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The exact place for selective internal radiation therapy (SIRT) in the therapeutic algorithm for hepatocellular carcinoma (HCC) is debated. There are limited data on its indications, efficacy, and safety in Australia.We performed a multicenter retrospective cohort study of patients undergoing SIRT for HCC in all Sydney hospitals between 2005 and 2019. The primary outcome was overall survival. Secondary outcomes were progression-free survival and adverse events.During the study period, 156 patients underwent SIRT across 10 institutions (mean age 67 years, 81% male). SIRT use progressively increased from 2005 (n = 2), peaking in 2017 (n = 42) before declining (2019: n = 21). Barcelona Clinic Liver Cancer stages at treatment were A (13%), B (33%), C (52%), and D (2%). Forty-four (28%) patients had tumor thrombus. After a median follow-up of 13.9 months, there were 117 deaths. Median overall survival was 15 months (95% confidence interval 11-19). Independent predictors of mortality on multivariable analysis were extent of liver involvement, Barcelona Clinic Liver Cancer stage, baseline ascites, alpha fetoprotein, and model for end-stage liver disease score. Median progression-free survival was 6.0 months (95% confidence interval 5.1-6.9 months). Following SIRT, 11% of patients were downstaged to curative therapy. SIRT-related complications occurred in 17%: radioembolization-induced liver disease (11%), pneumonitis (3%), gastrointestinal ulceration, and cholecystitis (1% each). Baseline ascites predicted for radioembolization-induced liver disease.We present the largest Australian SIRT cohort for HCC. We have identified several factors associated with a poor outcome following SIRT. Patients with early-stage disease had the best survival with some being downstaged to curative therapy.

In recent years, increasing evidence supports the notion that obesity risk is affected by residential greenness. However, limited studies have been established in low- and middle-income countries, especially in China. The study aimed to evaluate the associations of residential greenness with obesity and body mass index (BMI) level in Chinese rural-dwelling adults. A total of 39,259 adults from the Henan Rural Cohort Study (HRCS) were included in the analyses. According to the guideline for prevention and control of overweight and obesity in Chinese adults, obesity was defined as BMI ≥ 28 kg/m

Background Evidence remains limited and inconsistent for the associations between sustained air pollution exposures and diabetes development. This study aimed to determine the potential effects of particulate matter with a diameter of ≤10 micrometres (PM10), particulate matter with a diameter of ≤2.5 micrometres (PM2.5) and nitrogen dioxide (NO2) on alterations of fasting plasma glucose (FPG), glycated haemoglobin (HbA1c), in particular, on prevalence and incidence of diabetes. Methods Cross-sectional analyses were conducted based on 9628 participants aged ≥45 years from the baseline survey (2011) of the China Health and Retirement Longitudinal Study (CHARLS), whereas cohort analyses were based on 3510 individuals without diabetes at baseline in the third survey (2015). Residences of participants were geocoded and the air pollution exposures were estimated using a satellite-based spatiotemporal model. Linear, logistic and modified Poisson regression models, adjusting for multiple confounders, were applied to assess the associations between air pollution and FPG, HbA1c, prevalence and incidence of diabetes, respectively. Results Associations between PM10, PM2.5 and increased levels of FPG and HbA1c were identified. The levels of FPG and HbA1c increased by 0.025 mmol/L (95% CI: 0.007, 0.044) and 0.011 mmol/L (95% CI: 0.002, 0.019), respectively, for a 10-μg/m3 increase in PM10, and the levels of FPG and HbA1c increased by 0.061 mmol/L (95% CI: 0.028, 0.096) and 0.016 mmol/L (95% CI: 0.000, 0.031), respectively, for a 10-μg/m3 increase in PM2.5. There were also positive associations between diabetes prevalence and PM2.5 and PM10. In the cohort analyses, PM10, PM2.5 and NO2 were associated with a higher incidence of diabetes. Conclusion Air pollution was allied to diabetes development in elderly Chinese populations. Considering the impact of the dramatic increase in the incidence and prevalence of diabetes in China, interventions to improve air quality are urgently needed. This is a pre-copyedited, author-produced PDF of an article accepted for publication in International Journal of Epidemiology following peer review. The version of record [Sustained air pollution exposures, fasting plasma glucose, glycated haemoglobin, prevalence and incidence of diabetes: a nationwide study in China. International Journal of Epidemiology 51, 6 p1862-1873 (2022)] is available online at: https://doi.org/10.1093/ije/dyac162. Deposited by shareyourpaper.org and openaccessbutton.org. We've taken reasonable steps to ensure this content doesn't violate copyright. However, if you think it does you can request a takedown by emailing help@openaccessbutton.org.

BACKGROUND Endothelium injury and coagulation dysfunction play an important role in the pathogenesis of sepsis. Soluble thrombomodulin (sTM), tissue plasminogen activator-inhibitor complex (t-PAIC), thrombin-antithrombin complex (TAT) and α2-plasmin inhibitor-plasmin complex (PIC) are biomarkers of endothelium injury and coagulation dysfunction. This study aimed to explore the prognostic values and diagnostic performance for septic shock and sepsis-induced disseminated intravascular coagulation (DIC) of endothelial biomarkers. METHODS We conducted an observational study on patients with sepsis admitted to intensive care unit (ICU) at a teaching hospital from January 2016 to December 2018. Levels of sTM, t-PAIC, TAT and PIC were measured at admission day and day 5-7 after admission and detected by qualitative chemiluminescence enzyme immunoassay performed on HISCL automated analyzers. RESULTS A total of 179 septic patients and 125 non-septic ICU controls were enrolled. The level of sTM was higher in septic patients compared to ICU controls (OR =1.093, 95% CI: 1.045-1.151, P

ObjectiveCirculating tumour DNA (ctDNA) sequencing is increasingly used in the clinical management of patients with colorectal cancer. However, the genomic heterogeneity in ctDNA during treatments and its impact on clinical outcomes remain largely unknown.DesignWe conducted a prospective cohort study (NCT04228614) of 171 patients with unresectable metastatic colorectal cancer (mCRC) who underwent first-line treatment and prospectively collected blood samples with or without tumour samples from patients at baseline and sequentially until disease progression or last follow-up.ResultsThe RAS/BRAF alterations in paired baseline tissue and plasma samples from 63 patients displayed a favourable concordance (81.0%, 51/63). After a period of first-line treatment (median time between baseline and last liquid biopsy, 4.67 months), 42.6% (26/61) of RAS-mutant patients showed RAS clearance and 50.0% (5/10) of BRAF-mutant patients showed BRAF clearance, while 3.6% (3/84) and 0.7% (1/135) of patients showed new RAS or BRAF mutations in ctDNA. Patients with plasma RAS/BRAF clearance showed similar progression-free survival (PFS) and overall survival (OS) with patients who remained RAS/BRAF wild-type, while much better outcomes than those who remained RAS/BRAF mutant. Patients who gained new RAS/BRAF mutations showed similar prognosis as those who maintained RAS/BRAF mutations, and shorter PFS and OS than those who remained RAS/BRAF wild-type.ConclusionThis prospective, serial and large-scale ctDNA profiling study reveals the temporal heterogeneity of mCRC-related somatic variants, which should be given special attention in clinical practice, as evidenced by the finding that the shift in plasma RAS/BRAF mutational status can yield a drastic change in survival outcomes.

Background Bipolar disorder (BD) is a highly heritable psychiatric illness exhibiting substantial correlation with intelligence. Methods To investigate the shared genetic signatures between BD and intelligence, we utilized the summary statistics from genome-wide association studies (GWAS) to conduct the bivariate causal mixture model (MiXeR) and conjunctional false discovery rate (conjFDR) analyses. Subsequent expression quantitative trait loci (eQTL) mapping in human brain and enrichment analyses were also performed. Results Analysis with MiXeR suggested that approximately 10.3K variants could influence intelligence, among which 7.6K variants were correlated with the risk of BD (Dice: 0.80), and 47% of these variants predicted BD risk and intelligence in consistent allelic directions. The conjFDR analysis identified 37 distinct genomic loci that were jointly associated with BD and intelligence with a conjFDR < 0.01, and 16 loci (43%) had the same directions of allelic effects in both phenotypes. Brain eQTL analyses found that genes affected by the “concordant loci” were distinct from those modulated by the “discordant loci”. Enrichment analyses suggested that genes related to the “concordant loci” were significantly enriched in pathways/phenotypes related with synapses and sleep quality, whereas genes associated with the “discordant loci” were enriched in pathways related to cell adhesion, calcium ion binding, and abnormal emotional phenotypes. Conclusions We confirmed the polygenic overlap with mixed directions of allelic effects between BD and intelligence and identified multiple genomic loci and risk genes. This study provides hints for the mesoscopic phenotypes of BD and relevant biological mechanisms, promoting the knowledge of the genetic and phenotypic heterogeneity of BD. The essential value of leveraging intelligence in BD investigations is also highlighted.

Cancer greatly affects the quality of life of humans worldwide and the number of patients suffering from it is continuously increasing. Over the last century, numerous treatments have been developed to improve the survival of cancer patients but substantial progress still needs to be made before cancer can be truly cured. In recent years, antitumor immunity has become the most debated topic in cancer research and the booming development of immunotherapy has led to a new epoch in cancer therapy. In this review, we describe the relationships between tumors and the immune system, and the rise of immunotherapy. Then, we summarize the characteristics of tumor‐associated immunity and immunotherapeutic strategies with various molecular mechanisms by showing the typical immune molecules whose antibodies are broadly used in the clinic and those that are still under investigation. We also discuss important elements from individual cells to the whole human body, including cellular mutations and modulation, metabolic reprogramming, the microbiome, and the immune contexture. In addition, we also present new observations and technical advancements of both diagnostic and therapeutic methods aimed at cancer immunotherapy. Lastly, we discuss the controversies and challenges that negatively impact patient outcomes., In this review, we present a clear view of the major factors and regulators associated with cancer immunotherapy and to provide our point of view on the latest available technologies and treatment methods for resolving clinical problems.

Background A critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking. Methods Clinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis. Results Among fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor. Conclusions EPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.

Background Previous studies have suggested that exposure to air pollution may increase stroke risk, but the results remain inconsistent. Evidence of more recent studies is highly warranted, especially gas air pollutants. Methods We searched PubMed, Embase, and Web of Science to identify studies till February 2020 and conducted a meta-analysis on the association between air pollution (PM2.5, particulate matter with aerodynamic diameter less than 2.5 μm; PM10, particulate matter with aerodynamic diameter less than 10 μm; NO2, nitrogen dioxide; SO2, sulfur dioxide; CO, carbon monoxide; O3, ozone) and stroke (hospital admission, incidence, and mortality). Fixed- or random-effects model was used to calculate pooled odds ratios (OR)/hazard ratio (HR) and their 95% confidence intervals (CI) for a 10 μg/m3 increase in air pollutant concentration. Results A total of 68 studies conducted from more than 23 million participants were included in our meta-analysis. Meta-analyses showed significant associations of all six air pollutants and stroke hospital admission (e.g., PM2.5: OR = 1.008 (95% CI 1.005, 1.011); NO2: OR = 1.023 (95% CI 1.015, 1.030), per 10 μg/m3 increases in air pollutant concentration). Exposure to PM2.5, SO2, and NO2 was associated with increased risks of stroke incidence (PM2.5: HR = 1.048 (95% CI 1.020, 1.076); SO2: HR = 1.002 (95% CI 1.000, 1.003); NO2: HR = 1.002 (95% CI 1.000, 1.003), respectively). However, no significant differences were found in associations of PM10, CO, O3, and stroke incidence. Except for CO and O3, we found that higher level of air pollution (PM2.5, PM10, SO2, and NO2) exposure was associated with higher stroke mortality (e.g., PM10: OR = 1.006 (95% CI 1.003, 1.010), SO2: OR = 1.006 (95% CI 1.005, 1.008). Conclusions Exposure to air pollution was positively associated with an increased risk of stroke hospital admission (PM2.5, PM10, SO2, NO2, CO, and O3), incidence (PM2.5, SO2, and NO2), and mortality (PM2.5, PM10, SO2, and NO2). Our study would provide a more comprehensive evidence of air pollution and stroke, especially SO2 and NO2.

Background Secondary nosocomial infections, which are commonly caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) and vancomycin-resistant Enterococcus faecium (VRE), often develop in septic patients. This study aimed to identify the origin of secondary systemic pathogens and reveal the underlying mechanism of infection. Methods In this prospective, observational case–control study, a total of 34 septic patients, 33 non-septic intensive care unit (ICU) patients and 10 healthy individuals serving as controls were enrolled. Three hundred and twelve fecal samples were collected and subjected to 16S rRNA gene amplicon sequencing. Metagenome sequencing was performed to identify the homology between dominant CRKP or VRE in the intestine and pathogens isolated from secondary infectious sites. C57/BL mice were established as pseudo germ-free animal model by pretreatment with broad-spectrum antibiotics for two weeks. Results The abundance and diversity of the gut microbiota in septic patients was drastically decreased one week after ICU admission, potentially leading to the enrichment of antibiotic-resistant bacteria, such as CRKP. Furthermore, secondary bloodstream and abdominal infections caused by CRKP or VRE in septic patients occurred after intestinal colonization with the predominant bacterial species. Genomic analysis showed that bacteria isolated from secondary infection had high homology with the corresponding predominant intestinal opportunistic pathogens. In addition, animal model experiments validated the hypothesis that the administration of antibiotics caused the enrichment of CRKP and VRE among the intestinal microbiota, increasing the likelihood of permeation of other tissues and potentially causing subsequent systemic infection in pseudo germ-free mice. Conclusion Our study indicated that the pathogens causing secondary infection in septic patients might originate from the intestinal colonization of pathogens following broad-spectrum antibiotic treatment.

We previously demonstrated that circulating extracellular vesicles (EVs) from patients with valvular heart disease (VHD; vEVs) contain inflammatory components and inhibit endothelium-dependent vasodilation. Neutrophil chemotaxis plays a key role in renal dysfunction, and dexmedetomidine (DEX) can reduce renal dysfunction in cardiac surgery. However, the roles of vEVs in neutrophil chemotaxis and effects of DEX on vEVs are unknown. Here, we investigated the impact of vEVs on neutrophil chemotaxis in kidneys and the influence of DEX on vEVs. Circulating EVs were isolated from healthy subjects and patients with VHD. The effects of EVs on chemokine generation, forkhead box protein O3a (FOXO3a) pathway activation and neutrophil chemotaxis on cultured human umbilical vein endothelial cells (HUVECs) and kidneys in mice and the influence of DEX on EVs were detected. vEVs increased FOXO3a expression, decreased phosphorylation of Akt and FOXO3a, promoted FOXO3a nuclear translocation, and activated the FOXO3a signaling pathway in vitro. DEX pretreatment reduced vEV-induced CXCL4 and CCL5 expression and neutrophil chemotaxis in cultured HUVECs via the FOXO3a signaling pathway. vEVs were also found to suppress Akt phosphorylation and activate FOXO3a signaling to increase plasma levels of CXCL4 and CCL5 and neutrophil accumulation in kidney. The overall mechanism was inhibited in vivo with DEX pretreatment. Our data demonstrated that vEVs induced CXCL4-CCL5 to stimulate neutrophil infiltration in kidney, which can be inhibited by DEX via the FOXO3a signaling. Our findings reveal a unique mechanism involving vEVs in inducing neutrophils chemotaxis and may provide a novel basis for using DEX in reducing renal dysfunction in valvular heart surgery.

Acute heart failure (AHF) is a severe complication after cardiac surgery with cardiopulmonary bypass (CPB). Although some AHF biomarkers have been used in clinic, they have limitations when applied in the prediction and diagnosis of AHF after cardiac surgery with CPB, and there are still no effective and specific biomarkers. We and other researchers have shown that circulating microparticles (MPs) increased in a variety of cardiovascular diseases. However, whether the concentration of circulating MPs could be a new biomarker for AHF after cardiac surgery remains unknown. Here, 90 patients undergoing cardiac surgery with CPB and 45 healthy subjects were enrolled. Patients were assigned into AHF (n=14) or non-AHF (n=76) group according to the diagnosis criteria of AHF. The concentrations of circulating MPs were determined before, as well as 12 h and 3 days after operation with nanoparticle tracking analysis technique. MPs concentrations in patients before surgery were significantly higher than those of healthy subjects. Plasma levels of MPs were significantly elevated at 12 h after surgery in patients with AHF, but not in those without AHF, and the circulating MPs concentrations at 12 h after surgery were higher in AHF group compared with non-AHF group. Logistic regression analysis indicated that MPs concentration at postoperative 12 h was an independent risk factor for AHF. The area under receiver operating characteristic curve for MPs concentration at postoperative 12 h was 0.81 and the best cut-off value is 5.20×108 particles mL-1 with a sensitivity of 93% and a specificity of 10%. These data suggested that the concentration of circulating MPs might be a new biomarker for the occurrence of AHF after cardiac surgery with CPB.

AimsTo investigate the frequency of USH2A mutation and the clinical and genetic differences between Usher syndrome type II (USH2) and retinitis pigmentosa (RP) in a large cohort of Chinese patients.MethodsA total of 1381 patients with inherited retinal disease (IRD) were recruited. The phenotypic and genotypic information of patients with USH2A mutations was evaluated.ResultsThe prevalence of patients with USH2A mutations was 15.75%, which was the most frequently detected gene in this cohort of patients. Hotspot of USH2A mutations was c.8559-2A >G and c.2802T >G. Patients with USH2 had an earlier and more serious decline of visual function and damage to retina structure than did patients with RP in the first 10 years (p0.05). Missense variants had less severe consequences and were found more commonly in RP, whereas more deleterious genotypes were associated with an earlier onset of disease and were found more commonly in USH2.ConclusionsThis study provides detailed clinical–genetic assessment of patients with USH2A mutations of Chinese origin, enabling precise genetic diagnoses, better management of these patients and putative therapeutic approaches.

The interaction and action mechanism of starch with different phenolic compounds were investigated. By using scanning electron microscope, nuclear magnetic resonance, Fourier transform infra-red spectroscopy and thermogravimetric analysis, phenolic compounds exhibited the significant effects on the morphology, intensity of hydrogen bond, crystalline structure and thermal stability of starch, respectively. Furthermore, according to the analysis of molecular dynamics simulation by using short-chain glucose (SGS) as model, phenolic compounds could change the spatial configuration of starch, and had the obvious effects on the formation of hydrogen bonds (including intra- and intermolecular hydrogen bonds) and the strength of binding free energy. Meanwhile, epigallocatechin gallate possessed the strongest capacity to change the spatial configuration of starch with the consistent hydrogen bond occupancy and the lowest binding free energy. All present results suggested that phenolic compounds might be potentially utilised for improving the quality of starch in food industry.

Background The relationship of consumption of dietary fat and fatty acids with esophageal squamous cell carcinoma (ESCC) risk remains unclear. This study aimed to explore the relationship of dietary fat and fatty acids intake with ESCC risk. Methods This case-control study included 879 incident cases and 892 community-based controls recruited from Southwest China. A food frequency questionnaire was adopted to collect information about dietary information, and intake of fat, saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), and total fatty acid (TFA) was calculated. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were estimated using the logistic regression model. Results When comparing the highest with lowest intake quintiles, MUFA (OR: 0.33, 95% CI: 0.21–0.51), PUFA (OR: 0.32, 95% CI: 0.20–0.51), and TFA (OR: 0.44, 95% CI: 0.28–0.70) were related to a reduced risk of ESCC after adjusting for confounders; for non-drinkers rather than drinkers, the intake of SFA was significantly related to a 61% (OR: 0.39, 95% CI: 0.19–0.81) reduced risk of ESCC when comparing the highest with the lowest intake quintiles. Dietary fat was not related to the risk of ESCC. Conclusions This study suggested that the more intake of MUFA and PUFA, the lower risk of ESCC, whereas the protective effect of TFA was only observed among non-drinkers. Strategic nutritional programs should consider food rich in unsaturated fatty acids to mitigate the occurrence of ESCC.

To explore clinical effect of arthroscopic debridement combined with platelet-rich plasma (PRP) injection for Kellgren-Lawrence(K-L) gradeⅠ-Ⅲ knee osteoarthritis (KOA) .Totally 117 patients with KOA who underwent arthroscopic debridement combined with injection from November 2015 to January 2019 were retrospectively analyzed. According to different injection drugs, the patients were divided into sodium hyaluronate group(group A) and PRP group(group B). In group A, there were 60 patients, including 27 males and 33 females, aged from 49 to 67 years old with an average age of (54.1±4.8) years old;12 patients with gradeⅠ, 23 patients with gradeⅡand 25 patients with grade Ⅲ according to K-L clssification, 2 ml(20 g) sodium hyaluronate was injected into knee joint after intraoperative, 1, 2, 3 weeks after operation for 4 times. In group B, there were 57 patients, including 25 males and 32 females, aged from 47 to 70 years old with an average of (55.8±5.0) years old, 10 patients with gradeⅠ, 20 patients with gradeⅡand 27 patients with grade Ⅲ according to K-L classification, injected 5 ml PRP at the same time. Postoperative complications was recorded between two groups. Postoperative visual analogue scale(VAS) and Lysholm score at 3, 6, 12 months were used to evaluate improvement of knee pain and joint function.All patients were followed up for 12 to 19 months with an average of (14.1±1.6) months. There was no significant difference in postopertaive complications between group A and group B (Arthroscopic debridement combined with sodium hyaluronate or PRP injection for K-L gradeⅠ-Ⅲ KOA could effectively relieve pain and improve joint function with higher safety in short term, but the medium-long-term effect of PRP injection is stable.

The aim of this study was to investigate whether pentraxin 3 (PTX3) in microvesicles (MVs) can be a valuable biomarker for the prediction of acute heart failure (AHF) after cardiac surgery with cardiopulmonary bypass (CPB). One hundred and twenty-four patients undergoing cardiac surgery with CPB were included and analyzed (29 with AHF and 95 without AHF). The concentrations of PTX3 in MVs isolated from plasma were measured by ELISA kits before, 12 h, and 3 days after surgery. Patients' demographics, medical history, surgical data, and laboratory results were collected. The levels of PTX3 in MVs were significantly elevated during perioperative surgery, which was increased more in the AHF group. The concentrations of PTX3 in MVs at postoperative 12 h were independent risk factors for AHF with the area under the ROC curve of 0.920. The concentration of PTX3 in MVs may be a novel biomarker for prediction of AHF after cardiac surgery.

Background: Liver metastasis of colon cancer is strongly affected by the tumor microenvironment (TME), with interactions between tumor cells and cancer-associated fibroblasts (CAFs) in particular. TGF-β is well known for its ability to mediate the CAF phenotype, and CXCR4 expression is closely correlated to poor prognosis in CRC. The relationship between these two signaling pathways remains to be delineated in liver metastasis of colon cancer. Methods: Immunohistochemistry was employed to investigate CXCR4 expression in 45 human specimens of primary colorectal cancer (CRC) and liver metastasis. The functions of SDF-1 released by hepatic stellate cells (HSCs) on CXCR4 and TGF-β1 in CRC cells were investigated in vitro. The effects of CRC on HSCs differentiation into CAFs were confirmed using co-culture technology and expression analysis of CAFs markers by qPCR, western blot and immunofluorescence. The involvement of CXCR4 and TGF-β1 was verified with addition of CXCR4 inhibitor AMD3100 and TGF-β1 inhibitor cyclophosphamide (Cy) both in vitro and in vivo. Results: There were more CXCR4-positive cells at the liver metastatic tissues compared to the primary sites. CRC cells activated and transformed HSCs to CAFs after co-cultivating with HSCs. Activated HSCs stimulated TGF-β1 secretion from CRC cells after co-culture with CRC cells in vitro. Moreover, the expression of CAFs markers was increasing in the activated HSCs. In a mouse hepatic metastasis model, treated with AMD3100 or Cy blocked the metastatic potential of HCT116 cells and the hepatic CAFs differentiation. Conclusions: These results indicated that CXCR4/TGF-β1 axis plays an important role in CRC liver metastasis through mediating HSCs differentiation into CAFs, providing preclinical evidences that blockade of the axis might be beneficial for anti-metastasis therapy in CRC.

Background: Tumor microenvironment (TME) is a crucial part of tumor hallmarks. Mesenchymal stem cells (MSCs), important components of TME, are the main source of Carcinoma-associated fibroblasts (CAFs), but the mechanism of transformation regulation is still unclear. Transforming growth factor-β1 (TGF-β1), chemokine Stromal cell-derived factor-1 (SDF-1) and its endogenous receptor CXCR4 may play important roles during this process. Methods: Co-culture technique was used to explore the effects of MSCs on the proliferation, migration and invasion of colorectal carcinoma (CRC) cells and how they induced MSCs to differentiate into CAFs. The expression of α-SMA, Vimentin, S100A4 and FAP were detected as CAFs markers. Inhibitors AMD3100 and cyclophosphamide (Cy) were pre-treated in MSCs to verify the functions of CXCR4/TGF-β1. Finally, the xenograft models in nude mice were generated to further verify this process in vivo. Results: MSCs promoted the CRCs proliferation, invasion and migration, and induced SDF-1 expression and secretion, which dramatically up-regulated CXCR4 and TGF-β1 expression in MSCs. The levels of CAFs markers elevated in MSCs, indicating CAFs differentiation occurred in MSCs. AMD3100 and Cy treatment significantly blocked this differentiation process of MSCs by suppressing CXCR4 expression and TGF-β1 secretion. In vivo xenograft experiments also demonstrated that MSCs promoted differentiation into CAFs through CXCR4/TGF-β1 signaling in either primary tumor tissues or hepatic metastatic tissues of CRC. Conclusion: Our studies have revealed the essential role of CXCR4/TGF-β1 axis playing in the transformation of tumor microenvironment by mediating MSCs differentiation into CAFs, promoting CRCs growth and metastasis.

Epidemiological evidence linking type 2 diabetes mellitus (T2DM) with air pollution is discrepant and most are restricted to the influences of air-pollutant mass concentration. This study aims to explore the effects of long-term exposure to air pollution and its metal constituents on T2DM prevalence in China.We used data on 10,253 adult residents from the baseline survey of Wuhan Chronic Disease Cohort in 2019. Ambient PMA total of 673 T2DM cases (6.6%) were identified. The 3-year mean exposures to PMLong-term exposure to PM

Background The treatment of complex 3- and 4-part proximal humeral fractures has been controversial due to numerous postoperative complications. With the further study of medial support and blood supply of humeral head, new techniques and conception are developing. The study aims to illustrate the medial approach of the proximal humeral fracture through cadaver autopsy. Method Upper limbs from 19 cadavers have been dissected to expose the shoulder joint. We selected the coracoid process as the bony reference. Vernier caliper will be used to measure the following data, including distance from coracoid process to circumflex brachial artery, distance between anterior humeral circumflex artery (ACHA) and posterior circumflex brachial artery (PCHA) and their diameters. Assessment included the characteristics of the vascular supply around the humeral head, identification of the structures at risk, quality of exposure of the bony structures, and feasibility of fixation. Results The medial approach is appropriate in 86.84% anatomical patterns. Between the lower part of the shoulder capsule and the insertion of conjoined tendon, the bony surface exposed was limited by the interval between ACHA and PCHA. An interval of 2 to 3 cm (24.29 ± 3.42 mm) was available for medial plate. ACHA (49.35 ± 8.13 mm, 35.14–68.53 mm) and PCHA (49.62 ± 7.82 mm, 37.67–66.76 mm) were about 5 cm away from the coracoid process. Risk structures including ACHA and PCHA originate in common, PCHA originated from the deep brachial artery (DBA), the presence of perforator vessels, musculocutaneous nerve intersects with ACHA, the diameter of PCHA: ACHA Conclusion The medial approach opens a new perspective in the optimal management of complex fractures of proximal humerus. Anatomical research proves that the medial approach is feasible. The interval between ACHA and PCHA is suitable for placement. Anatomical pattern and indication have been discussed, and we hypothesized that ACHA has been destroyed in complex PHFs. With further studies on the anatomy and mechanism of injury, the development of more clinical cases will be an important work of our institution in the future.

Whether risk genes of severe coronavirus disease 2019 (COVID-19) from genome-wide association study could play their regulatory roles by interacting with host genes that were interacted with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins was worthy of exploration. In this study, we implemented a network-based approach by developing a user-friendly software Network Calculator (https://github.com/Haoxiang-Qi/Network-Calculator.git). By using Network Calculator, we identified a network composed of 13 risk genes and 28 SARS-CoV-2 interacted host genes that had the highest network proximity with each other, with a hub gene HNRNPK identified. Among these genes, 14 of them were identified to be differentially expressed in RNA-seq data from severe COVID-19 cases. Besides, by expression enrichment analysis in single-cell RNA-seq data, compared with mild COVID-19, these genes were significantly enriched in macrophage, T cell and epithelial cell for severe COVID-19. Meanwhile, 74 pathways were significantly enriched. Our analysis provided insights for the underlying genetic etiology of severe COVID-19 from the perspective of network biology.

Famine exposure or air pollution is linked to type 2 diabetes mellitus (T2DM). However, their combined effects on T2DM remain largely unknown. A total of 11,640 individuals were obtained from the Henan Rural Cohort Study. According to their birthdate, participants were divided into three famine exposure subgroups: fetal exposed, childhood exposed, and unexposed groups. The air pollutants (particles with aerodynamics diameters ≤ 1.0 µm (PM

Background Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in cancer therapy, only a limited fraction of patients benefit from it. Cancer stemness can be the potential culprit in ICI resistance, but direct clinical evidence is lacking. Methods Publicly available scRNA-Seq datasets derived from ICI-treated patients were collected and analyzed to elucidate the association between cancer stemness and ICI response. A novel stemness signature (Stem.Sig) was developed and validated using large-scale pan-cancer data, including 34 scRNA-Seq datasets, The Cancer Genome Atlas (TCGA) pan-cancer cohort, and 10 ICI transcriptomic cohorts. The therapeutic value of Stem.Sig genes was further explored using 17 CRISPR datasets that screened potential immunotherapy targets. Results Cancer stemness, as evaluated by CytoTRACE, was found to be significantly associated with ICI resistance in melanoma and basal cell carcinoma (both P < 0.001). Significantly negative association was found between Stem.Sig and anti-tumor immunity, while positive correlations were detected between Stem.Sig and intra-tumoral heterogenicity (ITH) / total mutational burden (TMB). Based on this signature, machine learning model predicted ICI response with an AUC of 0.71 in both validation and testing set. Remarkably, compared with previous well-established signatures, Stem.Sig achieved better predictive performance across multiple cancers. Moreover, we generated a gene list ranked by the average effect of each gene to enhance tumor immune response after genetic knockout across different CRISPR datasets. Then we matched Stem.Sig to this gene list and found Stem.Sig significantly enriched 3% top-ranked genes from the list (P = 0.03), including EMC3, BECN1, VPS35, PCBP2, VPS29, PSMF1, GCLC, KXD1, SPRR1B, PTMA, YBX1, CYP27B1, NACA, PPP1CA, TCEB2, PIGC, NR0B2, PEX13, SERF2, and ZBTB43, which were potential therapeutic targets. Conclusions We revealed a robust link between cancer stemness and immunotherapy resistance and developed a promising signature, Stem.Sig, which showed increased performance in comparison to other signatures regarding ICI response prediction. This signature could serve as a competitive tool for patient selection of immunotherapy. Meanwhile, our study potentially paves the way for overcoming immune resistance by targeting stemness-associated genes.

Programmed cell death 1 (PD-1) blockade is considered contraindicated in liver transplant (LT) recipients due to potentially lethal consequences of graft rejection and loss. Though post-transplant PD-1 blockade had already been reported, pre-transplant use of PD-1 blockade has not been thoroughly investigated. This study explores the safety and efficacy of neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC) after registration on the waiting list. Seven transplant recipients who underwent neoadjuvant PD-1 blockade combined with lenvatinib and subsequent LT were evaluated. The objective response rate (ORR) and disease control rate (DCR) was 71% and 85% according to the mRECIST criteria. Additionally, a literature review contained 29 patients were conducted to summarize the PD-1 blockade in LT for HCC. Twenty-two LT recipients used PD-1 inhibitors for recurrent HCC. 9.1% (2/22) and 4.5% (1/22) recipients achieved complete remission (CR) and partial remission (PR), respectively; 40.9% (9/22) recipients had progressive disease (PD). Allograft rejection occurred in 45% of patients. In total, seven patients from our center and three from the literature used pretransplant anti-PD-1 antibodies, eight patients (80%) had a PR, and the disease control rate was 100%. Biopsy-proven acute rejection (BPAR) incidence was 30% (3 in 10 patients), two patients died because of BPAR. This indicated that neoadjuvant PD-1-targeted immunotherapy plus tyrosine kinase inhibitors (TKI) exhibited promising efficacy with tolerable mortality in transplant recipients under close clinical monitoring.

Few studies have estimated the nonlinear association of ambient temperature with the risk of influenza. We therefore applied a time-series analysis to explore the short-term effect of ambient temperature on the incidence of influenza in Wuhan, China. Daily influenza cases were collected from Hubei Provincial Center for Disease Control and Prevention (Hubei CDC) from January 1st, 2014 to December 31st, 2017. The meteorological and daily pollutant data was obtained from the Hubei Meteorological Service Center and National Air Quality Monitoring Stations, respectively. We used a generalized additive model (GAM) coupled with the distributed lag nonlinear model (DLNM) to explore the exposure-lag-response relationship between the short-term risk of influenza and daily average ambient temperature. Analyses were also performed to assess the extreme cold and hot temperature effects. We observed that the ambient temperature was statistically significant, and the exposure-response curve is approximately S-shaped, with a peak observed at 23.57℃. The single-day lag curve showed that extreme hot and cold temperatures were both significantly associated with influenza. The extreme hot temperature has an acute effect on influenza, with the most significant effect observed at lag 0-1. The extreme cold temperature has a relatively smaller effect but lasts longer, with the effect exerted continuously during a lag of 2-4 days. Our study found significant nonlinear and delayed associations between ambient temperature and the incidence of influenza. Our finding contributes to the establishment of an early warning system for airborne infectious diseases.

Depressive symptoms have become a serious public health issue worldwide. Several studies showed that air pollution, especially fine particulate matter (PM

Introduction This study investigates the outcomes and safety of 70-150 μm and 100-300 μm doxorubicin drug-eluting bead transarterial chemoembolisation (DEB-TACE) in patients with unresectable hepatocellular carcinoma (HCC). Methods Retrospective, cohort study of 51 patients treated with DEB-TACE for unresectable HCC was studied: 23 with 100-300 μm particles and 28 with 70-150 μm particles. Overall, survival (OS), progression-free survival (PFS), tumour response and prognostic factors were assessed. Results The median OS of the entire cohort was 30 months. The median OS and median PFS for 70-150 μm particles were not reached, whilst for the 100-300 μm group, it was 29.2 months and 15.0 months, respectively. The 6-month, 1-year and 2-year OS for 70-150 μm was 96%, 86% and 85% versus the 100-300 μm particles size of 83%, 64% and 44%, respectively. At 1-month follow-up, patients treated with 70-150 μm had significantly better mRECIST tumour response compared to 100-300 μm (complete response 38.5% vs. 19%; partial response 57.7% vs. 42.9%; stable disease 0% vs. 4.8%; progressive disease 3.8% vs. 33.3%, P = 0.027). Patients treated with 100-300 μm DEBs were significantly more likely to have progressive disease on 1-month follow-up imaging compared those treated with 70-150 μm DEB sizes (odds ratio 7.15, P = 0.007). The 30-day mortality rate was similar between the two groups (3.6% for 70-150 μm vs. 4.3% for 100-300 μm). Multivariate analysis demonstrated entire cohort OS was significantly associated with BCLC stage (aHR: 10.5, P = 0.002), albumin (aHR: 15.0, P = 0.02) and ALP (aHR 62, P = 0.001). Conclusions DEB-TACE with 70-150 μm particles demonstrates improved 1-month objective tumour response compared to 100-300 μm, whilst having a similar safety profile. Elevated ALP, lower albumin and higher BCLC stage were significantly associated with poorer survival outcomes.

Abnormal tumor microenvironment and the epithelial‐mesenchymal transition (EMT) are important features of tumor metastasis. However, it remains unknown how signals can form complicated networks to regulate the sustainability of the EMT process. The aim of our study is to explore the possible interaction between tumor‐associated macrophages and tumor cells in the EMT process mediated by microRNA (miR)‐362‐3p. In this study, we found that by releasing TGF‐β, M2 macrophages mediate binding of Smad2/3 to miR‐362‐3p promoter, leading to overexpression of miR‐362‐3p. MicroRNA‐362‐3p maintains EMT by regulating CD82, one of the most important members of the family of tetraspanins. Our finding suggests that miR‐362‐3p can serve as a core factor mediating cross‐talk between the TGF‐β pathway in tumor‐associated macrophages and tetraspanins in tumor cells, and thus facilitates the EMT process.

Background:Previous meta-analyses have suggested primary tumor location as a predictive factor for efficacy of anti–epidermal growth factor receptor (EGFR) therapies in patients with metastatic colorectal cancer (mCRC). However, the recent phase III TAILOR trial addressing this issue was not included in those analyses. This meta-analysis incorporated data from the TAILOR trial to evaluate the efficacy of chemotherapy plus anti-EGFR agents (cetuximab [Cet] or panitumumab [Pani]) versus chemotherapy alone forRASwild-type (wt) right- and left-sided mCRC.Patients and Methods:A PubMed-based literature search was conducted to identify randomized controlled trials (RCTs) studying the additional efficacy of Cet/Pani in combination with chemotherapy versus chemotherapy alone inRASwt left- and right-sided mCRC. Study-level pooled analyses of hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and odds ratios (ORs) for objective response rate (ORR) were performed.Results:Three first-line RCTs (CRYSTAL, PRIME, and TAILOR) and one second-line RCT (20050181) were included. Significant OS benefits from Cet/Pani were observed in the left-sided (HR, 0.76; 95% CI, 0.66–0.86) but not right-sided subgroups (HR, 0.99; 95% CI, 0.78–1.27). However, the addition of Cet/Pani to chemotherapy significantly improved PFS and ORR in both the left-sided (HR, 0.70; 95% CI, 0.57–0.86, and OR, 3.28; 95% CI, 1.95–5.51, respectively) and right-sided subgroups (HR, 0.76; 95% CI, 0.59–0.99, and OR, 1.78; 95% CI, 1.08–2.93, respectively).Conclusions:The addition of Cet/Pani to chemotherapy significantly benefits PFS and ORR in patients withRASwt right-sided mCRC, indicating that anti-EGFR therapies may remain an option for selected patients.

Whether exposure to air pollution is associated with the increased incidence of childhood eczema is controversial. Only a few previous researches about the relationship between gestational and early-life exposures to ambient air pollutants and childhood eczema were conducted in China, and there is a lack of studies in Hubei province. This study aimed to explore the associations between air pollution exposure in gestation and the first year of life and childhood eczema. From November to December 2017, a total of 3383 children aged 3–6 years were recruited from 12 kindergartens in Hubei, China; 3167 were included in the final analysis. Parent-reported data involved with childhood eczema was inquired by questionnaire, and the concentrations of NO2, PM2.5, and PM10 were acquired from air quality monitoring stations which were the nearest to the twelve kindergartens. A binary logistic regression model was used to evaluate the associations of period-mean concentrations of individual pollutant exposure with childhood eczema. Of the 3167 children, 848 (26.8%) had a history of doctor-diagnosed eczema. After adjusting for the covariates, high levels of NO2, PM2.5, and PM10 exposures were significantly associated with a positive increase in risk of childhood eczema during the gestational period and the first year of life. In the gestational period, the estimate OR in the 3rd and 4th quartiles of NO2 was 1.256 and 1.496, respectively. During the first year of life, the estimate OR in the 3rd and 4th quartiles of NO2 was 1.371 and 1.335, respectively. Our study indicated that the gestational period and the first year of life exposures to high levels of ambient NO2, PM2.5, and PM10 were significantly associated with increased eczema among preschool children. Some effective measures of prevention and intervention could be developed for preschool children.

Nitroxyl (HNO), as an electron reduced and protonated form of nitric oxide, is emerging as a potential diagnostic and therapeutic biomarker. It is still of great interest to develop probes of desirable properties to study its biological functions. Here we develop a near infrared fluorescence probe for detecting and visualizing exogenous and endogenous HNO in living cells. The probe is designed by coupling a HNO-responsive moiety, diphenylphosphinobenzoyl group, with a near infrared fluorophore with large of Stokes shift via an ester linker. The probe was initially nonfluorescent. HNO-catalyzed oxidation reaction generates an aza-ylide, which intramolecularly attacks the carbonyl carbon, liberating the initial fluorophore with activated fluorescence signals. The probe is proportional to the concentrations of HNO in the range of 2.0–80 μM with a limit of detection of 0.05 μM. Furthermore, the probe also exhibits high selectivity and fast response (reaching plateau within 600 s) towards HNO in vitro. Moreover, imaging studies reveal that the probe is capable of detecting exogenous HNO with dose-dependent fluorescence signals. Its ability to image endogenous HNO without or with induction is also demonstrated in living cells. This turn-on fluorescence probe provides a useful tool for studying HNO in living cells.

DNA hydrogels are biocompatible and are suitable for many biomedical applications. However, to be useful imaging probes or drug carriers, the ordinary bulk size of DNA hydrogels must be overcome. Here we put forward a new strategy for fabricating a novel and simple protein-scaffolded DNA nanohydrogel, constructed through a direct DNA self-assembly using three types of streptavidin (SA)-based DNA tetrad for the activation of imaging and targeting therapy of cancer cells. The DNA nanohydrogels are easily prepared, and we show that by varying the initial concentration of DNA tetrad, it is possible to finely control their size within nanoscale range, which are favorable as carriers for intracellular imaging and transport. By further incorporating therapeutic agents and tumor-targeting MUC1 aptamer, these multifunctionalized SA-scaffolded DNA nanohydrogels (SDH) can specifically target cancer cells and selectively release the preloaded therapeutic agents via a structure switching when in an ATP-rich intracellular environment, leading to the activation of the fluorescence and efficient treatment of cancer cells. With the advantages of facile modular design and assembly, effective cellular uptake, and excellent biocompatibility, the method reported here has the potential for the development of new tunable DNA nanohydrogels with multiple synergistic functionalities for biological and biomedical applications.

A novel and versatile platform is developed for single-step amplified fluorescence detection of antibodies via specific proximity-induced hybridization chain assembly.

Background The epidemiological evidence on relationships between long-term exposure to particulate matter and hypertension and blood pressure has been inconclusive. Limited evidence was available for particulate matter with an aerodynamic diameter ≤ 1 μm (PM1) in rural areas of developing countries. Objective This study aimed to investigate the associations between long-term exposure to PM1 and hypertension and blood pressure among rural Chinese population. Methods This study included 39,259 participants who had completed the baseline survey from Henan Rural Cohort. Participants' exposure to PM1 was assessed by a satellite-based spatiotemporal model. The binary logistic regression model was used to examine the association between long-term PM1 exposure and hypertension, and multivariable linear regression model was used to investigate the associations between long-term PM1 exposure and systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and pulse pressure (PP). Moreover, we examined potential effect modifications by demographic, lifestyle and diet factors. Results The mean concentration of PM1 for all participants during the 3-year before baseline survey was 59.98 μg/m3. Each 1 μg/m3 increase in PM1 concentration was significantly associated with an increase of 4.3% [Odds ratio(OR) = 1.043, 95% confidence interval(CI): 1.033, 1.053] in odds for hypertension, an increase of 0.401 mm Hg (95% CI, 0.335, 0.467), 0.328 mm Hg (95% CI, 0.288, 0.369), 0.353 mm Hg (95% CI, 0.307, 0.399) and 0.073 mm Hg (95% CI, 0.030, 0.116) in SBP, DBP, MAP and PP, respectively. Further stratified analyses showed that the effect of PM1 on hypertension and blood pressure could be modified by sex, lifestyle and diet. Conclusions This study suggests that long-term exposure to ambient PM1 increases the risk of hypertension and is associated with elevations in blood pressure in rural Chinese adults, especially in male and those with unhealthy habits., Highlights • Rural cohort participants were exposed to high level of PM1 during the study period. • PM1 was related to increased risk of hypertension and elevated blood pressure. • Males and those with unhealthy habits were more susceptible to the adverse effect.

Increasing studies have discussed how ambient air pollution affects cognitive function, however, the results are inconsistent, and such studies are limited in developing countries. To fill the gap, in this study, we aimed to explore the effect of ambient particulate matters (PM

To evaluate the economics of Suhuang Zhike Capsules in the treatment of acute exacerbation of chronic obstructive pulmonary disease(AECOPD) for inpatients. Based on the published clinical research data, cost-utility analysis was used in this study to evaluate the pharmacoeconomics of Suhuang Zhike Capsules in treatment of AECOPD inpatients from the perspective of medical insu-rance. The test group was treated with Suhuang Zhike Capsules combined with conventional Western medicine, and the control group was treated with conventional Western medicine alone. Treeage software was used to construct a pharmacoeconomic model and perform simulation analysis. The results showed that the cost and output of Suhuang Zhike Capsules combined with the conventional Western medicine were 60 010.18 yuan and 1.92 quality adjusted life year(QALYs), respectively in the simulated 3 years of disease treatment. The cost and output of the conventional Western medicine were 96 730.60 yuan and 1.90 QALYs respectively. Suhuang Zhike Capsules combined with conventional Western medicine required lower cost but achieved higher output, showing cost-utility advantages, so this drug combination was a plan with pharmacoeconomic advantages. The sensitivity analysis results showed that the conclusion was relatively stable. Based on the above results, it is believed that as compared with the conventional Western medicine, Suhuang Zhike Capsules combined with conventional Western medicine have lower cost and higher output for the treatment of AECOPD inpatients, and it is a treatment plan with pharmacoeconomic advantages.

Background Precise methods for postoperative risk stratification to guide the administration of adjuvant chemotherapy (ACT) in localized colorectal cancer (CRC) are still lacking. Here, we conducted a prospective, observational, and multicenter study to investigate the utility of circulating tumor DNA (ctDNA) in predicting the recurrence risk. Methods From September 2017 to March 2020, 276 patients with stage II/III CRC were prospectively recruited in this study and 240 evaluable patients were retained for analysis, of which 1290 serial plasma samples were collected. Somatic variants in both the primary tumor and plasma were detected via a targeted sequencing panel of 425 cancer-related genes. Patients were treated and followed up per standard of care. Results Preoperatively, ctDNA was detectable in 154 of 240 patients (64.2%). At day 3–7 postoperation, ctDNA positivity was associated with remarkably high recurrence risk (hazard ratio [HR], 10.98; 95%CI, 5.31–22.72; P P P Conclusions Postoperative serial ctDNA detection predicted high relapse risk and identified disease recurrence ahead of radiological imaging in patients with stage II/III CRC. ctDNA may be used to guide the decision-making in postsurgical management.

BackgroundProgression-free survival (PFS) exhibits suboptimal performance as the surrogate endpoint for overall survival (OS) in trials studying immune checkpoint inhibitors (ICIs). Here we propose a novel surrogate endpoint, modified PFS (mPFS), which omits the events of disease progression (but not deaths) within 3 months after randomization.MethodsPubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for randomized trials studying ICIs in advanced solid tumors with available PFS and OS data up to May 2020. Individual patient-level data (IPD) for PFS and OS were reconstructed for eligible trials. A simulation-based algorithm was used to match the reconstructed, disconnected PFS and OS IPD, and 1000 independent simulated datasets of matched PFS-OS IPD were generated for each trial. mPFS durations and statuses were then measured for each of the matched PFS-OS IPD. Trial-level correlation between Cox HRs for PFS or mPFS and HRs for OS was assessed using Pearson correlation coefficient (rp) weighted by trial size; patient-level correlation between PFS or mPFS and OS was assessed using Spearman’s rank correlation coefficient (rs). Findings were further validated using the original IPD from two randomized ICI trials.ResultsFifty-seven ICI trials totaling 29,429 participants were included. PFS HR showed moderate correlation with OS HR (rp=0.60), and PFS was moderately correlated with OS at the patient level (median rs=0.66; range, 0.65–0.68 among the 1000 simulations). In contrast, mPFS HR achieved stronger correlation with OS HR (median rp=0.81; range, 0.77–0.84), and mPFS was more strongly correlated with OS at the patient level (median rs=0.79; range, 0.78–0.80). The superiority of mPFS over PFS remained consistent in subgroup analyses by cancer type, therapeutic regimen, and treatment setting. In both trials with the original IPD where experimental treatment significantly improved OS, mPFS successfully captured such clinical benefits whereas PFS did not.ConclusionsmPFS outperformed PFS as the surrogate endpoint for OS in ICI trials. mPFS is worthy of further investigation as a secondary endpoint in future ICI trials.

Background: Limited epidemiological literature identified the associations between residential greenness and hypertension in low/middle-income countries.Methods: A random sampling strategy was adopted to recruit 39 259 residents, ≥ 18 years, and from 5 counties in central China. Blood pressure was measured based on the protocol of the American Heart Association. Hypertension was defined according to the 2010 Chinese guidelines for the management of hypertension. The satellite-derived Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI) were applied to estimate the residential greenness. Mixed logit model and mixed linear model were utilized to explore the relationships of residential greenness with hypertension and blood pressure.Results: High residential greenness was associated with lower odds of hypertension and blood pressure levels. For instance, an interquartile range (IQR) increase in NDVI500m was linked with lower odds of hypertension (OR = 0.92, 95%CI 0.88 to 0.95), a decrease of -0.88 mm Hg (95%CI -1.17 to -0.58) and -0.64 mm Hg (95%CI -0.82 to -0.46) in SBP and DBP, respectively. The effect of residential greenness was more pronounced in males, smokers, and drinkers.Conclusions: Long-term exposure to residential greenness may reduce the risk of hypertension. More prospective studies are needed to verify the hypothesis.

Robot surgical system is the most advanced laparoscopic surgery technology, with obvious advantages in urology. Training in robotic surgery is essential for the application of future surgical techniques. A standardized training program should be established for robotic surgery in urology and andrology and form a disciplinary consensus of expert ideas based on the actual conditions of China and successful experience abroad. This article summarizes the development status, standardized training, training curriculum and evaluation tools in robotic surgery at home and abroad, exploring the bridging of the gaps in the training program, prospects, and establishment of a training system for robotic surgery operating standards in urology and andrology in China.

Leukemia is one of the most common cancers. We conducted this study to comprehensively analyze the temporal trends of leukemia mortality during 2003–2017 and project the trends until 2030. We extracted national-level data on annual leukemia mortality from China Health Statistics Yearbooks (2003–2017). We applied the Joinpoint regression model to assess leukemia mortality trends in urban and rural China by sex during 2003–2017. We also produced sex-specific leukemia mortality using the adjusted Global Burden Disease (GBD) 2016 projection model. In urban areas, age-standardized leukemia mortality decreased significantly among females during 2003–2017 (APC = −0.9%; 95% CI: −1.7, −0.1%). In rural areas, significant decreases of age-standardized leukemia mortality were both found among males (APC = −1.7%; 95% CI: −2.9, −0.5%) and females (APC = −1.6%; 95% CI: −2.6, −0.7%) from 2008 to 2017. Rural-urban and sex disparities of leukemia mortality will continue to exist until the year 2030. According to projection, the leukemia mortality rates of males and rural populations are higher than that of females and urban populations. In 2030, leukemia mortality is projected to decrease to 3.03/100,000 and 3.33/100,000 among the males in urban and rural areas, respectively. In females, leukemia mortality will decrease to 1.87/100,000 and 2.26/100,000 among urban and rural areas, respectively. Our study suggests that more precautionary measures to reduce leukemia mortality are need, and more attention should be paid to rural residents and males in primary prevention of leukemia in China.

Evidence on the associations between long-term exposure to ambient air pollutants (including particle with aerodynamic diameter ≤10 μm (PMA total of 10,253 residents living in Wuhan were recruited. The 3-year average concentrations of main pollutants (PMThe prevalence of MetS in Wuhan was 9.8%, and the 3-year exposure concentrations of PMLong-term exposure to higher concentrations of ambient air pollutants may elevate the prevalence of MetS in populations in Central China. Susceptible individuals especially those with unhealthy lifestyles had a higher risk for MetS.

Exposure to fine particulate matter (PM

The purpose of this study was to examine the changes in severity of anxiety and depression symptoms, stress and sleeping quality after three months of mass quarantine for COVID-19 among undergraduate fresh students compared to their pre-COVID-19 measures. We used participants from the Chinese Undergraduate Cohort (CUC), a national prospective longitudinal study to examine the changes in anxiety and depression symptoms severity, stress and sleep quality after being under mass quarantine for three months. Wilcoxon matched pair signed-rank test was used to compare the lifestyle indicators. Severity of anxiety, depression symptoms, stress and sleep quality were compared with Wilcoxon signed-rank test. We used generalized estimating equation (GEE) to further quantify the change in mental health indicators and sleep quality after the COVID-19 mass quarantine compared to baseline. This study found that there was no deterioration in mental health status among Chinese new undergraduate students in 2020 after COVID-19 mass quarantine compared with the baseline measures in 2019. There was an improvement in sleep quality and anxiety symptoms. After adjusting for age, sex, exercise habit, time spent on mobile gadgets, and time spent outdoors, year 2020 was significantly associated with severity of depression symptoms in males (OR:1.52. 95%CI:1.05–2.20, p-value = 0.027). Year 2020 was significantly associated with the improvement of sleeping quality in total (OR:0.45, 95%CI:0.38–0.52, p

Most studies of short-term exposure to ambient air pollution and cerebrovascular diseases focused on specific stroke-related outcomes, and results were inconsistent due to data unavailability and limited sample size. It is unclear yet how ambient air pollution contributes to the total cardiovascular mortality in central China. Daily deaths from cerebrovascular diseases were obtained from the Disease Surveillance Point System (DSPs) of Wuhan Center for Disease Control and Prevention during the period from 2013 to 2019. Air pollution data were obtained from Wuhan Ecology and Environment Institute from 10 national air quality monitoring stations, including average daily PM

Health effects induced by heavy metal components of particulate matter need further research. A total of 32 healthy volunteers were recruited to walk for 4 h in two different exposure scenarios in Wuhan from May 1 to Jun 30, 2019. Metabolomics technology was used to identify serum cardiovascular-related metabolites disturbance, and the health risk assessment model was employed to assess the non-carcinogenic and carcinogenic risks associated with airborne heavy metals. The results showed that the average mass concentrations of Co, Ni, Cd, Cu, Ag and Ba in PM10 from May 1 to Jun 30, 2019 were 0.22, 0.49, 11.53, 2.23, 34.47 and 4.19 ng/m3, respectively, and were 0.86, 128.47, 291.85, 291.94, 98.55 and 422.62 ng/m3 in PM2.5, respectively. Healthy young adults briefly exposed to heavy metals were associated with serum cardiovascular-related metabolites disturbance, including increased SM(d18:1/17:0) and Sphingomyelin, and decreased GlcCer(d16:1/18:0) and Galabiosylceramide, simultaneously accompanied by activation of the sphingolipid metabolism pathway. Non-carcinogenic and carcinogenic risks of airborne heavy metals via the inhalation route were observed, Ni and Cd most influenced to potential health risks. Findings indicated exposure to increment of heavy metals may increase health risks by causing cardiovascular-related metabolites disturbance via activating the sphingolipid metabolism pathway., Graphical Abstract ga1, Highlights • Heavy metal exposures were associated with serum metabolites disturbance. • Sphingolipid metabolism pathway plays key role in mediating heavy metals’ effects. • Non-carcinogenic risks of Ni and Cd in particulate matters were observed. • Cd in PM2.5 has potential risks of developing cancers among adults.

Background Decreased heart rate variability (HRV) is a predictor of autonomic system dysfunction, and is considered as a potential mechanism of increased risk of cardiovascular disease (CVD) induced by exposure to particulate matter less than 2.5 μm in diameter (PM2.5). Previous studies have suggested that exposure to PM2.5 may lead to decreased HRV levels, but the results remain inconsistent. Methods An updated systematic review and meta-analysis of panel studies till November 1, 2019 was conducted to evaluate the acute effect of exposure to ambient PM2.5 on HRV. We searched electronic databases (PubMed, Web of Science, and Embase) to identify panel studies reporting the associations between exposure to PM2.5 and the four indicators of HRV (standard deviation of all normal-to-normal intervals (SDNN), root mean square of successive differences in adjacent normal-to-normal intervals (rMSSD), high frequency power (HF), and low frequency power (LF)). Random-effects model was used to calculate the pooled effect estimates. Results A total of 33 panel studies were included in our meta-analysis, with 16 studies conducted in North America, 12 studies in Asia, and 5 studies in Europe. The pooled results showed a 10 μg/m3 increase in PM2.5 exposure which was significantly associated with a − 0.92% change in SDNN (95% confidence intervals (95%CI) − 1.26%, − 0.59%), − 1.47% change in rMSSD (95%CI − 2.17%, − 0.77%), − 2.17% change in HF (95%CI − 3.24%, − 1.10%), and − 1.52% change in LF (95%CI − 2.50%, − 0.54%), respectively. Overall, subgroup analysis suggested that short-term exposure to PM2.5 was associated with lower HRV levels in Asians, healthy population, and those aged ≥ 40 years. Conclusion Short-term exposure to PM2.5 was associated with decreased HRV levels. Future studies are warranted to clarity the exact mechanism of exposure to PM2.5 on the cardiovascular system through disturbance of autonomic nervous function.

CDC20 regulates cell cycle progression by targeting key substrates for destruction, but its role in hepatocellular carcinoma (HCC) tumorigenesis remains to be explored. Here, by using weighted gene co-expression network analysis (WGCNA), we identified CDC20 as a hub gene in HCC. We demonstrated that CDC20 expression is correlated with HIF-1 activity and overall survival (OS) of clinic HCC patients. The activity of HIF-1 is regulated by the stability of HIF-1a subunit, which is hydroxylated by oxygen-dependent prolyl hydroxylase enzymes, the PHDs. In addition, we show that genetic ablation or pharmacological inhibition of CDC20 can accelerate the degradation of HIF-1a and impair VEGF secretion in HCC cells. Mechanistically, we found that CDC20 binds to the destruction-box (D-box) motif present in the PHD3 protein to promote its polyubiquitination and degradation. The depletion of endogenous PHD3 in CDC20 knockdown HCC cells greatly attenuated the decline of HIF-1a protein and restored the secretion of VEGF. In contrast, overexpression of a non-degradable PHD3 mutant significantly inhibited the proliferation of HCC cells both in vitro and in vivo. Collectively, our findings indicate that CDC20 plays a crucial role in the development of HCC by governing PHD3 protein.

Background: Evidence suggests that air pollution is associated with many adverse health outcomes such as cardiovascular diseases (CVD), respiratory diseases, cancer, and birth defects. Yet few studies dig into the relationship between air pollution and airborne infectious diseases. Methods: Daily data on influenza incidence were obtained from Hubei Provincial Center for Disease Control and Prevention (Hubei CDC). Data on air pollutants including nitrogen dioxide (NO2), sulfur dioxide (SO2), ground-level ozone (O3), particulate matter (PM) with aerodynamic diameter ≤ 2.5 μm (PM2.5), and PM with aerodynamic diameter ≤ 10 μm (PM10) were retrieved from ten national air sampling stations located at Wuhan. We applied generalized additive model (GAM) to estimate the associations between air pollution and the risk of influenza in Wuhan, China during 2015–2017. Results: In the single-day lag model, the largest effect estimates were observed at lag 0. An increased relative risk (RR) of influenza was significantly associated with a 10 μg/m3 increase in SO2 (RR: 1.099; 95% confidence interval [CI]: 1.011–1.195), NO2 (RR: 1.039; 95% CI: 1.013–1.065), and O3 (RR: 1.005; 95% CI: 0.994–1.016), respectively. In the multi-day lag model, concentrations of SO2, NO2, and O3 were statistically significantly associated with the risk of influenza at lag 0–1. The seasonal analysis suggests that the influence of air pollution on influenza is greater in the cold season as compared in the warm season in the early lag days. The multi-pollutant model indicates that NO2 may be a potential confounder for co-pollutants. Conclusions: Our study shows that air pollution may be associated with the risk of influenza in a broad sense. Therefore, when formulating policies to deal with influenza outbreaks in the future, factors regarding air pollution should be taken into consideration.