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Background: MicroRNA (miR)-21 is overexpressed in numerous types of malignancy and participates in the development of cancer. However, the basic mechanism of the influence of miR-21 on the malignant phenotype of pancreatic cancer remains unclear. Purpose: The present study aimed to investigate the role of miR-21 in pancreatic cancer development and explore its molecular mechanism. Patients and methods: The tissue samples were collected at the Second Hospital of Tianjin Medical University (Tianjin, China) between January 2013 and December 2015. The expression of VHL in tissue samples was evaluated by IHC staining. The expression of miR-21 was measured by quantitative real-time polymerase chain reaction (qRT-PCR). MiR-21 target gene was detected by real-time PCR, Western blot and the luciferase reporter assay. Cell viability, cell proliferation, cell migration and invasion were evaluated by the MTT assays, the colony formation assays and the transwell assays. The nude mouse tumor xenograft model was performed to detect the effect of miR-21 on tumor growth in vivo. Results: Von Hippel-Lindau tumor suppressor (VHL) was downregulated in pancreatic cancer tissues compared with pancreatic non-tumor tissues. VHL was identified as a novel direct target of miR-21, by which it is negatively regulated. In PANC-1 cells, inhibition of miR-21 and upregulation of VHL significantly suppressed cell proliferation, migration and invasion. Knockdown of miR-21 inhibited the hypoxia-inducible factor (HIF)-1α/vascular endothelial growth factor (VEGF) pathway, while inhibiting the expression of matrix metallopeptidase (MMP)-2 and MMP-9. Silencing of miR-21 inhibited tumor growth in vivo. Conclusion: Knockdown miR-21 increased the expression of VHL, and thus modulated the HIF-1α/VEGF pathway and the expression of MMP-2 and MMP-9, which led to the inhibition of the proliferation, migration and invasion of pancreatic cancer cells. All of these results suggest that the miR-21/VHL interaction may be a novel potential target for pancreatic cancer prevention and therapy. [ABSTRACT FROM AUTHOR]

Abstract The North China Plain and the Yangtze River Delta are the two of the most heavily polluted regions in China. Observational studies revealed that 'explosive' PM 2.5 mass concentration growths frequently occurred in the two regions. This study analyzed all the PM 2.5 mass concentration growth processes from clean condition (i.e., <35 μg m−3) to heavy pollution condition (i.e., >150 μg m−3) in Beijing (BJ) and Shanghai (SH), two representative cities of the two regions, using hourly monitored PM 2.5 concentrations during 2013–2016. 173 and 76 growth processes were identified in BJ and SH, respectively. PM 2.5 rising rates (PMRR) and dynamic growth durations were calculated to illustrate the characteristics of the growth processes. Hourly particulate chemical composition data and meteorological data in BJ and SH were further analyzed. The 4-year averaged PMRR of PM 2.5 total mass were similarly of 7.11 ± 9.82 μg m−3 h−1 in BJ and 6.71 ± 6.89 μg m−3 h−1 in SH. A decreasing trend was found for the PM 2.5 growth processes in two cities from 2013 to 2016, reflecting the effectiveness of emission controls implemented in the past years. The contributions of particulate components to the PM 2.5 total mass growth were different in BJ and SH. Average PMRR value of PM 1 organic aerosols (OA), SO 4 2−, NO 3 −, and NH 4 + in BJ was 1.90, 0.95, 0.82, and 0.53 μg m−3 h−1, respectively. Average PMRR of PM 2.5 OA, SO 4 2−, NO 3 −, and NH 4 + in SH was 1.70, 1.18, 1.99 and 1.14 μg m−3 h−1, respectively. Based on the contributions of different components, the PM 2.5 mass concentration growth processes in BJ and SH were proposed to be classified into 'other components-dominant growth processes', 'all components-contributing growth processes', 'one or more explosive secondary components-dominant growth processes', and 'mixed-factor growth processes'. Potential source contribution function analysis and the meteorological condition analysis showed that source origins and prevailing wind for the two cities during different categories of growth processes had substantial difference. The important source areas included Hebei and Shandong for BJ, and Jiangsu and Anhui for SH. The dominant wind directions during growth processes were northeast, south and southwest in BJ, and were west to north in SH. The results suggested the contributing components, the prevailing wind conditions, and the formation processes were substantially different in the two cities, despite the similar PMRR of PM 2.5 total mass during the growth processes between BJ and SH. Future research is needed to study the detailed formation mechanisms of the different PM 2.5 mass concentration growth processes in the two cities. Highlights • PM 2.5 growth processes during 2013–2016 in the NCP and YRD region of China were investigated. • 4-year averaged PMRRs of PM 2.5 total mass are 7.07 ± 8.42 μg m−3 h−1 in BJ and 6.60 ± 5.99 μg m−3 h−1 in SH. • Organic aerosol is more important in BJ, while nitrate is more important in SH. • The PM2.5 growth processes in BJ and SH are proposed to be classified into four general categories. [ABSTRACT FROM AUTHOR]

PM 2.5 and O 3 controls are traditionally considered separately because PM 2.5 is usually high in winter while O 3 is generally high in summer. In this study, we explore the opportunity of controlling the two pollutants simultaneously through a better understanding of their intra-seasonal correlation and chemical-coupling behaviors under different meteorological conditions during the late summer and early fall (August–September) episodes in the San Joaquin Valley (SJV), California. A correlation analysis is first used to identify the temporal correlations between O 3 and PM 2.5 and their underlying physical and chemical drivers. Sensitivity analysis is then applied to determine the chemical coupling between PM 2.5 and O 3 and subsequent multipollutant control opportunities under two contrasting meteorological conditions using the Community Multi-Scale Air Quality (CMAQ) model. We find that O 3 and PM 2.5 are positively correlated on the daily timescale because both are sensitive to atmospheric stagnation. However, O 3 and PM 2.5 are negatively correlated on the hourly timescale determined by the negative correlation between hourly NO 3 − and O 3 , which is mainly due to the opposite effects of T and RH on the diurnal variations of NO 3 − and O 3. Reducing NO x on average lead to O 3 increase, but it can facilitate reducing O 3 at higher O 3 (>75 ppb) locations under the more stagnant conditions. NO x emission control could become beneficial for both O 3 and PM 2.5 when the NO x emissions in 2005 are further reduced by 15% under the more stagnant meteorological conditions and by 30% under the more ventilated meteorological conditions. [Display omitted] • High PM2.5 and O3 tend to occur together in SJV under stagnant conditions in late summer and early fall. • O3 and PM2.5 are positively correlated on the daily timescale, but negatively correlated on the hourly timescale. • Negative correlation between hourly PM2.5 and O3 is mainly driven by the opposite effects of T and RH. • NOx control can effectively reduce PM2.5, but on average has a disbenefit effect to O3 at the high PM locations. • Further 30% NOx reductions from 2005 emission level can become beneficial for both O3 and PM2.5 in SJV. [ABSTRACT FROM AUTHOR]

Laparoscopic cholecystectomy is considered the most effective treatment for gallstones. However, there is no agreement on the treatment of common bile duct stones, which are a common cause of abdominal pain. This article aims to evaluate and analyze the results of common bile duct exploration in elderly patients and compare the results of open and laparoscopic groups. We analyzed a case series of all elderly patients over 70 years who underwent common bile duct exploration in the Department of Hepatobiliary and Pancreatic Surgery between January 2020 and February 2021. All the operating procedures were carried out by the same surgical team. A total of 104 common bile duct explorations were performed on elderly patients with a mean age of 77.4 years (range, 70–87 years). Of these, 50 patients were in the open common bile duct exploration group, while the laparoscopic common bile duct exploration group included 54 patients, with 7 patients converted to open surgery and excluded from analysis. There were no statistically significant differences between the two groups in terms of risk factors before operation, such as hypertension, diabetes, heart diseases, cerebral vascular disease, and previous abdominal surgery. The duration of surgery for the laparoscopic common bile duct exploration group was significantly shorter than that of the open common bile duct exploration group (149.3 ± 49.0 min versus 191.7 ± 109.9 min; p = 0.015). Moreover, the laparoscopic common bile duct exploration group had a shorter postoperative hospital stay than the open common bile duct exploration group (10.6 ± 4.9 days versus14.0 ± 6.8 days; p = 0.006). Postoperative complications in the open common bile duct exploration group were higher than in the laparoscopic common bile duct exploration group. Laparoscopic common bile duct exploration can be considered a safe and effective treatment for elderly patients with common bile duct stones, not only for young people. Chinese Clinical Trial Registry Unique Identifying Number (UIN): ChiCTR2300071182 (https://www.chictr.org.cn/bin/project/edit?pid=188505). [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) may play a role in oxidative stress by altering the tumor microenvironment, thereby affecting pancreatic cancer progression. There is currently limited information on oxidative stress-related lncRNAs as novel prognostic markers of pancreatic cancer. Gene expression and clinical data of patients with pancreatic cancer were downloaded from The Cancer Genome Atlas (TCGA-PAAD) and the International Cancer Genome Consortium (ICGC-PACA) database. A weighted gene co-expression network analysis (WGCNA) was constructed to identify genes that were differentially expressed between normal and tumor samples. Based on the TCGA-PAAD cohort, a prediction model was established using lasso regression and Cox regression. The TCGA-PAAD and ICGC-PACA cohorts were used for internal and external validation, respectively. Furthermore, a nomogram based on clinical characteristics was used to predict mortality of patients. Differences in mutational status and tumor-infiltrating immune cells between risk subgroups were also explored and model-based lncRNAs were analyzed for potential immune-related therapeutic drugs. A prediction model for 6-lncRNA was established using lasso regression and Cox regression. Kaplan–Meier survival curves and receiver operating characteristic (ROC) curves indicated that patients with lower risk scores had a better prognosis. Combined with Cox regression analysis of clinical features, risk score was an independent factor predicting overall survival of patients with pancreatic cancer in both the TCGA-PAAD and ICGC-PACA cohorts. Mutation status and immune-related analysis indicated that the high-risk group had a significantly higher gene mutation rate and a higher possibility of immune escape, respectively. Furthermore, the model genes showed a strong correlation with immune-related therapeutic drugs. A pancreatic cancer prediction model based on oxidative stress-related lncRNA was established, which may be used as a biomarker related to the prognosis of pancreatic cancer to evaluate the prognosis of pancreatic cancer patients. [ABSTRACT FROM AUTHOR]

Southeastern Tibet is one of the most glaciated regions on the Tibetan Plateau both at present and during the Quaternary. Numerical dating of glacial deposits has allowed the establishment of a provisional chronology of Quaternary glacial fluctuations in this region, with the oldest glaciation (Guxiang Glaciation) occurring in marine oxygen isotope stage 6 (MIS-6). During our recent field investigations, a morphostratigraphically older lateral moraine than that of the Guxiang Glaciation has been first identified, which is ∼500–600 m above the Guxiang Glaciation moraine and discontinuously preserved on valley shoulders in the Bodui Zangbo River valley, eastern Nyainqêntanglha Range in southeastern Tibet. Considering the moraine is best preserved at Nitong Village, here we name the glacier advance which deposited the moraine as "Nitong Glaciation". Using electron spin resonance (ESR) technique, we dated the Nitong Glaciation moraine to 506.3±60.4 ka. Taking into account the age error and climatic conditions, we consider it most likely that the Nitong Glaciation occurred during MIS-12, although it might had happened sometime earlier. [ABSTRACT FROM AUTHOR]

Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1H-pyrazolo[3,4-d]pyrimidine dual ERK/PI3K inhibitors. Compound 32d was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound 32d possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that 32d was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors. [ABSTRACT FROM AUTHOR]

Epidemiological studies have shown that fine particulate matter (PM 2.5) has adverse impacts on human health. However, limited studies have investigated the effects of short-term exposure to PM 2.5 and its constituents on mortality in China. This study used the generalized linear model (GLM) to investigate the effects of PM 2.5 and its constituents, including organic carbon (OC), element carbon (EC), ammonium (NH 4 +), nitrate (NO 3 −), sulfate (SO 4 2−), on different causes of mortality in Shanghai from January 1, 2013 to December 31, 2015. The single-day lagged model and the moving average lagged model were used to examine the lagging effects of pollutants on mortality. At lag0 day, PM 2.5 had a significant effect on all-cause mortality, and a 10 μg/m3 increase leads to 0.68% increase in all-cause mortality (RR 1.0068, 95%CI 1.0013–1.0123). Among the five constituents, EC had the greatest impact on all-cause mortality in Shanghai, with 10.48% increase of mortality (RR 1.1048, 95%CI 1.0266–1.1891) per 10 μg/m3 increase of concentrations, followed by OC (RR 1.0577, 95%CI 1.0277–1.0886), NH 4 + (RR 1.0272, 95%CI 1.0028–1.0522) and SO 4 2− (RR 1.0104, 95%CI 1.0003–1.0206). For respiratory diseases mortality, EC, OC, NO 3 − and NH 4 + had significant impacts and caused an increase of mortality by 44.99% (RR 1.4499, 95%CI 1.1813–1.7794), 10.40% (RR 1.1040, 95%CI 1.0260–1.1880), 5.338% (RR 1.0533, 95%CI 1.0097–1.0989) and 7.34% (RR 1.0734, 95%CI 1.0015–1.1505) per 10 μg/m3 increase of concentrations, respectively. The cumulative effect of PM 2.5 on mortality was significant in Shanghai. Except for SO 4 2−, the RR value of the single-day lagged model was smaller than the moving average lagged model. • PM2.5 was associated with all-cause mortality and respiratory disease mortality in Shanghai. • EC had the highest relative risk for all-cause mortality among the constituents. • The risk of PM2.5 constituents on respiratory mortality was higher than that of circulatory mortality. • The relative risk value of the single-day lagged model was smaller than the moving average lagged model. [ABSTRACT FROM AUTHOR]

The peroxisome serves a significant role in the occurrence and development of cancers. Specifically, the peroxisomal biogenesis factor 13 (PEX13) is crucial to the occurrence of peroxisomes. However, the biological function of PEX13 in cancers remains unclear. To address this, various portals and databases such as The Cancer Genome Atlas Program, The Genotype-Tissue Expression project, the Gene Expression Profiling Interactive Analysis 2, cBioPortal, the Genomic Identification of Significant Targets In Cancer 2.0, Tumor Immune Estimation Resource 2, SangerBox, LinkedOmics, DAVID and STRING were applied to extract and analyze PEX13 data in tumors. The correlations between PEX13 and prognosis, genetic alterations, PEX13-related gene enrichment analysis, weighted gene co-expression network analysis (WGCNA), protein interaction, long non-coding (lnc)RNA/circular (circ)RNA-micro (mi)RNA network and tumor immunity were explored in various tumors. The lncRNA-miRNA-PEX13 and circRNA-miRNA-PEX13 regulatory networks were identified via miRabel, miRDB, TargetScan and ENCORI portals and Cytoscape tool. In vitro assays were applied to verify the biological functions of PEX13 in pancreatic adenocarcinoma (PAAD) cells. The findings revealed that PEX13 is upregulated in various tumors and high PEX13 mRNA expression is associated with poor prognosis in patients with multiple cancers. Genetic alterations in PEX13 such as amplification, mutation and deep deletion have been found in multiple cancers. PEX13-related genes were associated with T cell receptor, signaling pathway and hippo signaling pathway through 'biological process' subontology of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Through WGCNA analysis, it was discovered that PEX13 hub genes were mainly enriched in the Rap1, ErbB and AMPK signaling pathways in PAAD. Immune analysis showed that PEX13 was significantly related to tumor infiltration immune cells, immune checkpoint genes, microsatellite instability, TMB and tumor purity in a variety of tumors. Cell Counting Kit-8, wound healing, Transwell and colony formation assays displayed that PEX13 knockdown could suppress PAAD cell proliferation, migration, invasion, and colony formation in vitro, respectively. Overall, PEX13 is a potential predictor of immunotherapeutic and prognostic biomarkers in various malignant tumors, including ACC, KICH, LGG, LIHC and PAAD. [ABSTRACT FROM AUTHOR]

A major tool for curtailing the spread of COVID-19 pandemic in China was a nationwide lockdown implemented by the Chinese authorities, which also led to significant reductions in anthropogenic emissions and fine particulate matter (PM 2.5) concentrations. However, the lockdown measures did not prevent high PM 2.5 pollution episodes (EPs). Three severe EPs were identified in the Beijing-Tianjin-Hebei (BTH) region during the lockdown. The integrated process rate (IPR) analysis tool in the Community Multiscale Air Quality (CMAQ) model was employed to identify and quantify the contributions of individual atmospheric processes to PM 2.5 formation during the EPs in four representative cities (Beijing, Tianjin, Shijiazhuang, and Baoding) of the BTH. The influence of meteorological conditions on the accumulation and dispersion of PM 2.5 during the EPs was also elucidated. The results of the IPR showed that emissions and aerosol processes were the dominant sources of net surface PM 2.5 in Beijing and Tianjin, constituting a total of 86.2% and 92.9%, respectively, while emissions, horizontal transport, and aerosol processes dominated the net surface PM 2.5 formation in Shijiazhuang and Baoding. In addition, the three pollution episodes in Beijing and Tianjin were primarily driven by local emissions, while the pollution events in Shijiazhuang and Baoding were attributed to the combined local emissions and regional transport. Also, the EPs were driven by low planetary boundary layer heights, low vertical export of PM 2.5 from the boundary layer to the free troposphere, and substantial horizontal import, especially in Shijiazhuang and Baoding. Furthermore, the elevated PM 2.5 concentrations during the EPs were greatly enhanced by unfavorable meteorological conditions, with the first two EPs being characterized with low ventilation coefficient (VC) values in the four representative cities. This study improves the understanding of buildup of PM 2.5 during the pollution episodes, and the results provide insights for designing more effective emissions control strategies to mitigate future PM 2.5 pollution episodes. [Display omitted] • Emissions and aerosol processes dominated the surface PM 2.5 in Beijing and Tianjin. • The episodes in Shijiazhuang and Baoding were due to local emissions and horizontal transport. • Horizontal transport dominated PM 2.5 formation in Shijiazhuang during the episodes. • Vertical transport was the dominant sink of PM 2.5 during the pollution episodes. [ABSTRACT FROM AUTHOR]

Star-branched amphiphilic copolymer nanocarriers with high-density zwitterionic shell show great promise in drug delivery due to their controllable small size and excellent anti-biofouling properties. This gives the hydrophobic cargo with high stability and long blood circulation in vivo . In the present study, star-branched polylactic acid and poly(2-methacryloyloxyethyl phosphorylcholine) copolymers with (AB 3 ) 3 –type architecture (PLA- b -PMPC 3 ) 3 were conceived as drug vectors, and the copolymers were synthesized by an “arm-first” approach via the combination of ring opening polymerization (ROP), atom transfer radical polymerization (ATRP) and the click reaction. The self-assembled star-branched copolymer micelles (sCPM) had an average diameter of about 64.5 nm and exhibited an ultra-hydrophilic surface with an ultralow water contact angle of about 12.7°, which efficiently suppressed the adhesion of serum proteins. In vivo experiments showed that the sCPM loading strongly enhanced the blood circulation time of DiI and the plasma half-life of DiI in sCPM was 19.3 h. The relative accumulation concentration in tumor of DiI delivered by sCPM was 2.37-fold higher than that of PLA-PEG, at 4 h after intravenous injection. These results demonstrated that the star-branched copolymer (PLA- b -PMPC 3 ) 3 is a promising alternative carrier material for intravenous delivery versus classic PEG-modified strategies. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effects of myocardial injury in a minimally-invasive miniature swine model with different levels of coronary artery stenosis (CAS) and exposed to maximal tolerated +Gz. Proximal left anterior descending branch was ligated in 20 swine. Five swine underwent a sham operation. A trapezoid acceleration curve was used for +Gz stress. Pathological changes of myocardial tissue were detected by H&E staining. Apoptotic cardiomyocytes were detected by TUNEL. GRP78 and CHOP were investigated by immunohistochemistry and western blot. CAS models were successful in 18 animals.Compared with the sham-operated group (+8.00±0.71 Gz), the maximal tolerated +Gz values of the moderate stenosis (+6.00±0.89 Gz, P<0.05) and severe stenosis groups (+5.20±0.84 Gz, P<0.05) were decreased.Compared with sham animals (12.16±1.25%), after exposure to maximum +Gz, apoptotic cells of the moderate (43.53±8.42%, P<0.05) and severe stenosis group (60.50±9.35%, P<0.05) were increased, MDA content was increased (1.89 and 4.91 folds, respectively, P<0.05), and SOD activity was reduced (-13.66% and -21.71%, respectively). After exposure to maximum +Gz, GRP78 protein expression was low in the sham-operated (0.29±0.05) and mild stenosis groups (0.35±0.04), while expression was high in the moderate (0.72±0.04, P<0.05) and severe stenosis groups (0.65±0.07, P<0.05). CHOP protein expression was not observed in the sham-operated group, while expression was high in the moderate and severe stenosis groups. These results indicated that Under maximum exposure to +Gz stress, different levels of CAS led to different levels of myocardial injury. Endoplasmic reticulum response is involved in the apoptosis of cardiomyocytes after +Gz stress. [ABSTRACT FROM AUTHOR]

• 178 nitrate modeling studies in China published during 2007–2021 were reviewed. • Model performance on nitrate and possible reasons for model-observation biases were summarized. • The contribution of N 2 O 5 heterogeneous chemistry to nitrate varies from 21.0% to 51.6% among studies. • Decreased SO 2 emission, enhanced AOC, and weakened deposition account for increasing PM 2.5 nitrate fraction. • Multiple-pollutant control strategies involving NH 3 , NO x , and VOCs are needed to mitigate nitrate pollution. Particulate nitrate (pNO 3) is now becoming the principal component of PM 2.5 during severe winter haze episodes in many cities of China. To gain a comprehensive understanding of the key factors controlling pNO 3 formation and driving its trends, we reviewed the recent pNO 3 modeling studies which mainly focused on the formation mechanism and recent trends of pNO 3 as well as its responses to emission controls in China. The results indicate that although recent chemical transport models (CTMs) can reasonably capture the spatial–temporal variations of pNO 3 , model-observation biases still exist due to large uncertainties in the parameterization of dinitrogen pentoxide (N 2 O 5) uptake and ammonia (NH 3) emissions, insufficient heterogeneous reaction mechanism, and the predicted low sulfate concentrations in current CTMs. The heterogeneous hydrolysis of N 2 O 5 dominates nocturnal pNO 3 formation, however, the contribution to total pNO 3 varies among studies, ranging from 21.0% to 51.6%. Moreover, the continuously increasing PM 2.5 pNO 3 fraction in recent years is mainly due to the decreased sulfur dioxide emissions, the enhanced atmospheric oxidation capacity (AOC), and the weakened nitrate deposition. Reducing NH 3 emissions is found to be the most effective control strategy for mitigating pNO 3 pollution in China. This review suggests that more field measurements are needed to constrain the parameterization of heterogeneous N 2 O 5 and nitrogen dioxide (NO 2) uptake. Future studies are also needed to quantify the relationships of pNO 3 to AOC, O 3 , NOx, and volatile organic compounds (VOCs) in different regions of China under different meteorological conditions. Research on multiple-pollutant control strategies involving NH 3 , NO X, and VOCs is required to mitigate pNO 3 pollution, especially during severe winter haze events. [ABSTRACT FROM AUTHOR]