Design and synthesis 1H-Pyrrolo[2,3-b]pyridine derivatives as FLT3 inhibitors for the treatment of Acute myeloid Leukemia.

Acute myeloid leukemia (AML) is the most common type of blood cancer and has been strongly correlated with the overexpression of Fms-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family. With the emergence of FLT3 internal tandem duplication alteration (ITD) and tyrosine kinase domain (TKD) mutations, the development of FLT3 small molecule inhibitors has become an effective medicinal chemistry strategy for AML. Herein, we have designed and synthesized two series of 1H-pyrrolo[2,3-b]pyridine derivatives CM1-CM24, as FLT3 inhibitors based on F14, which we previously reported, that can target the hydrophobic FLT3 back pocket. Among these derivates, CM5 showed significant inhibition of FLT3 and FLT3-ITD, with inhibitory percentages of 57.72 % and 53.77 % respectively at the concentration of 1 µΜ. Furthermore, CM5 demonstrated potent inhibition against FLT3-dependent human AML cell lines MOLM-13 and MV4-11 (both harboring FLT3-ITD mutant), with IC50 values of 0.75 µM and 0.64 µM respectively. In our cellular mechanistic studies, CM5 also effectively induces apoptosis by arresting cell cycle progression in the G0/G1 phase. In addition, the amide and urea linker function were discussed in detail based on computational simulations studies. CM5 will serve as a novel lead compound for further structural modification and development of FLT3 inhibitors specifically targeting AML with FLT3-ITD mutations.

Effectiveness of Kurtosis-Adjusted Cumulative Noise Exposure in Assessing Occupational Hearing Loss Associated With Complex Noise.

OBJECTIVES: Occupational noise-induced hearing loss (NIHL) is one of the most prevalent occupational diseases worldwide. Few studies have been reported on applying kurtosis-adjusted noise energy (e.g., kurtosis-adjusted cumulative noise exposure, CNE-K) as a joint indicator for assessing NIHL. This study aimed to analyze the effectiveness of CNE-K in assessing occupational hearing loss associated with complex noise in typical manufacturing industries. DESIGN: A cross-sectional survey of 1404 Chinese manufacturing workers from typical manufacturing industries was conducted. General demographic characteristics, noise exposure data, and noise-induced permanent threshold shifts (NIPTS) at 3, 4, and 6 kHz (NIPTS 346 ) were collected and analyzed. The role of kurtosis in high-frequency noise-induced hearing loss (HFNIHL) was also analyzed. The degree of overlap of the two logistic curves (i.e., between complex noise CNE-K and HFNIHL%, and between Gaussian noise CNE and HFNIHL%) was used to evaluate the effectiveness of CNE-K, using a stratified analysis based on age, sex, industry, or job type. RESULTS: The binary logistic regression analysis showed that in addition to age, sex, exposure duration, and Eight-hour Continuous Equivalent A-weighted Sound Pressure Level (L Aeq,8h ), kurtosis was a key factor influencing HFNIHL% in workers (odds ratio = 1.18, p < 0.05), and its odds ratio increased with an increase in kurtosis value. Multiple linear regression analysis demonstrated that the contribution of kurtosis to NIPTS 346 was second to L Aeq,8h . Complex noise led to a higher risk of NIHL than Gaussian noise at frequencies of 3, 4, 6, and 8 kHz after adjusting for age, sex, and CNE ( p < 0.05). As kurtosis increased, the notch in the audiogram became deeper, and the frequency at which the notch began to deepen shifted from 3 to 1 kHz. The logistic curve between complex noise CNE-K and HFNIHL% nearly overlapped with that between Gaussian noise CNE and HFNIHL%, and the average difference in HFNIHL% between the two curves decreased from 8.1 to 0.4%. Moreover, the decrease of average difference in HFNIHL% between the two logistic curves was evident in several subgroups, such as male workers, aged <30 and 30 to 50 years, furniture and woodworking industries and gunning and nailing job types with relatively high kurtosis values. CONCLUSIONS: Kurtosis, as an indirect metric of noise temporal structure, was an important risk factor for occupational NIHL. Kurtosis-adjusted CNE metric could be more effective than CNE alone in assessing occupational hearing loss risk associated with complex noise.

Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.

Prospects for Anti-Tumor Mechanism and Potential Clinical Application Based on Glutathione Peroxidase 4 Mediated Ferroptosis.

Ferroptosis, characterized by excessive iron accumulation and lipid peroxidation, is a novel form of iron-dependent cell death, which is morphologically, genetically, and biochemically distinct from other known cell death types, such as apoptosis, necrosis, and autophagy. Emerging evidence shows that glutathione peroxidase 4 (GPX4), a critical core regulator of ferroptosis, plays an essential role in protecting cells from ferroptosis by removing the product of iron-dependent lipid peroxidation. The fast-growing studies on ferroptosis in cancer have boosted a perspective on its use in cancer therapeutics. In addition, significant progress has been made in researching and developing tumor therapeutic drugs targeting GPX4 based on ferroptosis, especially in acquired drug resistance. Selenium modulates GPX4-mediated ferroptosis, and its existing form, selenocysteine (Sec), is the active center of GPX4. This review explored the structure and function of GPX4, with the overarching goal of revealing its mechanism and potential application in tumor therapy through regulating ferroptosis. A deeper understanding of the mechanism and application of GPX4-mediated ferroptosis in cancer therapy will provide new strategies for the research and development of antitumor drugs.

Short-term effects of fine particulate matter constituents on myocardial infarction death.

Existing evidence suggested that short-term exposure to fine particulate matter (PM2.5) may increase the risk of death from myocardial infarction (MI), while PM2.5 constituents responsible for this association has not been determined. We collected 12,927 MI deaths from 32 counties in southern China during 2011-2013. County-level exposures of ambient PM2.5 and its 5 constituents (i.e., elemental carbon (EC), organic carbon (OC), sulfate (SO42-), ammonium (NH4+), and nitrate (NO3-)) were aggregated from gridded datasets predicted by Community Multiscale Air Quality Modeling System. We employed a space-time-stratified case-crossover design and conditional logistic regression models to quantify the association of MI mortality with short-term exposure to PM2.5 and its constituents across various lag days. Over the study period, the daily mean PM2.5 mass concentration was 77.8 (standard deviation (SD) = 72.7) µg/m3. We estimated an odds ratio of 1.038 (95% confidence interval (CI): 1.003-1.074), 1.038 (1.013-1.063) and 1.057 (1.023-1.097) for MI mortality associated with per interquartile range (IQR) increase in the 3-day moving-average exposure to PM2.5 (IQR = 76.3 µg/m3), EC (4.1 µg/m3) and OC (9.1 µg/m3), respectively. We did not identify significant association between MI death and exposure to water-soluble ions (SO42-, NH4+ and NO3-). Likelihood ratio tests supported no evident violations of linear assumptions for constituents-MI associations. Subgroup analyses showed stronger associations between MI death and EC/OC exposure in the elderly, males and cold months. Short-term exposure to PM2.5 constituents, particularly those carbonaceous aerosols, was associated with increased risks of MI mortality.

Observation-based sources evolution of non-methane hydrocarbons (NMHCs) in a megacity of China.

Both concentrations and emissions of many air pollutants have been decreasing due to implement of control measures in China, in contrast to the fact that an increase in emissions of non-methane hydrocarbons (NMHCs) has been reported. This study employed seven years continuous NMHCs measurements and the related activities data of Shanghai, a megacity in China, to explore evolution of emissions and effectiveness of air pollution control measures. The mixing ratio of NMHCs showed no statistical interannual changes, of which their compositions exhibited marked changes. This resulted in a decreasing trend of ozone formation potential by 3.8%/year (p < 0.05, the same below), which should be beneficial to ozone pollution mitigation as its production in Shanghai is in the NMHCs-limited regime. Observed alkanes, aromatics and acetylene changed by +3.7%/year, -5.9%/year and -7.4%/year, respectively, and alkenes showed no apparent trend. NMHCs sources were apportioned by a positive matrix factorization model. Accordingly, vehicular emissions (-5.9%/year) and petrochemical industry emissions (-7.1%/year) decreased significantly, but the decrease slowed down; significant reduction in solvent usage (-9.0%/year) appeared after 2010; however, emissions of natural gas (+12.6%/year) and fuel evaporation (with an increasing fraction) became more important. The inconsistency between observations and inventories was found in interannual trend and speciation as well as source contributions, emphasizing the need for further validation in NMHCs emission inventory. Our study confirms the effectiveness of measures targeting mobile and centralized emissions from industrial sources and reveals a need focusing on fugitive emissions, which provided new insights into future air policies in polluted region.

Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 µM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 µM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.

Differentiation and correlation of spatial pattern and multifunction in rural settlements considering topographic gradients: Evidence from Loess Hilly Region, China.

In the process of rapid industrialization and urbanization, China's rural settlements are undergoing rapid differentiation and reorganization. Their spatial pattern and multifunction have attracted much attention. In the Loess Hilly Region of China, topographic factors are deeply involved in the formation and evolution of the spatial pattern and multifunction in rural settlements. Therefore, this paper proposed a new method of topographic gradient analysis based on micro-geomorphic units. Taking Tianshui City in Longzhong Loess Hilly Region as an example, we analyzed the gradient differentiation and spatial correlation of the spatial pattern and multifunction in rural settlements. The results indicated that: (1) The topographic gradient differentiation of spatial pattern in rural settlements was distinct. As the topographic gradients rose, the numerical distributions of TA, AREA_CV, MPI, PR, and SHDI were generally concentrated from high to low values. The numerical distribution of LFI was generally scattered from low to high values. In addition, the numerical distribution of AWMSI and AWMPFD showed the "arch bridge" pattern. (2) The topographic gradient differentiation of multifunction in rural settlements was distinct. The overall level of LF was relatively low, and the numerical difference was small. It had the characteristics of concentrated distribution and marginal distribution in geographical space. The overall level of PF was low, and the spatial distribution had strong urban directivity and significant topographic gradient differences. The overall level of EF was relatively low, and the spatial distribution had significant horizontal zonality and topographic gradient differences. (3) Rural settlements' scale, distribution, and structure were generally synergistic with LF and PF, but there were trade-off relationships with EF. Moreover, the trade-off/synergy relationships between spatial pattern and multifunction had significant spatial heterogeneity in terms of spatial distribution. This paper is significant for formulating settlement development and construction plans, guiding spatial reconstruction and functional reorganization, improving settlement living environment, and promoting rural revitalization.

Synergistic inhibitory effect of berberine and icotinib on non-small cell lung cancer cells via inducing autophagic cell death and apoptosis.

Resistance to epidermal growth factor receptor-tyrosin kinase inhibitors (TKIs, e.g. icotinib) remains a major clinical challenge. Non-small cell lung cancer patients with wild-type EGFR and/or K-RAS mutation are primary resistance to EGFR-TKIs. Berberine has been found to have potent anticancer activities via distinct molecular mechanism. In this study, we sought to investigate the therapeutic utility of BBR in combination with icotinib to overcome icotinib resistance in NSCLC cells, and explore the molecular mechanism of synergism of icotinib and BBR to EGFR-resistant NSCLC cells. We used the two EGFR-resistant NSCLC cell lines H460 and H1299 for testing the inhibitory effect of icotinib and/or BBR on them. Moreover, xenograft mouse model was applied for assessing the anti-tumor activities of BBR and icotinib in combination. Results showed that BBR and icotinib have a synergistic inhibitory effect on H460 and H1299 cells through induction of autophagic cell death and apoptosis. Accordingly, the anti-cancer effect of BBR plus icotinib was further confirmed in the NSCLC xenograft mouse models. Combination of BBR and icotinib significantly inhibited the protein expression and the activity of EGFR by inducing autophagic EGFR degradation. BBR plus icotinib resulted in intracellular ROS accumulation, which could mediated autophagy and apoptosis and involved in the suppression of cell migration and invasion. In conclusions, combination application of BBR and icotinib could be an effective strategy to overcome icotinib resistance in the treatment of NSCLC.

Novel Solvent-Free Extraction Method for Analyzing Tobacco Heating Product Aerosols: An Analytical and In Vitro Toxicological Five-Way Product Comparison.

Harmful and potentially harmful constituents (HPHCs) in tobacco smoke are thought to be responsible for the increased health risks. Tobacco heating products (THPs) heat tobacco instead of burning it to achieve significantly fewer toxicants than conventional cigarettes. To assess the toxicity of THP aerosols, it is often desirable to extract the main constituents using a solvent method. In this study, we developed a high-speed centrifugal method for extracting the total particulate matter (TPM) from THPs to quantitatively compare the toxicity of different THPs and conventional cigarettes. Its TPM extraction efficiency exceeded 85%, and the primary aerosol components and typical HPHCs were comparable to those of the solvent method. The TPMs extracted from five THPs were subjected to 14 in vitro toxicology assessments, and the results were compared with those of a 3R4F reference cigarette. Physical separation can improve biases from solvent selectivity and potential interactions between solvent and aerosol constituents. By eliminating solvent influence, the extraction method could achieve high-dose exposures, enabling the toxicity comparison of different THPs. The relative toxicity of the THPs differed under different dosage units, including the TPM concentration, nicotine equivalent, and puff number.

Occupational Hearing Loss Associated With Non-Gaussian Noise: A Systematic Review and Meta-analysis.

OBJECTIVES: Epidemiological characteristics of occupational noise-induced hearing loss (NIHL) associated with non-Gaussian noise are still unclear and have been rarely reported in the literature. METHODS: The relationships between non-Gaussian noise exposure and occupational NIHL were analyzed based on the published papers. Systematic review and meta-analysis of epidemiological studies were performed. RESULTS: Of 78 epidemiological studies (47,814 workers) selected, there were seven cohort studies and 71 cross-sectional studies. The incidence of high-frequency NIHL (HFNIHL) and speech-frequency NIHL (SFNIHL) in the seven cohort studies was 10.9 and 2.9%, respectively. In 71 cross-sectional studies, the prevalence of HFNIHL and SFNIHL was 34.2 and 18.9%, respectively. The average hearing threshold level at the high frequencies was 42.1 ± 17.4 dB HL. Workers exposed to non-Gaussian noise had a higher risk of developing HFNIHL than those not exposed to noise (overall-weighted odds ratio [OR] = 4.46) or those exposed to Gaussian noise (overall-weighted OR = 2.20). The Chi-square trend test demonstrated that the prevalence of HFNIHL was positively correlated with age, cumulative noise exposure, and exposure duration (p < 0.001). CONCLUSIONS: Workers exposed to non-Gaussian noise suffered from greater NIHL than those exposed to Gaussian noise or not exposed to noise. Age, exposure duration, noise level, and noise temporal structure were the main risk factors for occupational NIHL. The A-weighted equivalent continuous sound pressure level (LAeq) is not a sufficient measurement metric for quantifying non-Gaussian noise exposure, and a combination of kurtosis and noise energy metrics (e.g., LAeq) should be used. It is necessary to reduce the exposure of non-Gaussian noise to protect the hearing health of workers.

Applying Kurtosis as an Indirect Metric of Noise Temporal Structure in the Assessment of Hearing Loss Associated With Occupational Complex Noise Exposure.

OBJECTIVE: The association of occupational noise-induced hearing loss (NIHL) with noise energy was well documented, but the relationship between occupational noise and noise temporal structure is rarely reported. The objective of this study was to investigate the principal characteristics of the relationship between occupational NIHL and the temporal structure of noise. METHODS: Audiometric and shift-long noise exposure data were collected from 3102 Chinese manufacturing workers from six typical industries through a cross-sectional survey. In data analysis, A-weighted 8-h equivalent SPL (LAeq.8h), peak SPL, and cumulative noise exposure (CNE) were used as noise energy indicators, while kurtosis (ß) was used as the indicator of noise temporal structure. Two NIHL were defined: (1) high-frequency noise-induced hearing loss (HFNIHL) and (2) noise-induced permanent threshold shift at test frequencies of 3, 4, and 6 kHz (noise-induced permanent threshold shift [NIPTS346]). The noise characteristics of different types of work and the relationship between these characteristics and the prevalence of NIHL were analyzed. RESULTS: The noise waveform shape, with a specific noise kurtosis, was unique to each type of work. Approximately 27.92% of manufacturing workers suffered from HFNIHL, with a mean NIPTS346 of 24.16 ± 14.13 dB HL. The Spearman correlation analysis showed that the kurtosis value was significantly correlated with the difference of peak SPL minus its LAeq.8h across different types of work (p < 0.01). For a kurtosis-adjusted CNE, the linear regression equation between HFNIHL% and CNE for complex noise almost overlapped with Gaussian noise. Binary logistic regression analysis showed that LAeq.8h, kurtosis, and exposure duration were the key factors influencing HFNIHL% (p < 0.01). The notching extent in NIPTS at 4 kHz became deeper with the increase in LAeq.8h and kurtosis. HFNIHL% increased most rapidly during the first 10 years of exposure. HFNIHL% with ß ≥ 10 was significantly higher than that with ß < 10 (p < 0.05), and it increased with increasing kurtosis across different CNE or LAeq.8h levels. When LAeq.8h was 80 to 85 dB(A), the HFNIHL% at ß ≥ 100 was significantly higher than that at 10 ≤ ß < 100 or ß < 10 (p < 0.05 and p < 0.01, respectively). CONCLUSIONS: In the evaluation of hearing loss caused by complex noise, not only noise energy but also the temporal structure of noise must be considered. Kurtosis of noise is an indirect metric that is sensitive to the presence of impulsive components in complex noise exposure, and thus, it could be useful for quantifying the risk for NIHL. It is necessary to re-evaluate the safety of permissible exposure limit of 85 dB(A) as noise with a high kurtosis value can aggravate or accelerate early NIHL.

Persistent high PM2.5 pollution driven by unfavorable meteorological conditions during the COVID-19 lockdown period in the Beijing-Tianjin-Hebei region, China.

Lockdown measures to curtail the COVID-19 pandemic in China halted most non-essential activities on January 23, 2020. Despite significant reductions in anthropogenic emissions, the Beijing-Tianjin-Hebei (BTH) region still experienced high air pollution concentrations. Employing two emissions reduction scenarios, the Community Multiscale Air Quality (CMAQ) model was used to investigate the PM2.5 concentrations change in this region. The model using the scenario (C3) with greater traffic reductions performed better compared to the observed PM2.5. Compared with the no reductions base-case (scenario C1), PM2.5 reductions with scenario C3 were 2.70, 2.53, 2.90, 2.98, 3.30, 2.81, 2.82, 2.98, 2.68, and 2.83 µg/m3 in Beijing, Tianjin, Shijiazhuang, Baoding, Cangzhou, Chengde, Handan, Hengshui, Tangshan, and Xingtai, respectively. During high-pollution days in scenario C3, the percentage reductions in PM2.5 concentrations in Beijing, Tianjin, Shijiazhuang, Baoding, Cangzhou, Chengde, Handan, Hengshui, Tangshan, and Xingtai were 3.76, 3.54, 3.28, 3.22, 3.57, 3.56, 3.47, 6.10, 3.61, and 3.67%, respectively. However, significant increases caused by unfavorable meteorological conditions counteracted the emissions reduction effects resulting in high air pollution in BTH region during the lockdown period. This study shows that effective air pollution control strategies incorporating these results are urgently required in BTH to avoid severe pollution.

Development and validation of a magnetic resonance imaging-based nomogram for predicting invasive forms of placental accreta spectrum disorders.

AIM: The aim of the study was to develop and validate a magnetic resonance imaging (MRI)-based nomogram for predicting invasive forms of placental accreta spectrum (PAS) disorders (placenta increta and percreta) with "uncertain ultrasound diagnosis." METHODS: This was a retrospective cohort study of a primary cohort of 118 patients and a validation cohort of 65 patients with "uncertain ultrasound diagnosis," who were further evaluated by MRI. MRI signs associated with PAS disorders were analyzed between invasive and noninvasive groups by both univariate and logistic regression to construct the nomogram. The accuracy and discriminative ability of the nomogram were measured by concordance index (C-index) and calibration curve internally and externally. RESULTS: The history of previous cesarean deliveries (odds ratio [OR], 3.27; 95% confidence interval [CI], 1.16-9.27), loss of double-line sign (OR, 9.49; 95% CI, 3.06-29.48), abnormal uterine bulging (OR, 4.05; 95% CI, 1.53-10.69), and disorganized abnormal placenta vascularity (OR, 3.38; 95% CI, 1.09-10.50) were imputed for the nomogram. The C-index of the nomogram was 0.85 for internal validation and 0.84 for external validation. Calibration curve showed good agreement with predicted risk and actual observation for both primary and validation cohort. CONCLUSIONS: MRI can be a useful adjunct for clinical staging of patients with "uncertain ultrasound diagnosis."

Design, synthesis and evaluation of 2-amino-imidazol-4-one derivatives as potent ß-site amyloid precursor protein cleaving enzyme 1 (BACE-1) inhibitors.

Inhibition of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) to prevent brain ß-amyloid (Aß) peptide's formation is a potential effective approach to treat Alzheimer's disease. In this report we described a structure-based optimization of a series of BACE1 inhibitors derived from an iminopyrimidinone scaffold W-41 (IC50 = 7.1 µM) by Wyeth, which had good selectivity and brain permeability but low activity. The results showed that occupying the S3 cavity of BACE1 enzyme could be an effective strategy to increase the biological activity, and five compounds exhibited stronger inhibitory activity and higher liposolubility than W-41, with L-5 was the most potent inhibitor against BACE1 (IC50 = 0.12 µM, logP = 2.49).

Assessing Contributions of Agricultural and Nonagricultural Emissions to Atmospheric Ammonia in a Chinese Megacity.

Ammonia (NH3) is the predominant alkaline gas in the atmosphere contributing to formation of fine particles-a leading environmental cause of increased morbidity and mortality worldwide. Prior findings suggest that NH3 in the urban atmosphere derives from a complex mixture of agricultural (mainly livestock production and fertilizer application) and nonagricultural (e.g., urban waste, fossil fuel-related emissions) sources; however, a citywide holistic assessment is hitherto lacking. Here we show that NH3 from nonagricultural sources rivals agricultural NH3 source contributions in the Shanghai urban atmosphere. We base our conclusion on four independent approaches: (i) a full-year operation of a passive NH3 monitoring network at 14 locations covering urban, suburban, and rural landscapes; (ii) model-measurement comparison of hourly NH3 concentrations at a pair of urban and rural supersites; (iii) source-specific NH3 measurements from emission sources; and (iv) localized isotopic signatures of NH3 sources integrated in a Bayesian isotope mixing model to make isotope-based source apportionment estimates of ambient NH3. Results indicate that nonagricultural sources and agricultural sources are both important contributors to NH3 in the urban atmosphere. These findings highlight opportunities to limit NH3 emissions from nonagricultural sources to help curb PM2.5 pollution in urban China.

Predicting Selection Preference of Robotic Pancreaticoduodenectomy (RPD) in a Chinese Single Center Population: Development and Assessment of a New Predictive Nomogram.

BACKGROUND Robotic pancreaticoduodenectomy (RPD) is a novel type of minimally invasive surgery to treat tumors located at the head of the pancreas. This study aimed to construct a novel prediction model for predicting selection preference for RPD in a Chinese single medical center population. MATERIAL AND METHODS The clinical data from 451 pancreatic ductal adenocarcinoma patients were collected and analyzed from January 2013 to December 2016. Twenty-three items affecting clinical strategies were optimized by LASSO (least absolute shrinkage and selection operator) regression analysis and then were incorporated in multivariable logistic regression analysis. C-index was used for evaluating the discriminative ability. Decision curve was applied to determine clinical application of this model and the calibration of this nomogram was evaluated by calibration plot. The model was internally validated through bootstrapping validation. RESULTS Clinicopathological factors included in the model were age, history of diabetes mellitus, history of hypertension, history of heart, brain and kidney disease, history of abdominal surgery, symptoms (jaundice, accidental discovery and weight loss), anemia, elevated carcinoembryonic antigen (CEA), smoking, alcohol intake, American Society of Anesthesiologists (ASA) scores, vascular invasion, overweight, preoperative lymph node metastasis and tumor size >3.5 cm. A C-index of 0.831 indicated good discrimination and calibration of this model. Interval validation generated an acceptable C-index of 0.787. When surgical approach was determined at the threshold of preference possibility less than 63%, decision curve analysis indicated that this model had good clinical application value in this range. CONCLUSIONS This new nomogram could be conveniently used to predict the selection preference of robotic surgery for patients with pancreatic head cancer.

A novel and efficient synthesis of phenanthrene derivatives via palladium/norbornadiene-catalyzed domino one-pot reaction.

Herein we report a novel palladium-catalyzed reaction that results in phenanthrene derivatives using aryl iodides, ortho-bromobenzoyl chlorides and norbornadiene in one pot. This dramatic transformation undergoes ortho-C-H activation, decarbonylation and subsequent a retro-Diels-Alder process. Pleasantly, this protocol has a wider substrate range, shorter reaction times and higher yields of products than previously reported methods.

Design, synthesis and structure-activity relationship of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure as multi-target inhibitors against receptor tyrosine kinase.

Inspired by that the multi-target inhibitors against receptor tyrosine kinases (RTKs) have significantly improved the effect of clinical treatment for cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (FLT-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor ß (PDGFR-ß) with its IC50 values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several cancer cells.

Protective effect of 6-O-methyl-scutellarein on repeated cerebral ischemia/reperfusion in rats.

Scutellarin (1) possesses protective effects against neuronal injury, while 6-O-methyl-scutellarein (3), as the main metabolite of scutellarin in vivo, has not been reported about its protective effects previously. The present study mainly investigated whether the neural injury caused by ischemia/reperfusion would be influenced by different doses of 6-O-methyl-scutellarein (3). The results of behavioral, neurological, and histological examinations indicated that 6-O-methyl-scutellarein (3) could improve neuronal injury, and exhibit significant difference among the various doses. More importantly, 6-O-methyl-scutellarein (3) had better protective effects than scutellarin in rat cerebral ischemia.