Pd(II)-Catalyzed ß-C(sp3)-H Alkynylation of Alanine in Di- and Tripeptides with Asn as an Endogenous Directing Group.

The introduction of alkyne moieties into peptides remains in demand as it represents a promising approach for further structural diversification of peptides. Herein, we describe the Pd(II)-catalyzed C(sp3)-H alkynylation of Ala-Asn-embedded di- and tripeptides using Asn as the endogenous lead group. In addition, a key building block for the glycopeptide Tyc4PG-14 and Tyc4PG-15 was produced by our methodology.

Identification of novel 3-aryl-1-aminoisoquinolines-based KRASG12C inhibitors: Rational drug design and expedient construction by CH functionalization/annulation.

Developing a synthetic methodology to expediently construct a specific drug scaffold with the desired biological activity remains challenging. Herein, we describe a work on rational application of a synthetic methodology in the synthesis of KRASG12C inhibitors. Novel KRASG12C inhibitors were initially designed with 1-amino-3-aryl isoquinoline scaffold using structure-based drug design strategy. A ruthenium-catalyzed direct monoCH functionalization/annulation cascade reaction of amidines and sulfoxonium ylides was then developed with high versatility of substrates and good tolerance for polar functional groups. By using this reaction, the target compounds 1-amino-3-aryl isoquinolines were facilely prepared. Further in vitro tests led to identification of two novel lead compounds with KRASG12C inhibitory activity.

Cascade Alkenylation/Intramolecular Friedel-Crafts Alkylation: High Selectivity at the C7-Position of BINOL.

An efficient and straightforward approach for the synthesis of C7 site-selective BINOL derivatives has been achieved via cost-effective Co(III)-catalyzed C-H cascade alkenylation/intramolecular Friedel-Crafts alkylation of BINOL units and propargyl cycloalkanols. Under the advantage of the pyrazole directing group, the protocol allows the rapid synthesis of various BINOL-tethered spiro[cyclobutane-1,1'-indenes].

C-O Coupling/[4+2] Cycloaddition Tandem Reactions via Oxidative Dearomatization of BINOLs: Access to Bridged Polycyclic Compounds.

Intramolecular C-H activation/C-O coupling, dearomatization, and [4+2] cycloaddition of BINOL units have been well developed in a one-pot approach with maleimide derivatives as the dienophiles. This tandem catalytic system generates a variety of functionalized bridged polycyclic products in a step-economical manner, which greatly enriches the modification methods and strategies for the BINOL skeletons.

Construction of C2-Quaternary-indol-3-ones via RhIII-Catalyzed [3+2] Spirocyclization from Indole Ketones and Nitroolefins.

Novel complex C2-quaternary-indol-3-one units bearing versatile nitro groups have been successfully developed from pseudo-indolones and α,ß-unsaturated nitroolefins through rhodium-catalyzed C-H activation/[3 + 2] spirocyclization. Notably, four diastereomers could be selectively obtained in the reaction by condition control.

Effects of long-term PM2.5 exposure on metabolic syndrome among adults and elderly in Guangdong, China.

BACKGROUND: We aimed to explore the association between long-term exposure to particulate matter ≤ 2.5 µm (PM2.5) and metabolic syndrome (MetS) and its components including fasting blood glucose (FBG), blood pressure, triglyceride (TG), high-density lipoprotein cholesterol (HDL-c) and waist circumference among adults and elderly in south China. METHODS: We surveyed 6628 participants in the chronic disease and risk factors surveillance conducted in 14 districts of Guangdong province in 2015. MetS was defined based on the recommendation by the Joint Interim Societies' criteria. We used the spatiotemporal land-use regression (LUR) model to estimate the two-year average exposure of ambient air pollutants (PM2.5, PM10, SO2, NO2, and O3) at individual levels. We recorded other covariates by using a structured questionnaire. Generalized linear mixed model was used for analysis. RESULTS: A 10-µg/m3 increase in the two-year mean PM2.5 exposure was associated with a higher risk of developing MetS [odd ratio (OR): 1.17, 95% confidence interval (CI): 1.01, 1.35], increased risk of fasting blood glucose level. (OR: 1.18, 95% CI: 1.02, 1.36), and hypertriglyceridemia (OR: 1.36, 95% CI: 1.18, 1.58) in the adjusted/unadjusted models (all P < 0.05). We found significant interaction between PM2.5 and the region, exercise on the high TG levels, and an interaction with the region, age, exercise and grain consumption on FBG (P interaction < 0.05). CONCLUSIONS: Long-term exposure to PM2.5 was associated with MetS, dyslipidemia and FBG impairment. Efforts should be made for environment improvement to reduce the burden of MetS-associated non-communicable disease.

Impact of polluting fuels for cooking on diabetes mellitus and glucose metabolism in south urban China.

We hypothesized that exposure to polluting fuels for cooking was associated with abnormality of glucose metabolism and diabetes mellitus (DM) in south urban China. 3414 residents were surveyed in 14 urban areas of Guangdong Province in 2018. We recorded polluting fuels for cooking exposure, different DM status (DM, prediabetes), fasting blood glucose (FBG), oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c ), and other covariates by using a structured questionnaire. We conducted logistic regression model and multivariate linear regression model based on propensity-score method (inverse probability of weighting) to examine the effect of polluting fuels for cooking exposure on DM and glucose metabolism. Exposure to polluting fuels for cooking was associated with DM (odds ratio: 2.57, 95% confidence interval: 1.71 to 3.86) and prediabetes (odds ratio: 1.98, 95% confidence interval: 1.52 to 2.58) in both the adjusted and unadjusted models (all p < 0.05). Exposure to polluting fuels for cooking was significantly associated with an increase of FBG (ß: 0.30 mmol/L, 95% confidence interval: 0.22 to 0.38 mmol/L). Sensitivity analysis showed that the results were not substantially changed. There was an increased risk of DM, prediabetes and high levels of FBG, OGTT, and HbA1c among participants aged ≥ 40 years with exposure to polluting fuels for cooking. We demonstrated that exposure to polluting fuels for cooking was associated with higher levels of FBG, which contributed to the increased risk of DM and prediabetes in middle-aged elderly Chinese population living in urban areas.

Health transition of the causes of mortality between 2005 and 2015 in Guangdong, China.

OBJECTIVES: To analyse the patterns of transition of health burden for 110 causes of death by stratification of age, sex and geographic regions in Guangdong between 2005 and 2015. METHODS: We analysed the age-specific, sex-specific, region-specific mortality in Guangdong based on assembled databases. County-level surveillance data were calculated to inform city-level changes. RESULTS: The age-standardised mortality of all causes, non-communicable diseases (NCDs), communicable diseases, maternal diseases, neonatal diseases, malnutrition and injury declined progressively. Despite declining mortality of NCDs, the overall burden of disease was dominated by NCDs (ie, cerebrovascular disease, chronic obstructive pulmonary disease) that still accounted for 86.93% and 88.12% of death in 2005 and 2015, respectively. Considerable variations across geographic regions were observed (lowest in Pearl River Delta and highest in west Guangdong). There was a modest shift to transport injuries at younger ages and unintentional injuries in the elderly. CONCLUSIONS: We have documented a dramatic change in the overall mortality and age-specific, sex-specific and cause-specific mortality in Guangdong province between 2005 and 2015. The significant burden of NCDs remains a major healthcare issue despite the notable progress in reducing mortality in Guangdong, China. Our findings highlight important unmet needs to refine healthcare services by taking into account the inequity of age, sex and geographic regions. Identification of the 'treatable' risk factors and improved disease surveillance should be continuously improved to minimised the overall and cause-specific mortality.

Serum Bioavailable, Rather Than Total, 25-hydroxyvitamin D Levels Are Associated With Hepatocellular Carcinoma Survival.

BACKGROUND AND AIMS: Free and bioavailable 25-hydroxyvitamin D (25OHD) are emerging measurements of vitamin D status. It remains unclear whether circulating free or bioavailable 25OHD are relevant to hepatocellular carcinoma (HCC) prognosis. Our aim was to test the hypothesis that bioavailable 25OHD may be a better serum biomarker of vitamin D status than total 25OHD on the association with HCC survival. APPROACH AND RESULTS: We included 1,031 newly diagnosed, previously untreated patients with HCC from the Guangdong Liver Cancer Cohort enrolled between September 2013 and April 2017. Serum total 25OHD levels were measured using an electrochemiluminescence immunoassay. Serum-free 25OHD levels were measured using a two-step enzyme-linked immunosorbent assay. Bioavailable 25OHD levels were calculated from measured free 25OHD and albumin using a previously validated equation. Primary outcomes were liver cancer-specific (LCSS) and overall survival (OS). Cox proportional hazards models were performed to calculate the multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). During a median follow-up of 726 days, 430 patients had deceased, including 393 deaths from HCC. In multivariable analyses, higher bioavailable 25OHD levels were significantly associated with better survival, independent of nonclinical and clinical prognostic factors including serum C-reactive protein, Barcelona Clinic Liver Cancer stage, and cancer treatment. The multivariable-adjusted HRs in the highest versus lowest quartile of bioavailable 25OHD levels were 0.69 (95% CI: 0.51, 0.93; P for trend = 0.014) for LCSS and 0.71 (95% CI: 0.53, 0.94; P for trend = 0.013) for OS. In contrast, neither total nor free 25OHD levels were associated with LCSS or OS. CONCLUSIONS: Higher bioavailable, rather than total, 25OHD levels were independently associated with improved survival in a population-based HCC cohort, suggesting a potential utility of bioavailable 25OHD in HCC prognosis.

Exposure to biomass fuel is associated with high blood pressure and fasting blood glucose impairment in females in southern rural China.

OBJECTIVES: We sought to investigate the association between household exposure to biomass fuel and metabolic syndrome (MetS) and its components including blood pressure, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG) and waist circumference among females in southern rural China. METHODS: We surveyed 1664 residents in the Chronic Disease and Risk Factors Surveillance, conducted in 14 districts of Guangdong province. We recorded the use of biomass fuel, MetS and its components, and other covariates by using a structured questionnaire. Logistic regression model and multivariate linear regression model were adopted for analysis. RESULTS: Exposure to biomass fuel was significantly associated with an increase of systolic blood pressure (SBP) (ß: 2.15, 95% confidence interval: 0.13 to 4.17) and FBG (ß: 0.19, 95% confidence interval: 0.01 to 0.37) in the adjusted and unadjusted models (all P < 0.05). Among participants with exposure to biomass fuel, being overweight or obese was associated with an increased risk of having hypertension (odds ratio: 3.19, 95% confidence interval: 2.13 to 4.76) and higher FBG levels (odds ratio: 2.10, 95% confidence interval: 1.46 to 3.02). Exposure to biomass fuel was significantly associated with a decrease of the prevalence of central obesity (P < 0.05). However, exposure to biomass fuel was not associated with MetS, diastolic blood pressure and TG (all P > 0.05). CONCLUSIONS: Exposure to biomass fuel is associated with an increase in blood pressure and FBG levels, but not MetS per se. Efforts should be made to protect females in southern rural China from the adverse effects associated with biomass fuel pollution.

Role of "Stiff Rim" sign obtained by shear wave elastography in diagnosis and guiding therapy of breast cancer.

Background: Because the halo around the tumor in shear wave elastography (SWE) is defined as the "stiff rim" sign, the diagnosis of breast lesions with the stiff rim sign is popular. However, only a few studies have described the stiff rim sign quantitatively. Objective: This study aimed to investigate the usefulness of the stiff rim sign in the diagnosis and tumor, node, metastasis stage of breast cancer. Methods: Two hundred and ten breast lesions were analyzed retrospectively. The maximum, mean, minimum Young's modulus (YM), and the YM standard deviation in the lesion, the peritumoral stiffness (shell), and the region containing lesion and shell were obtained. The suspicious SWE feature with the best diagnostic performance was chosen to downgrade or upgrade the Breast Imaging Reporting and Data System (BI-RADS) classification. The coincidence rates of SWE and B-mode ultrasound in T staging and their positive predictive value (PPV) for T staging were compared. Results: The presence of "stiff rim" sign was selected to upgrade or downgrade the BI-RADS classification because of its best performance. In pathological benign lesions, 18.9% (25 of 132) of lesions should undergo biopsy if BI-RADS combined with the stiff rim sign were referred while it was 57.6% (76 of 132) if BI-RADS alone was referred. The coincidence rate of T2 staging evaluated by SWE was significantly higher than B-mode ultrasound (about 30% increase, P < 0.001). The PPVs of SWE for T1 and T2 staging were higher than B-mode ultrasound (P < 0.05). Conclusions: BI-RADS combined with "stiff rim" sign is expected to improve the diagnostic performance of breast lesions to avoid unnecessary biopsy. The maximum diameter of the lesion measured in SWE is more accurate than B-mode ultrasound in the estimation of T staging, which is beneficial to the treatment and prognosis of breast cancer.

Trends and external causes of traumatic brain injury and spinal cord injury mortality in south China, 2014-2018: an ecological study.

BACKGROUND: The epidemiological evidence of traumatic brain injury (TBI) and spinal cord injury (SCI) mortality in mainland China is lacking. We aimed to assess the trends of TBI and SCI mortality, and their association with sex, age, location and external causes of injury in south China. METHODS: Mortality data were derived from the Disease Surveillance Points (DSPs) system of Guangdong province between 2014 and 2018. We examined the trends in mortality with Cochran-Armitage trend test, and the association between the socio-demographic factors and the TBI and SCI mortality by using negative binomial models. Subgroup analysis was performed by stratifying the external causes of TBI and SCI. RESULTS: The age-standardized TBI mortality remained relatively stable (from 11.6 to 15.4 per 100,000), while the SCI mortality increased by 148.3% from 2014 to 2018. Compared with females and urban residents, the adjusted mortality rate ratios of males and rural residents were 2.3 and 2.0 for TBI, and 2.2 and 4.6 for SCI, respectively. TBI and SCI mortality increased substantially with age. Motor vehicle crashes and falls were the leading causes of TBI mortality in residents aged under 75 years and over 75 years, respectively. Falls were the most important external cause for SCI death of all ages. CONCLUSIONS: Being male, rural and elderly residents are at higher risk of dying from TBI and SCI. The substantial burden of TBI and SCI caused by road traffic crashes and falls has called for the urgent need to improve injury prevention, pre-hospital aid, hospital treatment and recovery.

Effects of cigarette smoking and biomass fuel on lung function and respiratory symptoms in middle-aged adults and the elderly in Guangdong province, China: A cross-sectional study.

We sought to investigate the association between active cigarette smoking (ex- and current smokers) with or without exposure to biomass fuels and respiratory symptoms/lung function in middle-aged adults and the elderly. In the chronic obstructive pulmonary disease surveillance conducted in six cities of Guangdong province, China, we surveyed 1986 residents aged 40-93 years. We recorded respiratory symptoms, smoking status, use of biomass fuel, and other covariates by using a structured questionnaire. All models were adjusted for second-hand smoking. Active smoking with or without exposure to biomass fuels was significantly associated with wheezing, chronic cough, and phlegm (all P < .05). Active smoking alone with or without exposure to biomass fuels was associated with 2.5% and 0.6% reduction in the mean forced vital capacity predicted, 6.8% and 4.2% reduction in the mean forced expiratory volume in one second predicted, and 9.0% and 4.7% reduction in the mean maximal mid-expiratory flow predicted compared with the exposure to neither smoking nor biomass fuels, respectively. However, exposure to biomass fuel alone was associated with neither greater lung function impairment nor respiratory symptoms except for chronic cough. Efforts should be made to protect home owners and their family from adverse effects of indoor air pollution.

Temperature-dependent effects on CO2 water bath therapy induced changes in blood flow and vascularity in hind limb ischemia.

To test if magnitudes of the beneficial actions of CO2 water bath therapy on blood flow and vascular density are dependent upon temperature, ischemia in the hind limb of rats was induced by occluding the left femoral artery for 2 weeks and the animals were exposed to water bath therapy with or without CO2 at 34 or 41 °C for 4 weeks (20 min treatment each day for 5 days/week). CO2 water bath therapy at 34 °C increased peak, minimal, and mean blood flow by 190%-600% in the ischemic limb. On the other hand, CO2 water bath treatment at 41 °C increased these parameters of blood flow by 37%, 55%, and 41%, respectively, in the ischemic limb. The small blood vessel count, an index of vascular density, in the ischemic limb was increased by CO2 water bath therapy at 34 and 41 °C by 32% and 122%, respectively. No changes in the ischemic animals by CO2 water bath therapy at 34 or 41 °C were observed in the heart rate, R-R interval, and plasma lipid or glucose levels. These data indicate that the beneficial effect of CO2 water bath therapy at 34 °C on blood flow in the ischemic muscle is greater whereas that on vascular density is smaller than changes in these parameters at 41 °C.

Role of lysophosphatidic acid in vascular smooth muscle cell proliferation.

Lysophosphatidic acid (LPA) is an important lipid molecule for signal transduction in cell proliferation. Although the effects of LPA on vascular smooth muscle (VSM) cell growth have been reported previously, the underlying mechanisms of its action are not fully understood. The present study was undertaken to investigate the effects of some inhibitors of different protein kinases and other molecular targets on LPA-induced DNA synthesis as well as gene expression in the aortic VSM cells. The DNA synthesis was studied by the [3H]thymidine incorporation method and the gene expression was investigated by the real-time PCR technique. It was observed that the LPA-induced DNA synthesis was attenuated by inhibitors of protein kinase C (PKC) (staurosporine, calphostin C, and bisindolylmaleimide), phosphoinositide 3-kinase (PI3K) (wortmannin and LY294002), and ribosomal p70S6 kinase (p70S6K) (rapamycin). The inhibitors of guanine protein coupled receptors (GPCR) (pertussis toxin), phospholipase C (PLC) (U73122 and D609), and sodium-hydrogen exchanger (NHE) (amiloride and dimethyl amiloride) were also shown to depress the LPA-induced DNA synthesis. Furthermore, gene expressions for PLC ß1 isoform, PKC δ and ε isoforms, casein kinase II ß isoform, and endothelin-1A receptors were elevated by LPA. These results suggest that the LPA-induced proliferation of VSM cells is mediated through the activation of GPCR and multiple protein kinases as well as gene expressions of some of their specific isoforms.

Age-standardized mortality, disability-adjusted life-years and healthy life expectancy in different cultural regions of Guangdong, China: a population-based study of 2005-2015.

BACKGROUND: Guangdong province is dominated by three cultural regions: Canton, Hakka and Hoklo. However, little is known about the disease burden within these regions, particularly because different population,environmental and socioeconomic risk factors might cause different patterns of mortality, disability-adjusted life-years (DALY), life expectancy and healthy life expectancy (HALE). We aimed to compare the patterns of disease burden in Canton, Hakka and Hoklo regions between 2005 and 2015. METHOD: We calculated the mortality, YLL, YLD for 116 diseases for different cultural regions between 2005 and 2015. We calculated the DALYs for 116 causes as the sum of YLLs and YLDs. We estimated the life expectancy and HALE by using sex-specific mortality rates and YLDs for the three cultural regions. RESULTS: With a respective reduction of 22.3, 15.8 and 17.8% in 2015 compared with 2005, the age-standardized DALY rates in 2015 was 19,988.0, 14,396.5 and 20,436.6 in Hakka, Canton and Hoklo region. Canton region had a significantly lower mortality and DALYs in most diseases, followed by Hoklo and Hakka regions. The life expectancy and HALE at birth were highest in Canton region in both 2005 and 2015, than in Hoklo and Hakka region. CONCLUSIONS: Our findings call for improved public health care via the refinement of policy and effective measures for disease prevention. Understanding the environmental and culture-related risk factors of diseases in Hoklo and Hakka regions may help inform public health sectors to reduce the disease burden and the between-region inequality.

Serum copper and zinc levels at diagnosis and hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort.

Copper and zinc are essential micronutrients, whose imbalance may be involved in the development and progression of cancer. However, the role of copper and/or zinc imbalance in the prognosis of hepatocellular carcinoma (HCC) is currently unclear. Our objective was to investigate the association between serum levels of copper, zinc and their ratio (copper/zinc) at diagnosis with HCC survival. We included 989 patients with incident HCC in this prospective cohort study, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study within 30 days of diagnosis between September 2013 and February 2017. Serum copper and zinc were measured using inductively coupled plasma mass spectrometry. Primary outcomes were liver cancer-specific survival (LCSS) and overall survival (OS). Cox proportional hazards models were used to calculate the multivariable hazard ratios (HRs) and 95% confidence interval (CI). Higher serum copper levels were strongly associated with worse LCSS (Q4 vs. Q1: HR = 1.87, 95% CI: 1.22-2.86; p < 0.01 for trend) and OS (Q4 vs. Q1: HR = 2.06, 95% CI: 1.36-3.11; p < 0.01 for trend). The calculated copper/zinc ratio was positively associated with LCSS (Q4 vs. Q1: HR = 1.31, 95% CI: 0.89-1.92; P = 0.04 for trend) and OS (Q4 vs. Q1: HR = 1.43, 95% CI: 0.99-2.08; P = 0.01 for trend). No overall associations were observed between serum zinc levels and LCSS or OS in the entire cohort. The results suggest that higher serum copper and copper in relation to zinc levels (i.e., higher copper/zinc ratio) may be associated with worse HCC survival, but serum zinc levels may be not associated with HCC survival.

Diastereoselective α-Amination of N- tert-Butanesulfinyl Imidates Using N-Aryl- N-diphenylphosphinyldiazenes.

Diastereoselective α-amination of N- tert-butanesulfinyl imidates has been developed using N-aryl (or N- tert-butyl) N-diphenylphosphinyldiazenes as nitrogen sources. The chiral 1-azaenolates derived from imidates undergo nucleophilic addition with diazenes to give α-hydrazino imidates in good yields.

Serum folate concentrations at diagnosis are associated with hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort study.

Existing data on folate status and hepatocellular carcinoma (HCC) prognosis are scarce. We prospectively examined whether serum folate concentrations at diagnosis were associated with liver cancer-specific survival (LCSS) and overall survival (OS) among 982 patients with newly diagnosed, previously untreated HCC, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study between September 2013 and February 2017. Serum folate concentrations were measured using chemiluminescent microparticle immunoassay. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95 % CI by sex-specific quartile of serum folate. Compared with patients in the third quartile of serum folate, patients in the lowest quartile had significantly inferior LCSS (HR = 1·48; 95 % CI 1·05, 2·09) and OS (HR = 1·43; 95 % CI 1·03, 1·99) after adjustment for non-clinical and clinical prognostic factors. The associations were not significantly modified by sex, age at diagnosis, alcohol drinking status and Barcelona Clinic Liver Cancer (BCLC) stage. However, there were statistically significant interactions on both multiplicative and additive scale between serum folate and C-reactive protein (CRP) levels or smoking status and the associations of lower serum folate with worse LCSS and OS were only evident among patients with CRP > 3·0 mg/l or current smokers. An inverse association with LCSS were also observed among patients with liver damage score ≥3. These results suggest that lower serum folate concentrations at diagnosis are independently associated with worse HCC survival, most prominently among patients with systemic inflammation and current smokers. A future trial of folate supplementation seems to be promising in HCC patients with lower folate status.

Diastereoselective α-Fluorination of N- tert-Butanesulfinyl Imidates.

A diastereoselective α-fluorination of N- tert-butanesulfinyl imidates was developed. Deprotonation of N- tert-butanesulfinyl imidates with lithium hexamethyldisilazide generates aza-enolates that can be intercepted, with excellent diastereocontrol, by the inexpensive electrophilic fluorinating agent NFSI. This protocol was applied to the preparation of synthetically useful trans-2-fluoro-cyclohexamine with high enantiomeric purity (99.5% ee).