at 4°C, and 1 week in -80°C. There were no differences of concentrations between plasma and serum for the five drugs. Moreover, there were positive correlations between methotrexate and vancomycin concentrations and creatinine, as well as positive correlation between imatinib concentration and age of the patient. CONCLUSIONS: The UPLC-MS/MS method was competent for the simultaneous monitoring of vancomycin, norvancomycin, methotrexate, paclitaxel, and imatinib because of its short analysis time, high specificity, and accuracy.

A Pragmatic Study of Basal and Mid-Mixture Insulins as Starter Insulins in Chinese Patients With Type 2 Diabetes: Observations From Long-Term, Real-World Experience.

INTRODUCTION: According to Chinese guidelines, basal insulin (BI) or premixed insulins are recommended insulin starters following the failure of oral antihyperglycemic medication (OAM) in Chinese patients with type 2 diabetes (T2D). This pragmatic study investigated the long-term effectiveness, safety, and cost of add-on BI and mid-mixture insulin analog (MMI) regimens in Chinese patients with T2D. METHODS: This multicenter, open-label, pragmatic study randomized patients 1:1 to receive either BI or MMI with OAMs adjusted according to current standards of care. We evaluated the change in glycated hemoglobin (HbA1c) from baseline, safety parameters, and antidiabetic medication costs. RESULTS: Change in HbA1c from baseline showed a statistically greater decrease at week 48 in the MMI group (MMI: - 2.03% [0.06] vs. BI: - 1.82% [0.06]; P < 0.05). Both groups showed decreases in fasting plasma glucose (mmol/L) (MMI: - 2.53 [0.14] vs. BI: - 3.19 [0.14]; P < 0.01) and postprandial glucose (mmol/L) (MMI: - 4.35 [0.22] vs. BI: - 4.33 [0.23]). More patients in the BI group showed increases in OAM use, while OAM use decreased in the MMI group. Both groups showed stable glycemic control with a very limited insulin dose change from week 24 to week 48. The incidence of total hypoglycemia was higher in the MMI group (MMI: 124% [30.7] vs. BI: 76% [18.5], P < 0.0001), but no incidence of severe hypoglycemia was reported in either group. Treatment costs, in terms of average daily cost and cost of glycemic control, were higher in the BI group. CONCLUSION: In long-term real-world use, the MMI and BI groups demonstrated improved glycemic control, with the MMI group showing more significant improvement than the BI group. Hypoglycemia incidence was higher in the MMI group, with no major safety issues through week 48. MMI is likely to provide better price value than BI for the treatment of T2D in Chinese patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03018938.

Nucleofection and In Vivo Propagation of Chicken Eimeria Parasites.

Transfection is a technical process through which genetic material, such as DNA and double-stranded RNA, are delivered into cells to modify the gene of interest. Currently, transgenic technology is becoming an indispensable tool for the study of Eimeria, the causative agents of coccidiosis in poultry and livestock. This protocol provides a detailed description of stable transfection in eimerian parasites: purification and nucleofection of sporozoites or second-generation merozoites, and in vivo propagation of transfected parasites. Using this protocol, we achieved transfection in several species of Eimeria. Taken together, nucleofection is a useful tool to facilitate genetic manipulation in eimerian parasites.