Targeting mPGES-2 to protect against acute kidney injury via inhibition of ferroptosis dependent on p53.

Acute kidney injury (AKI) is a clinical syndrome with high morbidity and mortality but no specific therapy. Microsomal prostaglandin E synthase-2 (mPGES-2) is a PGE2 synthase but can metabolize PGH2 to malondialdehyde by forming a complex with heme. However, the role and mechanism of action of mPGES-2 in AKI remain unclear. To examine the role of mPGES-2, both global and tubule-specific mPGES-2-deficient mice were treated with cisplatin to induce AKI. mPGES-2 knockdown or overexpressing HK-2 cells were exposed to cisplatin to cause acute renal tubular cell injury. The mPGES-2 inhibitor SZ0232 was used to test the translational potential of targeting mPGES-2 in treating AKI. Additionally, mice were subjected to unilateral renal ischemia/reperfusion to further validate the effect of mPGES-2 on AKI. Interestingly, both genetic and pharmacological blockage of mPGES-2 led to decreased renal dysfunction and morphological damage induced by cisplatin and unilateral renal ischemia/reperfusion. Mechanistic exploration indicated that mPGES-2 deficiency inhibited ferroptosis via the heme-dependent regulation of the p53/SLC7A11/GPX4 axis. The present study indicates that mPGES-2 blockage may be a promising therapeutic strategy for AKI.

Cost-Effectiveness Analysis of Risk Factor-Based Lung Cancer Screening Program by Low-Dose Computer Tomography in Current Smokers in China.

Although the effectiveness of lung cancer screening by low-dose computed tomography (LDCT) could be shown in China, there could be variation in the evidence concerning the economic impact. Our study explores the cost-effectiveness of lung cancer screening and optimizes the best definition of a high-risk population. A Markov model consisting of the natural history and post-diagnosis states was constructed to estimate the costs and quality-adjusted life years (QALYs) of LDCT screening compared with no screening. A total of 36 distinct risk factor-based screening strategies were assessed by incorporating starting ages of 40, 45, 50, 55, 60 and 65 years, stopping ages of 69, 74 and 79 years as well as smoking eligibility criteria. Screening data came from community-based mass screening with LDCT for lung cancer in Guangzhou. Compared with no screening, all screening scenarios led to incremental costs and QALYs. When the willingness-to-pay (WTP) threshold was USD37,653, three times the gross domestic product (GDP) per capita in China, six of nine strategies on the efficiency frontier may be cost-effective. Annual screening between 55 and 79 years of age for those who smoked more than 20 pack-years, which yielded an incremental cost-effectiveness ratio (ICER) of USD35,000.00 per QALY gained, was considered optimal. In sensitivity analyses, the result was stable in most cases. The trends of the results are roughly the same in scenario analyses. According to the WTP threshold of different regions, the optimal screening strategies were annual screening for those who smoked more than 20 pack-years, between 50 and 79 years of age in Zhejiang province, 55-79 years in Guangdong province and 65-74 years in Yunnan province. However, annual screening was unlikely to be cost-effective in Heilongjiang province under our modelling assumptions, indicating that tailored screening policies should be made regionally according to the local epidemiological and economic situation.

H2O2 activated moxa ash via ball milling for ultrafast removal of mitoxantrone.

As emerging contaminants, antineoplastic drugs are widely used, but their residues in water may cause long-term genotoxicity to aquatic organisms and human beings. Here, waste moxa ash was selected as biomass raw material and modified by ball milling to obtain carbon-based materials with excellent adsorption performance, which were used to remove the antineoplastic drug mitoxantrone (MTX) from water. The experimental results indicate that moxa ash modified by ball milling in hydrogen peroxide exhibits ultrafast removal of MTX (the removal efficiency reaches 97.66% in 1 min and 99.72% in 30 min). The pseudo-second-order kinetics and Freundlich isotherm models accurately describe the MTX adsorption process, and the mechanism of adsorption probably involves pore filling, hydrogen bond, π-π interaction and electrostatic attraction. Not only that, moxa ash also has the ability to remove dyes such as malachite green (97.81%) and methylene blue (99.97%). In this study, a simple and environmentally friendly process was used to convert waste moxa ash into an effective MTX adsorbent, providing a feasible solution for controlling MTX pollution and identifying a circular and economic way to reuse the waste.

Regular Glucosamine Use May Have Different Roles in the Risk of Site-Specific Cancers: Findings from a Large Prospective Cohort.

BACKGROUND: Previous studies indicated that glucosamine supplements may have a general anticancer effect. This study aimed to assess whether the potential effect differs across different types of cancers in a large prospective cohort study. METHODS: All participants from the UK Biobank who were free of cancers and had complete information on glucosamine use at baseline were included and followed up from 2006 until 2021. Cox proportional hazards models were used to assess the associations between regular glucosamine use and different site-specific cancers. Subgroup analyses were performed to explore potential interactions. Several sensitivity analyses were conducted to assess the robustness of the main findings. RESULTS: A total of 450,207 eligible participants (mean age: 56.2 years; females: 53.3%) were included, of whom 84,895 (18.9%) reported regular glucosamine use at baseline. During a median of 12.5 years follow-up, glucosamine use was significantly associated with an increased risk of overall cancer [HR, 1.04; 95% confidence interval (CI), 1.01-1.06], skin cancer (HR, 1.11; 95% CI, 1.07-1.15), and prostate cancer (HR, 1.07; 95% CI, 1.01-1.13), and with a reduced risk of lung cancer (HR, 0.88; 95% CI, 0.79-0.97) after adjusting for potential confounders. Statistical interaction was observed for gender, age, and education for the association of glucosamine use with overall cancer risk (all Pinteraction < 0.027). These results remained unchanged in the sensitivity analyses. CONCLUSIONS: Regular glucosamine use was associated with lower risk of lung cancer but higher risk of skin cancer, prostate cancer, and overall cancer. IMPACT: The roles of glucosamine use potentially differ in the development of different site-specific cancers.

Egg consumption associated with all-cause mortality in rural China: a 14-year follow-up study.

BACKGROUND: Dietary recommendations regarding egg intake remain controversial topic for public health. We hypothesized that there was a positive association between egg consumption and all-cause mortality. METHODS: To test this hypothesis, we enrolled 9885 adults from a community-based cohort in Anhui Province, China during 2003-05. Egg consumption was assessed by food questionnaire. Stratified analyses were performed for age, sex, body mass index (BMI), blood pressure, smoking, drinking and laboratory tests. RESULTS: After an average follow-up of 14.1 years, 9444 participants were included for analysis. A total of 814 deaths were recorded. Participants' BMI and lipid profile had no significantly difference between three egg consumption groups. BMI was 21.6±2.7 of the whole population, especially BMI>24 was only 17.3%. A bivariate association of egg consumption >6/week with increased all-cause mortality was observed compared with ≤6/week (RR: 1.35, 95% CI: 1.05, 1.73, P = 0.018). A significant interaction was observed for BMI ≥ 21.2 kg/m2 vs. BMI<21.2 kg/m2 (P for interaction: 0.001). No other significant interactions were found. CONCLUSIONS: In this study, consuming >6 eggs/week increased risk of all-cause mortality, even among lean participants, especially who with BMI ≥ 21.2 kg/m2. Eggs are an easily accessible and constitute an affordable food source in underdeveloped regions. Consuming <6 eggs/week may be the most suitable intake mode.

Plasma Magnesium Concentrations and Risk of Incident Cancer in Adults with Hypertension: A Nested Case-Control Study.

OBJECTIVE: The association between plasma magnesium and risk of incident cancer remains inconclusive in previous studies. We aimed to investigate the prospective relationship of baseline plasma magnesium concentrations with the risk of incident cancer and to examine possible effect modifiers. METHODS: A nested case-control study with 228 incident cancer cases and 228 matched controls was conducted using data from the China Stroke Primary Prevention Trial (CSPPT), a randomized, double-blind, controlled trial, conducted from May 2008 to August 2013. Study outcomes included incident cancer and its subtypes. RESULTS: When plasma magnesium concentrations were assessed as quartiles, a significantly higher incident risk of total cancer was found in participants in quartile 1 (<0.76 mmol/L; odds ratio [OR] = 2.70; 95% CI: 1.33-5.49) and quartile 4 (≥0.89 mmol/L; OR = 2.05; 95% CI: 1.12-3.76), compared with those in quartile 3 (0.83 to <0.89 mmol/L). In cancer site-specific analyses, similar trends were found for gastrointestinal cancer, esophageal cancer, gastric cancer, breast cancer, lung cancer, and other cancers. Furthermore, none of the variables, including age, sex, current smoking status, current alcohol intake, BMI, systolic blood pressure, and total cholesterol levels at baseline significantly modified the association between plasma magnesium and cancer risk. CONCLUSIONS: Both low and high plasma magnesium concentrations were significantly associated with an increased incident risk of cancer, compared with the reference concentrations of 0.83 to <0.89 mmol/L among hypertensive adults.

Positive relationship of hypertensive retinopathy with carotid intima--media thickness in hypertensive patients.

OBJECTIVES: We aimed to explore the relationship of hypertensive retinopathy with carotid intima--media thickness (CIMT), and to examine the possible effect modifiers in Chinese adults with hypertension. METHODS: We conducted a cross-sectional study of 12 342 hypertensive patients with complete exit site visit data from the China Stroke Primary Prevention Trial. CIMT was measured by carotid ultrasonography. Hypertensive retinopathy was diagnosed according to the Keith--Wagener--Barker classification. RESULTS: The mean (SD) CIMT among study participants was 739.9 (111.4) µm. Compared with patients with grade 1 hypertensive retinopathy or without hypertensive retinopathy, a significantly higher CIMT level (ß, 7.63, 95% CI: 2.54--12.73) was observed in patients with grade 2-4 hypertensive retinopathy. Moreover, the association between hypertensive retinopathy (grade 2-4 versus grade 1 or normal) and CIMT was stronger in participants of younger age (<60 years; ß, 13.70, 95% CI: 5.65--21.75; versus ≥60 years; ß, 1.03, 95% CI: -5.58 to 7.63; P interaction = 0.006); or with lower total homocysteine levels [<12.1 µmol/l (median); ß, 12.70, 95% CI: 5.98--19.42; versus ≥12.1 µmol/l; ß, 2.07, 95% CI: -5.63 to 9.78; P interaction = 0.030). None of the other variables, including sex, BMI, study centers, treatment group, SBP, triglycerides, total cholesterol, fasting blood glucose, folate, serum creatinine, current smoking and alcohol drinking, significantly modified the relation of hypertensive retinopathy with CIMT levels. CONCLUSION: Hypertensive retinopathy (grade 2 and higher) was significantly associated with increased CIMT in hypertensive patients. The association was stronger in those of younger age or with lower total homocysteine levels.

Association of plasma retinol levels with incident cancer risk in Chinese hypertensive adults: a nested case-control study.

We aimed to investigate the association between plasma retinol and incident cancer among Chinese hypertensive adults. We conducted a nested case-control study, including 231 patients with incident cancer and 231 matched controls during a median 4·5-year follow-up of the China Stroke Primary Prevention Trial. There was a significant, inverse association between retinol levels and digestive system cancer (per 10 µg/dl increases: OR 0·79; 95 % CI 0·69, 0·91). When compared with participants in the first quartile of retinol (< 52·3 µg/dl), a significantly lower cancer risk was found in participants in quartile 2-4 ( ≥ 52·3 µg/dl: OR 0·31; 95 % CI 0·13, 0·71). However, there was a U-shaped association between retinol levels and non-digestive system cancers where the risk of cancers decreased (although not significantly) with each increment of plasma retinol (per 10 µg/dl increases: OR 0·89; 95 % CI 0·60, 1·31) in participants with retinol < 68·2 µg/dl, and then increased significantly with retinol (per 10 µg/dl increase: OR 1·65; 95 % CI 1·12, 2·44) in participants with retinol ≥ 68·2 µg/dl. In conclusion, there was a significant inverse dose-response association between plasma retinol and the risk of digestive system cancers. However, a U-shaped association was observed between plasma retinol and the risk of non-digestive cancers (with a turning point approximately 68·2 µg/dl).

Treatment Outcomes in Patients With Newly Diagnosed Multiple Myeloma Who Are Ineligible for Stem-Cell Transplantation: Systematic Review and Network Meta-analysis.

Many new regimens have been applied to newly diagnosed transplant-ineligible multiple myeloma, but no head-to-head research has been performed to compare the efficacy of these treatments. Currently lenalidomide plus dexamethasone (Rd) is one of the standard treatments. Our aim was to make a comparison of these treatments to Rd by a network meta-analysis. We performed a systematic review and network meta-analysis. We searched PubMed, Embase, and the Cochrane Library for articles published from January 1, 1988, to April 26, 2018, as well as research presented at 5 international conferences (American Society of Clinical Oncology, American Society of Hematology, European Hematology Association, European Society of Medical Oncology, and International Myeloma Working Group) between January 2015 and December 2018. Our interest outcomes were hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS). Bayesian fixed-effects mixed-treatment comparisons were used for this study. A total of 23 articles describing 10,401 participants were included for this network meta-analysis. Lenalidomide and dexamethasone plus daratumumab (HR, 0.57; 95% credible interval [CrI], 0.43-0.73), daratumumab plus bortezomib, melphalan, and prednisone (HR, 0.59; 95% CrI, 0.36-0.91), and the combination of bortezomib with lenalidomide and dexamethasone (RVd) (HR, 0.72, 95% CrI, 0.56-0.90) all showed significant effect compared to Rd for PFS. RVd demonstrated significant benefit compared to Rd (HR, 0.72; 95% CrI, 0.53-0.96) for OS. Our study results suggested that lenalidomide and dexamethasone plus daratumumab; daratumumab plus bortezomib, melphalan, and prednisone; and RVd showed better efficacy than Rd in PFS; and RVd showed better efficacy than Rd in OS in patients with newly diagnosed transplant-ineligible multiple myeloma in the absence of head-to-head research.

A Nested Case-Control Study on Plasma Vitamin E and Risk of Cancer: Evidence of Effect Modification by Selenium.

BACKGROUND: Evidence from epidemiologic studies has been inconsistent regarding the role of vitamin E in cancer incidence risk. OBJECTIVE: The aim of this study was to evaluate the prospective association between baseline plasma vitamin E levels and subsequent cancer risk in Chinese adults with hypertension, and to identify effect modifiers. DESIGN: A nested, case-control study was conducted from 20,702 hypertensive participants in the China Stroke Primary Prevention Trial, a randomized, double-blind, controlled trial, conducted from May 2008 to August 2013. PARTICIPANTS: The current study included 229 new cancer cases and 229 controls matched for age (±1 year), sex, treatment group, and study site. MAIN OUTCOME MEASURES: Plasma vitamin E was measured by liquid chromatography with tandem quadrupole mass spectrometers and plasma selenium was measured by inductively coupled plasma mass spectrometry using Thermo Fisher iCAP Q ICP-MS. STATISTICAL ANALYSES: Odds ratios (OR) of cancer in relation to plasma concentrations of vitamin E were calculated using conditional logistic regression models. RESULTS: Median follow-up duration was 4.5 years. Overall, vitamin E was not associated with subsequent risk of total cancer (per 1-mg/L [2.3 µmol/L] increase: OR 1.01, 95% CI 0.93 to 1.09) and non-gastrointestinal cancer (OR 1.10, 95% CI 0.98 to 1.24). However, there was a significant, inverse association between vitamin E and gastrointestinal cancer (OR 0.86, 95% CI 0.75 to 0.99), particularly esophageal cancer (OR 0.67, 95% CI 0.48 to 0.95). Moreover, high vitamin E decreased the risk of total cancer (OR 0.91, 95% CI 0.84 to 0.99) and gastrointestinal cancer (OR 0.83, 95% CI 0.73 to 0.95) among patients with high selenium levels (median≥83.7 µg/L [1.1 µmol/L]), and increased the risk of total cancer (OR 1.13, 95% CI 1.00 to 1.26) and non-gastrointestinal cancer (OR 1.25, 95% CI 1.03 to 1.50) among those with low selenium levels (<83.7 µg/L [1.1 µmol/L]). CONCLUSIONS: This study suggests that higher levels of plasma vitamin E are associated with reduced risk of gastrointestinal cancer. High vitamin E decreased the risk of total cancer among patients with high selenium levels, but increased the risk of total cancer among those with low selenium levels.

Plasma 25-hydroxyvitamin D concentrations and risk of incident cancer in adults with hypertension: A nested case-control study.

BACKGROUND & AIMS: Evidence from epidemiologic studies on the association of circulating 25-hydroxyvitamin D [25(OH)D] concentrations with the incident risk of cancer has been inconsistent. We aimed to investigate the prospective relationship of baseline plasma 25(OH)D concentrations with the risk of cancer, and to examine possible effect modifiers. METHODS: We employed a nested case-control study design, including 231 patients with incident cancer during a median 4.5 years of follow up, and 231 matched controls from the China Stroke Primary Prevention Trial (CSPPT). RESULTS: The prevalence of plasma 25(OH)D <15, <20 and <30 ng/mL was 23.6%, 47.4% and 85.5%, respectively. Overall, there was an inverse relation between risk of cancer and plasma 25(OH)D. The Odds ratios (95% CI) for participants in the second (15.1 to <20.6 ng/mL), third (20.6 to <26.4 ng/mL) and fourth quartiles (≥26.4 ng/mL) were 0.45 (95% CI: 0.25-0.80), 0.53 (95% CI: 0.27-1.06) and 0.55 (95% CI: 0.27-1.10), respectively, compared with those in quartile 1. Conversely, low 25(OH)D (<15.1 ng/mL) concentrations were associated with increased risk of cancer (OR, 2.08; 95% CI: 1.20-3.59) compared to higher concentrations. These associations were consistent across subtypes of cancer. Several potential effect modifiers were identified, including plasma vitamin E concentrations and alcohol intake. CONCLUSIONS: Low plasma 25(OH)D concentrations (<15.1 ng/mL) were associated with increased total cancer risk among Chinese hypertensive adults, compared to higher 25(OH)D concentrations. This finding and the possible effect modifiers warrant additional investigation.

Systematic review and meta-analysis of the efficacy and safety of novel monoclonal antibodies for treatment of relapsed/refractory multiple myeloma.

Although two newly launched monoclonal antibodies (mAbs), elotuzumab and daratumumab, performed well in patients with relapsed or relapsed/refractory multiple myeloma (RRMM), their efficacy and safety remain uncertain. We therefore performed a systematic review and meta-analysis of the most recent clinical trials that evaluated elotuzumab and/or daratumumab for the treatment of patients with RRMM. Our meta-analysis included 13 clinical trials with 2,402 patients participating. The overall response rate (ORR) was 57% (95% confidence interval [CI]: 38-76%), and the at least very good partial response rate (VGPR) was 32% (95% CI: 19-46%). mAb-based regimens prolonged progression-free survival (PFS, hazard ratio: 0.52, 95% CI: 0.36-0.75) compared to non-mAb-based regimens. Additionally, the efficacy of triplet regimens was superior to that of single or doublet regimens. The same trend was observed in a subgroup analysis of daratumumab and elotuzumab. The most common grade 3/4 adverse events included neutropenia, lymphopenia, thrombocytopenia, anemia, leukopenia, pneumonia, and fatigue. Elotuzumab and daratumumab improved the ORR, at least VGPR, and PFS compared to non-mAb-based regimens. In a pooled analysis, both mAbs had promising efficacy and safety profiles, particularly in triplet regimens. The same trend was observed in daratumumab- and elotuzumab-based regimens. Daratumumab triplet therapy (daratumumab, lenalidomide, and dexamethasone) was superior to other triplet regimens for the treatment of RRMM, and daratumumab monotherapy was more effective than either single agent in heavily pretreated MM patients, suggesting CD38 is an effective target for treatment of RRMM. Additional clinical studies of elotuzumab and daratumumab will be required to validate these results.

Scalable and versatile graphene functionalized with the Mannich condensate.

The functionalized graphene (JTPG) is fabricated by chemical conversion of graphene oxide (GO), using tea polyphenols (TP) as the reducer and stabilizer, followed by further derivatization through the Mannich reaction between the pyrogallol groups on TP and Jeffamine M-2070. JTPG exhibits solubility in a broad spectrum of solvents, long-term stability and single-layered dispersion in water and organic solvents, which are substantiated by AFM, TEM, and XRD. The paper-like JTPG hybrids prepared by vacuum-assisted filtration exhibits an unusual combination of high toughness (tensile strength of ~275 MPa and break strain of ~8%) and high electrical conductivity (~700 S/m). Still, JTPG is revealed to be very promising in the fabrication of polymer/graphene composites due to the excellent solubility in the solvent with low boiling point and low toxicity. Accordingly, as an example, nitrile rubber/JTPG composites are fabricated by the solution compounding in acetone. The resulted composite shows low threshold percolation at 0.23 vol.% of graphene. The versatilities both in dispersibility and performance, together with the scalable process of JTPG, enable a new way to scale up the fabrication of the graphene-based polymer composites or hybrids with high performance.