Calcium-sensing receptor and NF-κB pathways in TN breast cancer contribute to cancer-induced cardiomyocyte damage via activating neutrophil extracellular traps formation.

Cardiovascular disorders are commonly prevalent in cancer patients, yet the mechanistic link between them remains poorly understood. Because neutrophil extracellular traps (NETs) have implications not just in cardiovascular diseases (CVD), but also in breast cancer (BC), it was hypothesized to contribute to CVD in the context of oncogenesis. We established a mouse model using nude mice to simulate liver metastasis of triple-negative BC (TNBC) through the injection of MDA-MB-231 cells. Multiple imaging and analysis techniques were employed to assess the cardiac function and structure, including echocardiography, HE staining, Masson staining, and transmission electron microscopy (TEM). MDA-MB-231 cells underwent treatment with a CaSR inhibitor, CaSR agonist, and NF-κB channel blocker. The phosphorylation of NF-κB channel protein p65 and the expression and secretion of IL-8 were assessed using qRT-PCR, Western Blot, and ELISA, respectively. In addition, MDA-MB-231 cells were co-cultured with polymorphonuclear neutrophils (PMN) under varying conditions. The co-localization of PMN extracellular myeloperoxidase (MPO) and DNA were observed by cellular immunofluorescence staining to identify the formation of NETs. Then, the cardiomyocytes were co-cultured with the above medium that contains NETs or not, respectively; the effects of NETs on cardiomyocytes apoptosis were perceived by flow cytometry. The ultrastructural changes of myocardial cells were perceived by TEM, and ELISA detected the levels of myocardial enzyme (LDH, MDA and SOD). Overall, according to our research, CaSR has been found to have a regulatory role in IL-8 secretion in MDA-MB-231 cells, as well as in the formation of NETs by PMN cells. These findings suggest CaSR-mediated stimulation in PMN can lead to increased NETs formation and subsequently to cytotoxicity in cardiomyocytes, which potentially via activation of the NF-κB signaling cascade of BC cell.

Inflammatory Cell-Derived MYDGF Attenuates Endothelial LDL Transcytosis to Protect Against Atherogenesis.

BACKGROUND: Inflammation contributes to the pathogenesis of atherosclerosis. But little is known about the potential benefits of inflammatory cells to atherosclerosis. The aim of this study was to investigate the function of inflammatory cells/endothelium axis and determine whether and how inflammatory cell-derived MYDGF (myeloid-derived growth factor) inhibited endothelial LDL (low-density lipoprotein) transcytosis. METHODS: In in vivo experiments, both loss- and gain-of-function strategies were used to evaluate the effect of inflammatory cell-derived MYDGF on LDL transcytosis. We generated monocyte/macrophage-targeted MYDGF-null mice on an Ldlr (LDL receptor)-/- background in the loss-of-function strategy and restored the inflammatory cell-derived MYDGF by bone marrow transplantation and inflammatory cell-specific overexpression of MYDGF mice model in the gain-of-function strategy. In in vitro experiments, coculture experiments between primary mouse aortic endothelial cells and macrophages and mouse aortic endothelial cells supplemented with or without recombinant MYDGF were conducted. RESULTS: Inflammatory cell-derived MYDGF deficiency aggravated endothelial LDL transcytosis, drove LDL uptake by artery wall, and thus exacerbated atherosclerosis in vivo. Inflammatory cell-derived MYDGF restoration by bone marrow transplantation and inflammatory cell MYDGF overexpression alleviated LDL transport across the endothelium, prevented LDL accumulation in the subendothelial space, and subsequently ameliorated atherosclerosis in vivo. Furthermore, in the in vitro study, macrophages isolated from MYDGF+/+ mice and recombinant MYDGF attenuated LDL transcytosis and uptake in mouse aortic endothelial cells. Mechanistically, MYDGF inhibited MAP4K4 (mitogen-activated protein kinase kinase kinase kinase isoform 4) phosphorylation, enhanced activation of Akt (protein kinase B)-1, and diminished the FoxO (forkhead box O) 3a signaling cascade to exert protective effects of MYDGF on LDL transcytosis and atherosclerosis. CONCLUSIONS: The findings support a role for inflammatory cell-derived MYDGF served as a cross talk factor between inflammatory cells and endothelial cells that inhibits LDL transcytosis across endothelium. MYDGF may become a novel therapeutic drug for atherosclerosis, and the beneficial effects of inflammatory cell in atherosclerosis deserve further attention.

Serum phosphorus concentration and its association with the degree and pattern of intracranial arterial calcification.

BACKGROUND AND AIM: The aim of this study was to determine whether the serum phosphorus concentrations (SPC) are associated with the degree and pattern of intracranial arterial calcification (IAC) in patients with normal renal function or mild-moderate renal impairment. METHODS AND RESULTS: A total of 513 patients were enrolled in this study. The degree of IAC measured by IAC scores was evaluated on non-contrast head computed tomography (CT) images and IAC was classified as intimal or medial calcification. Study participants were classified according to IAC degrees (mild, moderate and severe) and patterns (intimal and medial calcification). A multivariate regression model was used to assess the independent relationship of SPC with IAC scores and patterns. Of 513 study participants (mean [SD] age, 68.3 [10.3] years; 246 females [48%]), the mean SPC was 1.07 ± 0.17 mmol/L and IAC scores was 4.0 (3.0-5.0). Multivariate analysis showed that higher serum phosphorus was a significant risk factor for moderate/severe IAC in both patients with eGFR ≥60 ml/min/1.73 m2 (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.01-1.59; P < 0.05) and eGFR <60 ml/min/1.73 m2 (OR, 1.92; 95% CI, 1.04-3.57; P < 0.05), when those with mild IAC were considered as the reference group. However, higher SPC was associated with an increased odds of medial calcification only in patients with eGFR <60 ml/min/1.73 m2 (OR, 1.67; 95% CI, 1.08 to 2.61). CONCLUSIONS: High levels of serum phosphorus were positively correlated with the degree of IAC, and this significant effect on medial IAC was only present in patients with impaired renal function (eGFR <60 ml/min/1.73 m2).

Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues.

Herein, we present a unified chemical synthesis of three subgroups of cephalotaxus diterpenoids. Key to the success lies in adopting a synthetic strategy that is inspired by biosynthesis but is opposite in nature. By employing selective one-carbon introduction and ring expansion operations, we have successfully converted cephalotane-type C18 dinorditerpenoids (using cephanolide B as a starting material) into troponoid-type C19 norditerpenoids and intact cephalotane-type C20 diterpenoids. This synthetic approach has enabled us to synthesize cephinoid H, 13-oxo-cephinoid H, 7-oxo-cephinoid H, fortalpinoid C, 7-epi-fortalpinoid C, cephanolide E, and 13-epi-cephanolide E. Furthermore, through the development of an intermolecular asymmetric Michael reaction between ß-oxo esters and ß-substituted enones, we have achieved the enantioselective synthesis of advanced intermediates within our synthetic sequence, thus formally realizing the asymmetric total synthesis of the cephalotaxus diterpenoids family.

Association between Obstructive Sleep Apnea and Intracranial Artery Calcification Stratified by Gender and Body Mass Index: A Hospital-Based Observational Study.

BACKGROUND AND OBJECTIVES: Obstructive sleep apnea (OSA) is an independent risk factor for stroke. Furthermore, intracranial arterial calcification (IAC) has been validated as a marker for subclinical cerebrovascular disease. However, the relationship between OSA with IAC was less studied compared with its established association with coronary artery calcification. In this study, we aimed to investigate the association between the severity of OSA and the degree of IAC in hospitalized patients without preexisting cardiovascular disease. METHODS: This hospital-based observational study was conducted from June 1, 2017, to May 1, 2019. In total, 901 consecutive patients who underwent head computed tomography scans and portable sleep monitoring were included. On the basis of the apnea-hypopnea index (AHI), patients were divided into four OSA severity groups (normal: AHI <5/h; mild: 5≤ AHI <15/h; moderate: 15≤ AHI <30/h; severe: AHI ≥30/h). Associations of OSA with IAC scores were assessed by using multivariate logistic regression analysis. RESULTS: Of the 901 patients, 484 (53.7%) were men; the mean (SD) age was 66.1 (10.0) years. The non-OSA group included 207 (23.0%) patients; mild OSA, 209 (23.2%); moderate OSA, 235 (26.1%); and severe OSA, 169 (18.8%). Mean IAC scores were higher in the severe OSA group compared with non-, mild, and moderate OSA groups (4.79 vs. 2.58; 4.79 vs. 2.94; 4.79 vs. 3.39; p < 0.001). Multivariate analysis adjusted for confounding factors revealed that only severe OSA was associated with a higher IAC score (odds ratio [OR]: 1.65; 95% confidence interval [CI]: 1.43-1.91; p < 0.001). In stratified analyses by BMI, among participants with a BMI <25 kg/m2, the positive association between AHI values and IAC scores was found in the moderate OSA group (OR: 1.23; 95% CI: 1.05, 1.43; p = 0.01) and the severe OSA group (OR: 1.96; 95% CI: 1.55, 2.48; p < 0.001). When stratified by gender, in women, the positive association was found in the moderate OSA group (adjusted OR: 1.21; 95% CI: 1.02-1.51; p = 0.016) and the severe OSA group (adjusted OR: 1.76; 95% CI: 1.36-2.25; p < 0.001). For the men group, a positive association between IAC scores and AHI was only observed in the severe OSA group. DISCUSSION: These findings suggest that OSA, in particular severe OSA (AHI ≥30), is independently associated with higher IAC scores. Women and no-obesity individuals appeared more susceptible to adverse OSA-related subclinical cerebrovascular disease as measured by IAC scores.

Opportunistic screening for asymptomatic left ventricular dysfunction in type 2 diabetes mellitus.

BACKGROUND: International guidelines recommend natriuretic peptide biomarker-based screening for patients at high heart failure (HF) risk to allow early detection. There have been few reports about the incorporation of screening procedure to existing clinical practice. OBJECTIVE: To implement screening of left ventricular dysfunction in patients with type 2 diabetes mellitus (DM). METHOD: A prospective screening study at the DM complication screening centre was performed. RESULTS: Between 2018 and 2019, 1043 patients (age: 63.7±12.4 years; male: 56.3%) with mean glycated haemoglobin of 7.25%±1.34% were recruited. 81.8% patients had concomitant hypertension, 31.1% had coronary artery disease, 8.0% had previous stroke, 5.5% had peripheral artery disease and 30.7% had chronic kidney disease (CKD) stages 3-5. 43 patients (4.1%) had an elevated N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentration above the age-specific diagnostic thresholds for HF, and 43 patients (4.1%) had newly detected atrial fibrillation (AF). The prevalence of elevated NT-proBNP increased with age from 0.85% in patients aged <50 years to 7.14% in those aged 70-79 years and worsening kidney function from 0.43% in patients with CKD stage 1 to 42.86% in CKD stage 5. In multivariate logistic regression, male gender (OR: 3.67 (1.47-9.16), p = 0.005*), prior stroke (OR: 3.26 (1.38-7.69), p = 0.007*), CKD (p<0.001*) and newly detected AF (OR: 7.02 (2.65-18.57), p<0.001*) were significantly associated with elevated NT-proBNP. Among patients with elevated NT-proBNP, their mean left ventricular ejection fraction (LVEF) was 51.4%±14.7%, and 45% patients had an LVEF <50%. CONCLUSION: NT-proBNP and ECG screening could be implemented with relative ease to facilitate early detection of cardiovascular complication and improve long-term outcomes.

Fiscal centralization and urban industrial pollution emissions reduction: Evidence from the vertical reform of environmental administrations in China.

The relationship between fiscal regimes and urban industrial pollution emissions is unclear. This paper aims to explore the effects and mechanisms of fiscal centralization on urban industrial pollution emissions and environmental quality. Using the vertical reform of environmental administrations (VREA) in China as a quasi-natural experiment of fiscal centralization, this study applies a staggered difference-in-differences (DID) model to explore the differences in industrial pollution emissions between centralization cities and decentralization cities. The main findings are: (1) VREA significantly inhibits regional industrial pollution emissions, and the reform effect increases over time. This conclusion still holds after considering a series of robustness issues. (2) Industrial sulfur dioxide (SO2) and solid particulate emissions in the fiscal centralization cities have decreased significantly by 0.3281% and 0.2240%, respectively. However, there is no significant change in industrial wastewater discharges. (3) Environmental regulations, environmental expenditures, and pollution control investments of local governments are the main channels through which VREA reduces industrial pollution emissions. (4) The effects of VREA are more significant in central and western cities and small cities. (5) Relative to decentralization cities, centralization cities have improved air and water quality by 0.0825% and 0.1628%, respectively. These findings help to accurately assess the effects of fiscal centralization on regional environmental governance and provide a decision-making reference for further deepening environmental centralization reform in China.

Neuregulin 4 Attenuates Osteoarthritis Progression by Inhibiting Inflammation and Apoptosis of Chondrocytes in Mice.

Osteoarthritis (OA) is characterized by chondrocyte apoptosis and increased degradation of type II collagen. Inflammation is one of the major risk factors involved in the pathophysiology of OA. Neuregulin 4 (Nrg4) plays a protective role in a variety of low-level inflammatory diseases, such as non-alcoholic fatty liver disease, inflammatory bowel disease, or type 2 diabetes mellitus. Here we found that (1) Nrg4 deficiency aggravated the destruction and inflammation of articular cartilage and the apoptosis of chondrocytes in vivo. (2) Nrg4 restoration reversed these changes in vivo. (3) Murine recombinant Nrg4 (rNrg4) suppressed inflammation and apoptosis of chondrocytes and decreased the degradation of extracellular matrix in vitro. (4) Mechanistically, the mitogen-activated protein kinase/c-jun N-terminal kinase (MAPK/JNK) signaling pathway may be involved in the regulation of Nrg4 in the pathophysiology of OA. Therefore, we concluded that Nrg4 alleviated the progression of OA by inhibiting the inflammation, protecting against apoptosis of chondrocyte, and decreasing the degradation of extracellular matrix in a manner involving MAPK/JNK signaling.

Nitroreductase-induced bioorthogonal ligation for prodrug activation: A traceless strategy for cancer-specific imaging and therapy.

Prodrug development is of great interest in cancer therapy. From bio-friendly standpoints, traceless prodrug activation would be an ideal approach for cancer treatment owning to the avoidance of byproduct which might induce side effects in living system. Here, we report a fully traceless strategy for cancer imaging and therapy via a metal-free bioorthogonal ligation triggered by nitroreductase (NTR) overexpressed in solid tumors. The reduction of nitro substrates to amines by NTR and further condensation of amines with aldehydes can be seamlessly combined to yield imine-based resveratrol (RSV) with water as the only byproduct. In comparison with RSV, this precursor exhibited not only the same level of anticancer efficiency both in vitro and in vivo under hypoxia, but also a high sensitivity to hypoxia and much lower perturbation towards normal cells, which holds a great potential of theranostic prodrug for cancer therapy.

Body volume is the major determinant of worsening renal function in acutely decompensated heart failure with reduced left ventricular ejection fraction.

AIMS: Little is known about the relative importance of body volume and haemodynamic parameters in the development of worsening of renal function in acutely decompensated heart failure (ADHF). To study the relationship between haemodynamic parameters, body water content and worsening of renal function in patients with heart failure with reduced ejection fraction (HFrEF) hospitalised for ADHF. METHODS AND RESULTS: This prospective observational study involved 51 consecutive patients with HFrEF (age: 73±14 years, male: 60%, left ventricular ejection fraction: 33.3%±9.9%) hospitalised for ADHF. Echocardiographic-determined haemodynamic parameters and body volume determined using a bioelectric impedance analyser were serially obtained. All patients received intravenous furosemide 160 mg/day for 3 days. There was a mean weight loss of 3.95±2.82 kg (p<0.01), and brain natriuretic peptide (BNP) reduced from 1380±901 pg/mL to 797±738 pg/mL (p<0.01). Nonetheless serum creatinine (SCr) increased from 134±46 µmol/L to 151±53 µmol/L (p<0.01), and 35% of patients developed worsening of renal function. The change in SCr was positively correlated with age (r=0.34, p=0.017); and negatively with the ratio of extracellular water to total body water, a parameter of body volume status (r=-0.58, p<0.001); E:E' ratio (r=-0.36, p=0.01); right ventricular systolic pressure (r=-0.40, p=0.009); and BNP (r=-0.40, p=0.004). Counterintuitively, no correlation was observed between SCr and cardiac output, or total peripheral vascular resistance. Regression analysis revealed that normal body volume and lower BNP independently predicted worsening of renal function. CONCLUSIONS: Normal body volume and lower serum BNP on admission were associated with worsening of renal function in patients with HFrEF hospitalised for ADHF.

Risk of Accidents or Chronic Disorders From Improper Use of Mobile Phones: A Systematic Review and Meta-analysis.

BACKGROUND: Mobile phone use has brought convenience, but the long or improper use of mobile phones can cause harm to the human body. OBJECTIVE: We aimed to assess the impact of improper mobile phone use on the risks of accidents and chronic disorders. METHODS: We systematically searched in PubMed, EMBASE, Cochrane, and Web of Science databases for studies published prior to April 5, 2019; relevant reviews were also searched to identify additional studies. A random-effects model was used to calculate the overall pooled estimates. RESULTS: Mobile phone users had a higher risk of accidents (relative risk [RR] 1.37, 95% CI 1.22 to 1.55). Long-term use of mobile phones increased accident risk relative to nonuse or short-term use (RR 2.10, 95% CI 1.63 to 2.70). Compared with nonuse, mobile phone use resulted in a higher risk for neoplasms (RR 1.07, 95% CI 1.01 to 1.14), eye diseases (RR 2.03, 95% CI 1.27 to 3.23), mental health disorders (RR 1.16, 95% CI 1.02 to 1.32), and headaches (RR 1.25, 95% CI 1.18 to 1.32); the pooled risk of other chronic disorders was 1.20 (95% CI 0.90 to 1.59). Subgroup analyses also confirmed the increased risk of accidents and chronic disorders. CONCLUSIONS: Improper use of mobile phones can harm the human body. While enjoying the convenience brought by mobile phones, people have to use mobile phones properly and reasonably.

A network analysis framework of genetic and nongenetic risks for type 2 diabetes.

Both genetic and nongenetic factors have been found to be associated with type 2 diabetes, however, the correlation between them is still unclear. In the present study, we aimed to fully decipher the nongenetic and genetic factor association network for type 2 diabetes. We identified risk factors for type 2 diabetes by systematically searching for related meta-analyses and genome-wide association studies (GWAS) database. Among a total of 27,822 studies screened, 202 articles were eligible, from which 174 nongenetic factors and 210 genetic factors associated with type 2 diabetes were identified. Then, we obtained 584 associations between the nongenetic and genetic factors of type 2 diabetes, based on which a risk factor association network was conducted. The nongenetic factors could be classified into seven categories according to the Global Burden of Diseases (GBD). Of these seven categories of nongenetic factors, five were found to be correlated with genes associated with type 2 diabetes, including environmental risks, behavioral risks, metabolic risks, related disease of type 2 diabetes, and treatments. Specifically, air pollutants of environmental risks, alcohol using of behavioral risks, obesity of metabolic risks, rheumatoid arthritis of related disease risk, and simvastatin of treatment was correlated with the largest number of genes. In summary, the correlation between genetic factors and nongenetic factors identified in this study indicates that there is a common phenotype-genotype association in type 2 diabetes, with the combinations of genotypes ("genetic signature") clustering in phenotypes related to type 2 diabetes. Thus, we should take a systematic approach to explore the relationship of various factors for type 2 diabetes, as well as other noncommunicable diseases.

Cell-Penetrating Streptavidin: A General Tool for Bifunctional Delivery with Spatiotemporal Control, Mediated by Transport Systems Such as Adaptive Benzopolysulfane Networks.

In this report, cell-penetrating streptavidin (CPS) is introduced to exploit the full power of streptavidin-biotin biotechnology in cellular uptake. For this purpose, transporters, here cyclic oligochalcogenides (COCs), are covalently attached to lysines of wild-type streptavidin. This leaves all four biotin binding sites free for at least bifunctional delivery. To maximize the standards of the quantitative evaluation of cytosolic delivery, the recent chloroalkane penetration assay (CAPA) is coupled with automated high content (HC) imaging, a technique that combines the advantages of fluorescence microscopy and flow cytometry. According to the resulting HC-CAPA, cytosolic delivery of CPS equipped with four benzopolysulfanes was the best among all tested CPSs, also better than the much smaller TAT peptide, the original cell-penetrating peptide from HIV. HaloTag-GFP fusion proteins expressed on mitochondria were successfully targeted using CPS carrying two different biotinylated ligands, HaloTag substrates or anti-GFP nanobodies, interfaced with peptide nucleic acids, flipper force probes, or fluorescent substrates. The delivered substrates could be released from CPS into the cytosol through desthiobiotin-biotin exchange. These results validate CPS as a general tool which enables unrestricted use of streptavidin-biotin biotechnology in cellular uptake.

Probing for Thiol-Mediated Uptake into Bacteria.

Cellular uptake mediated by cyclic oligochalcogenides (COCs) is emerging as a conceptually innovative method to penetrate mammalian cells. Their mode of action is based on dynamic covalent oligochalcogenide exchange with cellular thiols. To test thiol-mediated uptake in bacteria, five antibiotics have been equipped with up to three different COCs: One diselenolane and two dithiolanes. We found that the COCs do not activate antibiotics in Gram-negative bacteria. In Gram-positive bacteria, the COCs inactivate antibiotics that act in the cytoplasm and reduce the activity of antibiotics that act on the cell surface. These results indicate that thiol-mediated uptake operates in neither of the membranes of bacteria. COCs are likely to exchange with thiols on the inner, maybe also on the outer membrane, but do not move on. Concerning mammalian cells, the absence of a COC-mediated uptake into bacteria observed in this study disfavors trivial mechanisms, such as passive diffusion, and supports the existence of more sophisticated, so far poorly understood uptake pathways.

Unified Model for Size-Dependent to Size-Independent Transition in Yield Strength of Crystalline Metallic Materials.

Size-dependent yield strength is a common feature observed in miniaturized crystalline metallic samples, and plenty of studies have been conducted in experiments and numerical simulations to explore the underlying mechanism. However, the transition in yield strength from bulklike to size-affected behavior has received less attention. Here a unified theoretical model is proposed to probe the yield strength of crystalline metallic materials with sample size from nanoscale to macroscale. We show that the transition in yield strength versus size can be fully explained by the competition between the stresses required for dislocation source activation and dislocation motion, which is regulated by dislocation density, irradiation defect, grain boundary, and so on. Based on various grain boundary densities, the extended Hall-Petch relation, incorporated into the unified model, captures the reverse size effect for polycrystalline samples. The proposed model predictions agree well with reported experimental measurements of various specimens, including the prestrained nickel, irradiated copper, ultrafine grain tungsten, and so on.

Naphthalenediimides with Cyclic Oligochalcogenides in Their Core.

Naphthalenediimides (NDIs) are privileged scaffolds par excellence, of use in functional systems from catalysts to ion channels, photosystems, sensors, ordered matter in all forms, tubes, knots, stacks, sheets, vesicles, and colored over the full visible range. Despite this extensively explored chemical space, there is still room to discover core-substituted NDIs with fundamentally new properties: NDIs with cyclic trisulfides (i.e., trisulfanes) in their core absorb at 668 nm, emit at 801 nm, and contract into disulfides (i.e., dithietes) upon irradiation at <475 nm. Intramolecular 1,5-chalcogen bonds account for record redshifts with trisulfides, ring-tension mediated chalcogen-bond-mediated cleavage for blueshifts to 492 nm upon ring contraction. Cyclic oligochalcogenides (COCs) in the NDI core open faster than strained dithiolanes as in asparagusic acid and are much better retained on thiol exchange affinity columns. This makes COC-NDIs attractive not only within the existing multifunctionality, particularly artificial photosystems, but also for thiol-mediated cellular uptake.

Automated high-content imaging for cellular uptake, from the Schmuck cation to the latest cyclic oligochalcogenides.

Recent progress with chemistry tools to deliver into living cells has seen a shift of attention from counterion-mediated uptake of cell-penetrating peptides (CPPs) and their mimics, particularly the Schmuck cation, toward thiol-mediated uptake with cell-penetrating poly(disulfide)s (CPDs) and cyclic oligochalcogenides (COCs), here exemplified by asparagusic acid. A persistent challenge in this evolution is the simultaneous and quantitative detection of cytosolic delivery and cytotoxicity in a high-throughput format. Here, we show that the combination of the HaloTag-based chloroalkane penetration assay (CAPA) with automated high-content (HC) microscopy can satisfy this need. The automated imaging of thousands of cells per condition in multiwell plates allows us to obtain quantitative data on not only the fluorescence intensity but also on the localization in a very short time. Quantitative and statistically relevant results can be obtained from dose-response curves of the targeted delivery to selected cells and the cytotoxicity in the same experiment, even with poorly optimized cellular systems.

Mediation of the effect of serum uric acid on the risk of developing hypertension: a population-based cohort study.

BACKGROUND: Serum uric acid (SUA) had been associated with incident hypertension, but it is uncertain whether and to what extent the effect of SUA is mediated by other metabolic factors. METHODS: Data from the China Health and Retirement Longitudinal Study (CHARLS) during 2011 to 2015 was employed for this study. A total of 7639 participants aged between 35 and 96 years without hypertension was included. Cox proportional hazards model was used to investigate the association between elevated SUA and hypertension. A mediation model was used to separately explore mediating effects (MEs) of metabolic factors on the association between SUA and incident hypertension. RESULTS: During a median 4.0 years of follow-up, 2348 individuals were diagnosed with hypertension. After adjustment for metabolic confounders, participants with the highest SUA quartile had a hazard ratio of 1.16 (1.02-1.33) compared with the lowest category for incident hypertension. The association between SUA and incident hypertension were partially mediated by waist circumference (WC; ME = 0.034), body mass index (BMI; ME = 0.016), triglycerides (TG; ME = 0.024), total cholesterol (TC; ME = 0.009), high density lipoprotein cholesterol (HDL-C; ME = 0.009), fasting plasma glucose (FPG; ME = 0.005), and glycated hemoglobin (HbA1c; ME = - 0.002). Additionally, proportional mediation was 32.7% by WC and 15.4% by BMI for obesity indicators; 23.1% by TG, 8.7% by TC, and 8.7% by HDL-C for blood lipid; and 4.8% by FPG and - 1.9% by HbA1c for blood glucose. CONCLUSIONS: The positive association between elevated SUA concentration and hypertension was reconfirmed in a Chinese population. Obesity indicators, blood lipids, and blood glucose may play important mediating roles in the pathways.

Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention of Recurrent Cardiovascular Events in a Real-World Cohort of Post-Acute Myocardial Infarction Patients.

BACKGROUND: Patients who survive myocardial infarction (MI) are at risk of recurrent cardiovascular (CV) events. This study stratified post-MI patients for risk of recurrent CV events using the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS 2°P). Methods and Results: This was an observational study that applied TRS 2°P to a consecutive cohort of post-MI patients. The primary outcome was a composite endpoint of CV death, non-fatal MI, and non-fatal ischemic stroke. A total of 1,688 post-MI patients (70.3±13.6 years; male, 63.1%) were enrolled. After a mean follow-up of 41.5±34.4 months, 405 patients (24.0%) had developed a primary outcome (9.3%/year) consisting of 278 CV deaths, 134 non-fatal MI, and 33 non-fatal strokes. TRS 2°P was strongly associated with the primary outcome. The annual incidence of primary composite endpoint for patients with TRS 2°P 0 was 1.0%, and increased progressively to 39.9% for those with TRS 2°P ≥6 (HR, 27.6; 95% CI: 9.87-77.39, P<0.001). The diagnostic sensitivity of TRS 2°P for the primary composite endpoint was 76.3% (95% CI: 72.1-80.5%). Similar associations were also observed between TRS 2°P and CV death and non-fatal MI, but not non-fatal ischemic stroke. CONCLUSIONS: TRS 2°P reliably stratified post-MI patients for risk of future CV events.

Smog and risk of overall and type-specific cardiovascular diseases: A pooled analysis of 53 cohort studies with 21.09 million participants.

The reported associations of smog with the risk of cardiovascular disease (CVD) and CVD subtypes were inconsistent. We systematically searched the Pubmed (Medline) and Embase databases (from the inception to April 25, 2018) to identify the cohort studies investigating the association between smog and CVD and specific types of CVD. We conducted a meta-analysis for different types of air pollutants (PM2.5, PM10, NO2, and O3) in smog with the risk of specific types of CVD separately. We summarized the study-specific effect estimates using both the fixed effect model and the random effect model. The meta-analysis included 35 publications with 53 cohort studies. Overall, the associations between per 10 µg/m3 increase in PM2.5 exposure and risk of CVD events, stroke events, ischemic heart disease(IHD) events were significant, with relative risks (RRs) of 1.11 (95% confidence interval: 1.07-1.15), 1.12 (95% CI: 1.08-1.16) and 1.14(95% CI: 1.08-1.21), respectively. PM2.5, PM10, NO2, and O3 exposure were associated with an increased risk of CVD mortality, with RRs of 1.11 (95% CI: 1.07-1.15), 1.09 (95% CI: 1.02-1.16), 1.23 (95% CI: 1.15-1.31) and 1.03 (95% CI: 1.02-1.05), respectively. Compared with PM10, NO2, and O3 exposure, PM2.5 exposure had a greater risk of stroke incidence and IHD incidence (RR 1.12, 95% CI 1.05-1.19 for stroke incidence; 1.19, 1.09-1.30 for IHD). However, no clear evidence for the associations of PM10 exposure with risk of CVD incidence, stroke incidence, and IHD incidence was observed. This meta-analysis confirms the evidence that PM2.5 exposure was significantly associated with increased risk of CVD, stroke, and IHD. PM2.5, PM10, NO2, and O3 exposure were separately associated with an increased risk of CVD mortality. There was a stronger association between PM2.5 exposure and the risk of stroke and IHD incidence. It urgently needs well-designed studies to further to elaborate the biological and epidemiological mechanisms that link smog with CVD. MAIN FINDINGS: Compared with PM10, NO2, and O3 exposures, PM2.5 exposure was positively associated with increased risk of stroke and IHD incidence. For air pollutants and CVD events, the association of NO2 with the risk CVD mortality is more significant.