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Abstract We conducted this cross-sectional study to investigate the independent associations between lipid metabolites and osteoporotic fractures among participants aged 40–69 years from the UK Biobank. Serum lipid, lipoprotein levels and nuclear magnetic resonance (NMR) based metabolic biomarkers were measured at the baseline. We conducted multivariable logistic analyses to investigate potential independent associations between concentrations of lipid metabolites and osteoporotic fractures in both men and women. The odds ratios (ORs) for lipid metabolites were calculated based on their lowest tertile. Over a median follow-up period of 15 years, a total of 978 men and 4515 women were diagnosed with osteoporosis, whereas 138 men and 327 women encountered incident fractures. Statistically significant disparities were identified in NMR-based metabolic biomarkers among men and women with incident fractures compared to those without. Out of the 144 distinct lipid metabolites known, 35 exhibited significant associations with incident fractures in patients diagnosed with osteoporosis. Following the adjustment for confounding factors, degree of unsaturation (p = 0.0066) and docosahexaenoic acids (p = 0.0011) in male patients increased the risk of incident fractures. And high level of different metabolites of HDL (p = 0.0153), 3-Hydroxybutyrate (p = 0.0012) and Sphingomyelins (p = 0.0036) decreased the risk of incident fractures in female patients. This outcome indicates that these identified lipid metabolites may potentially have unique roles in independently contributing to the occurrence of osteoporotic fractures.

Abstract Super-enhancers are a class of DNA cis-regulatory elements that can regulate cell identity, cell fate, stem cell pluripotency, and even tumorigenesis. Increasing evidence shows that epigenetic modifications play an important role in the pathogenesis of various types of cancer. However, the current research is far from enough to reveal the complex mechanism behind it. This study found a super-enhancer enriched with abnormally active histone modifications in pancreatic ductal adenocarcinoma (PDAC), called DKK1-super-enhancer (DKK1-SE). The major active component of DKK1-SE is component enhancer e1. Mechanistically, AP1 induces chromatin remodeling in component enhancer e1 and activates the transcriptional activity of DKK1. Moreover, DKK1 was closely related to the malignant clinical features of PDAC. Deletion or knockdown of DKK1-SE significantly inhibited the proliferation, colony formation, motility, migration, and invasion of PDAC cells in vitro, and these phenomena were partly mitigated upon rescuing DKK1 expression. In vivo, DKK1-SE deficiency not only inhibited tumor proliferation but also reduced the complexity of the tumor microenvironment. This study identifies that DKK1-SE drives DKK1 expression by recruiting AP1 transcription factors, exerting oncogenic effects in PDAC, and enhancing the complexity of the tumor microenvironment.

Programmed death-1 (PD-1) acts as a T cell checkpoint and is important in controlling T cell exhaustion. Blocking the intercommunication across PD-1 and PD-L1 is promising for advanced lung cancer treatment. However, the response rate requires being strengthened. This study aimed to determine whether the combination treatment of Qingfei mixture (QFM) and PD-1 inhibitor could improve the sensitivity of monoclonal antibody by regulating STAT1/IDO1-mediated tryptophan (Trp)-kynurenine (Kyn) pathway. The in vivo imaging system, immunofluorescence, hematoxylin-eosin staining, TUNEL, flow cytometry, HPLC, and ELISA were used to estimate the anti-tumor effects in LLC-luc tumor-bearing C57BL/6 mice treated with QFM, PD-1 inhibitor, 2-NP (enhancer of STAT1 transcription), and FICZ (AhR agonist) alone or in combination. IFN-γ-mediated A549 and LLC cells were treated with QFM-containing serum and fludarabine (FLU, STAT1 inhibitor), and cell viability, apoptosis, and Kyn content were then evaluated using CCK-8 assays, flow cytometry, and HPLC assays, respectively. Additionally, the expressions of STAT1, IDO1, AhR, NFATc1, TRIP12, PD-1, and PD-L1 were measured in vivo and in vitro. We found QFM increased the anti-cancer actions of PD-1 inhibitors by increasing the CD8+IFNγ+ T cells infiltration and decreasing the ratio of Kyn/Trp. Besides, QFM-containing serum suppressed the proliferation and promoted apoptosis in A549 and LLC cells, meanwhile, FLU boosted the effects of QFM-containing serum. Moreover, the suppression of tumor growth in the combination therapy was attenuated in the mice receiving 2-NP or FICZ. The occurrence of the above results was accompanied by a decrease in STAT1, IDO1, AhR, PD-1, and PD-L1 expressions. Collectively, the findings suggested that QFM may increase the influences of PD-1 inhibitors at least partially by blocking the STAT1/IDO1-mediated tryptophan-kynurenine pathway in lung cancer.

The Dlk1-Dio3 domain is important for normal embryonic growth and development. The heart is the earliest developing and functioning organ of the embryo. In this study, we constructed a transcriptional termination model by inserting termination sequences and clarified that the lack of long non-coding RNA (lncRNA) expression in the Dlk1-Dio3 domain caused the death of maternal insertion mutant (MKI) and homozygous mutant (HOMO) mice starting from E13.5. Parental insertion mutants (PKI) can be born and grow normally. Macroscopically, dying MKI and HOMO embryos showed phenomena such as embryonic edema and reduced heart rate. Hematoxylin and eosin (H.E.) staining showed thinning of the myocardium in MKI and HOMO embryos. In situ hybridization (IHC) and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) showed downregulation of lncGtl2, Rian, and Mirg expression in MKI and HOMO hearts. The results of single-cell RNA sequencing (scRNA-Seq) analysis indicated that the lack of lncRNA expression in the Dlk1-Dio3 domain led to reduced proliferation of epicardial cells and may be an important cause of cardiac dysplasia. In conclusion, this study demonstrates that Dlk1-Dio3 domain lncRNAs play an integral role in ventricular development.

Abstract Background A workplace-based primary prevention intervention be an effective approach to reducing the incidence of hypertension (HTN). However, few studies to date have addressed the effect among the Chinese working population. We assessed the effect of a workplace-based multicomponent prevention interventions program for cardiovascular disease on reducing the occurrence of HTN through encouraging employees to adopt a healthy lifestyle. Methods In this post hoc analysis of cluster randomized controlled study, 60 workplaces across 20 urban regions in China were randomized to either the intervention group (n = 40) or control group (n = 20). All employees in each workplace were asked to complete a baseline survey after randomization for obtaining sociodemographic information, health status, lifestyle, etc. Employees in the intervention group were given a 2-year workplace-based primary prevention intervention program for improving their cardiovascular health, including (1) cardiovascular health education, (2) a reasonable diet, (3) tobacco cessation, (4) physical environment promotion, (5) physical activity, (6) stress management, and (7) health screening. The primary outcome was the incidence of HTN, and the secondary outcomes were improvements of blood pressure (BP) levels and lifestyle factors from baseline to 24 months. A mix effect model was used to assess the intervention effect at the end of the intervention in the two groups. Results Overall, 24,396 participants (18,170 in the intervention group and 6,226 in the control group) were included (mean [standard deviation] age, 39.3 [9.1] years; 14,727 men [60.4%]). After 24 months of the intervention, the incidence of HTN was 8.0% in the intervention groups and 9.6% in the control groups [relative risk (RR) = 0.66, 95% CI, 0.58 ~ 0.76, P

Background: Osteosarcoma, the most common primary malignant bone tumor, is currently treated with surgery combined with chemotherapy, but the limited availability of targeted drugs contributes to a poor prognosis. Identifying effective therapeutic targets is crucial for improving the prognosis of osteosarcoma patients. Methods: We screened the DepMap database to identify essential genes as potential therapeutic targets for osteosarcoma. Gene Set Enrichment Analysis (GSEA) was employed to elucidate the biological roles of these essential genes. Promising candidates were filtered through univariate and multivariate Cox analyses, as well as Kaplan-Meier survival analyses using the GSE21257-OSA and TARGET-OSA datasets. The functional role of the target gene was assessed through cell experiments. Additionally, an in situ nude mice model was established to observe the gene's function, and RNA sequencing was utilized to explore the underlying molecular mechanism. Results: A total of 934 essential genes were identified based on their effects (Chronos) using the DepMap database. These genes were primarily enriched in the ribosome pathway according to GSEA analysis. Among them, 195 genes were associated with the ribosome pathway. Rps28, Rps7, and Rps25 were validated as promising candidates following univariate and multivariate Cox analyses of the TARGET-OSA and GSE21257-OSA datasets. Kaplan-Meier survival analyses indicated Rps28 represented an especially promising target, with high expression correlating with poor prognosis. Knockdown of small ribosomal subunit protein eS28, the protein of Rps28, inhibited proliferation, migration, and invasion in both in vitro and in vivo experiments. Silencing RPS28 affected the MAPK signaling pathway in osteosarcoma. Conclusion: In summary, Rps28 has been identified as an essential gene for osteosarcoma cell survival and eS28 may serve as a potential vulnerability in osteosarcoma.

Abstract Background Metabolic syndrome (MetS) is characterized by a cluster of signs of metabolic disturbance and has caused a huge burden on the health system. The study aims to explore the prevalence and characteristics of MetS defined by different criteria in the Chinese population. Methods Using the data of the China Hypertension Survey (CHS), a nationally representative cross-sectional study from October 2012 to December 2015, a total of 28,717 participants aged 35 years and above were included in the analysis. The MetS definitions of the International Diabetes Federation (IDF), the updated US National Cholesterol Education Program Adult Treatment Panel III (the revised ATP III), and the Joint Committee for Developing Chinese Guidelines (JCDCG) on Prevention and Treatment of Dyslipidemia in Adults were used. Multivariable logistic regression was used to identify factors associated with MetS. Results The prevalence of MetS diagnosed according to the definitions of IDF, the revised ATP III, and JCCDS was 26.4%, 32.3%, and 21.5%, respectively. The MetS prevalence in men was lower than in women by IDF definition (22.2% vs. 30.3%) and by the revised ATP III definition (29.2% vs. 35.4%), but the opposite was true by JCDCG (24.4%vs 18.5%) definition. The consistency between the three definitions for men and the revised ATP III definition and IDF definition for women was relatively good, with kappa values ranging from 0.77 to 0.89, but the consistency between the JCDCG definition and IDF definition (kappa = 0.58) and revised ATP III definition (kappa = 0.58) was poor. Multivariable logistic regression showed that although the impact and correlation intensity varied with gender and definition, area, age, education, smoking, alcohol use, and family history of cardiovascular disease were factors related to MetS. Conclusions The prevalence and characteristics of the MetS vary with the definition used in the Chinese population. The three MetS definitions are more consistent in men but relatively poor in women. On the other hand, even if estimated according to the definition of the lowest prevalence, MetS is common in China.

Abstract In the course of chemotherapy for breast cancer, doxorubicin (DOX) is one of the most commonly prescribed agents. However, it has been recognized as clinically circumscribed on account of its poor selectivity and toxic reactions to normal tissues. Fortunately, the distinct merit of photochemical-responsive nanoparticle delivery systems to enhance cellular drugs uptake through localized concentration, adequate selective and minimizing systemic toxicity has aroused substantial interest recently. In this study, we synthesized photochemical-responsive nanoparticle by incorporating DOX, curcumin (CUR), and perfluorooctyl bromide (PFOB) into poly(lactic-co-glycolic acid) (PLGA) via double emulsification (DOX–CUR–PFOB–PLGA). The synthesized composite nanoparticles, which featured good ultrasound imaging, engendered photochemical activation for drug release when given laser irradiation. Cumulative release rates for DOX were 76.34%, and for CUR were 83.64%, respectively. Also, MCF-7 cells displayed significant intracellular DOX uptake and reactive oxygen species (ROS) levels, degraded cytoskeleton, and decreased cell growth and migration capacity. At the molecular level, cellular pAKT levels decreased, which resulted in downregulated HIF-1α and BAX/BCl-2 levels, leading to Caspase-3 activation and thus induction of apoptosis. Therefore, the photochemical-responsive nanoparticles possess the potential to elicit apoptosis in MCF-7 cells via enhanced DOX uptake.

Abstract Background Advanced non-squamous non-small cell lung cancer (NS-NSCLC) patients without driver gene mutations are usually treated with immune checkpoint inhibitors (ICIs) plus pemetrexed as maintenance therapy after first-line ICIs plus 4–6 cycles of pemetrexed/platinum. Some patients in the real world receive ICIs monotherapy as maintenance therapy. No clinical study has compared the efficacy and safety of ICIs with or without pemetrexed as maintenance therapy. Methods We performed a retrospective study analyzing clinical data of patients with NS-NSCLC who were diagnosed in Zhejiang Cancer Hospital from September 2018 to May 2021 and received maintenance therapy after 4–6 cycles of ICIs plus pemetrexed/platinum. Patients were divided into ICIs plus pemetrexed group and ICIs monotherapy group. Progression Free Survival 1 (PFS1) and PFS2, defined as the interval from the date of initial treatment and maintenance therapy to the date of systemic progression/death or the last follow-up, respectively. Results A total of 120 patients received ICIs with or without pemetrexed as maintenance therapy. Eighty-two patients received ICIs plus pemetrexed as maintenance therapy, and 38 patients received ICIs monotherapy. There were no statistically significant difference in median PFS1 between the ICIs monotherapy group and ICIs plus pemetrexed group (12.00 months vs. 12.07 months, P = 0.979). Among patients with PD-L1 TPS

Abstract Background Anlotinib is a multitarget tyrosine kinase inhibitor for treating patients with advanced non-small cell lung cancer (NSCLC). We aimed to assess the efficacy and safety of anlotinib in elder patients with advanced NSCLC. Methods Elder patients with advanced NSCLC who received anlotinib were enrolled. They were all age ≥ 65 years and with demonstrated records of EGFR gene status. All patients had received treatment with anlotinib or immune checkpoint inhibitors (ICIs)/EGFR-TKIs. The efficacy was evaluated according to the efficacy evaluation criteria for solid tumors (RECIST 1.1). Common Adverse Events Evaluation Criteria (CTCAE 4.03) were used to evaluate adverse drug reactions. Results A total of 91 patients were included in this study. We divided the patients into two groups (EGFR wild type: 60 patients; EGFR mutation: 31 patients). Among EGFR negative patients, the progression-free survival (PFS) for anlotinib monotherapy and anlotinib combination ICI therapy was 3.2 months and 5.0 months, respectively (P = 0.012). The difference in overall survival (OS) between monotherapy and combination therapy was also significant (9.5 vs. 18.4 months, respectively P = 0.010). Interestingly, we further analyzed differences between patients with hypertension and without hypertension, and found that hypertension was associated with better prognosis (5.7 vs. 1.4 months, P

Abstract This study intended to compare the prevalence of hypertension in adolescents aged 15–17 years in China according to different criteria defined by various guidelines. We included 28 715 adolescents aged 15–17 years from the China Hypertension Survey study (CHS) 2012–2015, and the 2017 American Association of Pediatrics (AAP) Clinical Practice Guideline and 2018 Chinese guidelines for children and adults were used to define hypertension. The prevalence of hypertension among Chinese adolescents aged 15–17 years was 24.4% according to the 2018 Chinese guidelines for children; the corresponding values were 18.6% according to the 2017 AAP Guidelines, and 3.5% according to 2018 Chinese guidelines for adults. The age‐specific prevalence of hypertension in the age of 15, 16, and 17 years in the same population was 26.2%, 24.4%, and 23.3% according to 2018 Chinese guidelines for children; 18.8%, 17.9%, and 19.2% as per the 2017 AAP Guidelines; 3.4%, 3.4%, and 3.6% as per the 2018 Chinese guidelines for adults. A highest prevalence of hypertension was observed according to 2018 Chinese guidelines for children than the other two guidelines. Compared with the 2018 Chinese guidelines for children, a higher 95th percentile BP (systolic and diastolic) was also observed in the present study in each gender‐age‐height‐specific group. And the height, which was key factor to influence blood pressure, was similar between adolescents aged 15–17 and adults, and a paralleled result was seen in the present study. Therefore, the 2018 Chinese guidelines for adults may also be appropriate for adolescents aged 15–17 years.

BackgroundThe association between reproductive lifespan and risk of hypertension among postmenopausal women is unclear.MethodsA total of 94,141 postmenopausal women with a mean age of 64.8 years from the China Hypertension Survey were enrolled at baseline from 2012 to 2015. A standardized questionnaire was used to collect relevant information by well-trained interviewers. Blood pressure and physical examination of the participants were performed by trained medical staff. Logistic regression was used to estimate the odds ratios for hypertension by years of reproductive lifespan.ResultsThe average years of reproductive lifespan in Chinese women was 34.0 years. Women who were longer in reproductive lifespan were more likely to have older age at recruitment, higher body mass index, larger waist circumference, lower mean systolic blood pressure, and higher mean diastolic blood pressure (p < 0.05). After adjustments, odds ratios (95% confidence interval) for hypertension were 1.035 (0.988–1.085), 1.007 (0.966–1.048), 1.000 (reference), 0.932 (0.899–0.967), and 0.953 (0.909–0.997) for those with reproductive lifespan at ≤ 28, 29–31, 32–34 (reference), 35–37, and ≥ 38 years, respectively, with a significantly inverse association was seen in those with reproductive lifespan at 35–37 and ≥ 38 years. The overall risk of hypertension declined with the increase in reproductive lifespan, and the risk of hypertension was reduced by 1.1% for every 1-year increase in the reproductive lifespan (odds ratio, 0.989; 95% confidence interval, 0985–0.994) per year. The negative association between reproductive lifespan and hypertension was evident among age at recruitment groups, body mass index categories, and education levels, with the strongest association among women aged ≥ 70 years. Positive associations between reproductive lifespan and risk of hypertension were evident among women aged < 60 years, and this association was stronger among current alcohol drinkers.ConclusionBased on the large nationally representative sample, Chinese postmenopausal women with a shorter reproductive lifespan have a higher risk of hypertension.

Abstract Super-enhancers or stretch enhancers (SEs) consist of large clusters of active transcription enhancers which promote the expression of critical genes that define cell identity during development and disease. However, the role of many super-enhancers in tumor cells remains unclear. This study aims to explore the function and mechanism of a new super-enhancer in various tumor cells. A new super-enhancer that exists in a variety of tumors named EphA2-Super-enhancer (EphA2-SE) was found using multiple databases and further identified. CRISPR/Cas9-mediated deletion of EphA2-SE results in the significant downregulation of its target gene EphA2. Mechanistically, we revealed that the core active region of EphA2-SE comprises E1 component enhancer, which recruits TCF7L2 and FOSL2 transcription factors to drive the expression of EphA2, induce cell proliferation and metastasis. Bioinformatics analysis of RNA-seq data and functional experiments in vitro illustrated that EphA2-SE deletion inhibited cell growth and metastasis by blocking PI3K/AKT and Wnt/β-catenin pathway in HeLa, HCT-116 and MCF-7 cells. Overexpression of EphA2 in EphA2-SE−/− clones rescued the effect of EphA2-SE deletion on proliferation and metastasis. Subsequent xenograft animal model revealed that EphA2-SE deletion suppressed tumor proliferation and survival in vivo. Taken together, these findings demonstrate that EphA2-SE plays an oncogenic role and promotes tumor progression in various tumors by recruiting FOSL2 and TCF7L2 to drive the expression of oncogene EphA2.

The overproduction of osteoclasts, leading to bone destruction in patients with rheumatoid arthritis (RA), is well established. However, little is known about the metabolic dysfunction of osteoclast precursors (OCPs) in RA. Herein, we show that increasing fatty acid oxidation (FAO) induces OCP fusion. Carnitine palmitoyltransferase IA (CPT1A), which is important for carnitine transportation and is involved in FAO in the mitochondria, is upregulated in RA patients. This metabolic change further increases the expression of clathrin heavy chain (CLTC) and clathrin light chain A (CLTA) by enhancing the binding of the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) to the promoters of CLTA and CLTC. This drives clathrin-dependent endocytosis pathway, which attenuates fusion receptors in the cellular membrane and contributes to increased podosome structure formation. This study reveals a new mechanism through which FAO metabolism participates in joint destruction in RA and provides a novel therapeutic direction for the development of drugs against bone destruction in patients with RA.

Metabolic syndrome (MetS) is associated with cardiovascular risk, and there are various definitions, but which is most predictive of future cardiovascular disease (CVD) in the Chinese population is still unclear. MetS was defined with the revised ATP III (Third Adult Treatment Panel Report), International Diabetes Federation (IDF), and the Joint Committee for Developing Chinese Guidelines (JCDCG) definitions. Cox regression was used to estimate the hazard risk of cardiovascular disease among 20,888 participants using the Chinese Hypertension Survey (CHS) data. Sensitivity, specificity, and receiver operating characteristic (ROC) curve distance were used to test the ability of three MetS criteria to identify CVD. During an average follow-up of 4.89 years of 20,888 participants, 925 CVD events occurred (stroke, 560; coronary heart disease, 275; and other cardiovascular events, 119). The revised ATP III criteria identified the most individuals with MetS and had the highest prevalence of MetS. In addition, MetS was associated with a high risk of CVD in both men and women, according to three criteria. The highest diagnostic specificity was for IDF in men and JCDCG in women. The revised ATP III criteria had the highest sensitivity and shortest ROC curve distance in both men and women. Although the MetS definitions, including the revised ATP III, IDF, and JCDCG, are all related to the increased risks of CVD, overall, the revised ATP III performs best and is the most recommended for the Chinese population.

Background The efficacy of docetaxel-based chemotherapy is limited by the development of drug resistance. Recent studies demonstrated the efficacy of anti-programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapies in metastatic prostate cancer. The ataxia telangiectasia mutation (ATM) protein plays a crucial role in maintaining genome stability and function of mitosis. Here, we aimed to determine whether PD-1/PD-L1 signaling contributes to the resistance to DTX and to elucidate the mechanism underlying DTX-induced PD-L1 expression.Methods In this retrospective study, PD-L1 expression was analyzed in 33 tumor tissue samples from prostate cancer patients. Prostate cell lines were used to perform functional assays and examine underlying mechanisms in vitro. A fully mouse prostate cancer model and a humanized chimeric mouse bearing human prostate tumors and peripheral blood mononuclear cells were used for in vivo assays.Results We have shown that DTX, a chemotherapeutic drug which causing microtubule interference, could significantly induce the expression of PD-L1 in prostate cancer cells. This effect is blocked by the inhibition of ATM, suggesting that it plays an essential role in PD-L1 expression upregulated by DTX. Mechanistic studies have shown that ATM activity in cancer cells enhances the stability of the NF-κB essential modulator (NEMO), which leading to an increase in the NF-κB activity and PD-L1 expression. Using the mouse model, it was further demonstrated that a combination of ATM and NEMO inhibitors along with DTX augmented the antitumor efficacy of chemotherapy, which are comparable to that of PD-L1 antibody.Conclusions Our findings have revealed that a previously unrecognized ATM-NEMO signaling which induced by DTX is capable of suppressing tumor immunity by activating the expression of PD-L1, suggesting that the ATM-NEMO-NF-κB axis can be exploited to restore the immune balance and overcome cancer resistance triggered by DTX.Graphic Abstract: supplementary file 1

The Dlk1-Dio3 imprinted domain on mouse chromosome 12 contains three well-characterized paternally methylated differentially methylated regions (DMRs): IG-DMR, Gtl2-DMR, and Dlk1-DMR. These DMRs control the expression of many genes involved in embryonic development, inherited diseases, and human cancer in this domain. The first maternal methylation DMR discovered in this domain was the Meg8-DMR, the targets and biological function of which are still unknown. Here, using an enhancer-blocking assay, we first dissected the functional parts of the Meg8-DMR and showed that its insulator activity is dependent on the CCCTC-binding factor (CTCF) in MLTC-1. Results from RNA-seq showed that the deletion of the Meg8-DMR and its compartment CTCF binding sites, but not GGCG repeats, lead to the downregulation of numerous genes on chromosome 12, in particular the drastically reduced expression of Dlk1 and Rtl1 in the Dlk1-Dio3 domain, while differentially expressed genes are enriched in the MAPK pathway. In vitro assays revealed that the deletion of the Meg8-DMR and CTCF binding sites enhances cell migration and invasion by decreasing Dlk1 and activating the Notch1-Rhoc-MAPK/ERK pathway. These findings enhance research into gene regulation in the Dlk1-Dio3 domain by indicating that the Meg8-DMR functions as a long-range regulatory element which is dependent on CTCF binding sites and affects multiple genes in this domain.

Abstract Background The aim of the study was to assess the association between chronic kidney disease (CKD) and obesity in predicting CKD among Chinese adults, distinguishing between 5 different adiposity indices: visceral fat index (VFI), percentage body fat (PBF), body mass index (BMI), waist circumference (WC) and waist-to-height ratio (WHtR). Methods A total of 29,516 participants aged 35 years or above were selected using a stratified multistage random sampling method across China during 2012–2015. CKD was defined as an estimated glomerular filtration (eGFR)

Background Data regarding the metabolic risk factors clustering on the risk of left ventricular diastolic dysfunction (LVDD) are lacking among people living at high altitude and under hypoxic conditions. In this study, we explored the association between metabolic risk factor clustering and LVDD among the Tibetan population of China. Methods and Results We conducted a cross‐sectional survey in a representative sample of 1963 Tibetans in 2014 to 2016. Grading LVDD was based on recommendations for the evaluation of LV diastolic function by echocardiography (2009). The prevalence of LVDD among 1963 participants (mean age: 51.51 years, 41.11% male) was 34.39%. Odds ratios (95% CI) of LVDD for the 1, 2, and 3 to 5 risk factors clustering were 1.45 (0.96–2.17), 2.68 (1.8–3.98), and 2.9 (1.9–4.43), respectively (P for trend

Rheumatoid arthritis (RA) is an autoimmune-mediated disease that is associated with significant cartilage damage and immunosenescence. Despite decades of research, the major signal pathways that initiate RA are still unclear. The DNA damage response (DDR) is a specific and hierarchical network that includes cell cycle checkpoints, DNA repair, and DNA-damage tolerance pathways. Recent studies suggest that this condition is associated with deficits in telomere maintenance and overall genomic instability in the T cells of RA patients. Analysis of the underlying mechanisms has revealed defects in DDR pathways. Particularly, the DNA repair enzyme, ataxia telangiectasia mutated (ATM), is downregulated, which leaves the damaged DNA breaks in RA-associated T cells unrepaired and pushes them to apoptosis, exhausts the T cell pool, and promotes the arthritogenesis effector function of T cells. This review discusses recent advancements and illustrates that risk factors for RA, such as viral infections, environmental events, and genetic risk loci are combat with DDR signals, and the impaired DDR response of RA-associated T cells, in turn, triggers disease-related phenotypes. Therefore, DDR is the dominant signal that converts genetic and environmental stress to RA-related immune dysfunction. Understanding the orchestration of RA pathogenesis by DDR signals would further our current knowledge of RA and provide novel avenues in RA therapy.

Due to their unique physical and chemical properties, hygrogels have been applied in various industrial and agricultural fields. Biomedicine is another high value-added and attractive area for the application of hydrogels. For this reason, a novel temperature/pH sensitive cellulose based hydrogel was synthesized based on the cellulose from Phyllostachys heterocycla. Its synthesis conditions were optimized, and its loading and release capabilities for model drugs were investigated in detail. The resultant data showed that the synthesized hydrogel exhibited the highest swelling ratio at 37 °C and pH 7.4, corresponding to the temperature and pH of the human intestinal environment. The hydrogel held excellent load performance for model drug MB and an obvious temperature dependence at 37 °C (body temperature of human) when the model drug was released from it. These positive results suggest that the synthesized temperature/pH sensitive cellulose-based hydrogel has a great potential for oral drug delivery applications.

Background and objective Molecular targeting therapy is the direction of individualized treatment of lung cancer, scholars has been established targeted therapy prediction models which provide more guidance for clinical individual therapy. This study investigated the relationship among pulmonary surfactant-associated protein D (SP-D), transforming growth factor α (TGF-α), matrix metalloproteinase 9 (MMP-9), tissue polypeptide specific antigen (TPS), and Krebs von den Lungen-6 (KL-6) and response as well as survival in the patients with recurrent non-small cell lung cancer, which Erlotinib was as second line treatment after failure to chemotherapy. This study also established a predictive prognostic model. Methods Serum levels of SP-D, TGF-α, MMP-9, TPS, and KL-6 in 114 patients before erlotinib treatment were detected by ELISA method. Combined with clinical factors, these levels were used to investigate the relationship with efficacy in erlotinib treatment and construct a predicted prognostic model by Kaplan-Meier curve and Cox proportional hazard model multivariate analysis. Results The objective response rate (ORR) and disease control rate (DCR) in the 114 patients, were 22.8% (26/114) and 72.8% (83/114), to Erlotinib treatment respectively. The median progression-free survival (PFS) and one year survival rate with Erlotinib treatment were 5.13 months and 69.3%, respectively. Patients in the SP-D>110 ng/mL group exhibited more ORR (33.3% vs 13.3%, P=0.011) and DCR (83.3% vs 63.3%, P=0.017) than those in the ≤110 ng/mL group. Patients in the MMP-9≤535 ng/mL group showed more DCR (83.9%) than those in the >535 ng/mL group (62.1%) (P=0.009). Patients in the TPS110 ng/mL (5.95 months vs 3.25 months, P=0.009), MMP-9≤535 ng/mL (5.83 months vs 3.47 months, P=0.046), KL-6

Preoperative elevation of serum C-reactive protein (CRP) is reportedly associated with poor prognosis in several types of cancer. This study investigated the role of serum CRP as a prognostic factor in early-stage esophageal squamous cell carcinoma (ESCC). The preoperative serum CRP levels were measured in 156 newly diagnosed pT1–2N0M0 patients using an enzyme-linked immunosorbent assay. Correlations between serum CRP levels and other clinical parameters were analyzed. Multivariate analyses were performed to find prognostic markers using Cox's proportional hazards model. CRP concentrations were within the normal range in 117 (75%) individuals, but were elevated in 39 (25%) patients. Serum CRP levels were significantly correlated with the tumor length (p = 0.032), depth (T classification, p = 0.0157), or histologic grade (p = 0.034). The overall 5-year survival rates were 76.3% and 50.2% in the low- and high-CRP groups, respectively (p = 0.005). By multivariate analyses, the elevated serum CRP level was found to be an independent prognostic factor for poor survival (hazard ratio = 2.131; p = 0.007), regardless of tumor classification or other prognostic factors. In conclusion, preoperative, high serum CRP is an independent determinant of poor prognosis in early-stage ESCC.

Background and objective BIM gene is a member of the BCL-2 family, is involved in cell death. The aim of this study is to explore the relationship between BIM gene polymorphism and therapeutic efficacy in the retreatment advanced non-small cell lung cancer (NSCLC) with tyrosine kinase inhibitor (EGFR-TKI). Methods In the study, there were 123 patients who were diagnosed with advanced NSCLC in Zhejiang Province Cancer Hospital bewteen January 2009 to October 2012, all of who were received gefitinib and erlotinib therapy after failure to chemotherapy. We detected the genotype of peripheral blood leukocytes of patients with BIM gene polymorphism though polymerase chain reaction (PCR). Statistical analysis was performed by SPSS version 13.0. Results On the disease control rates, BIM gene with no polymorphism type was slightly better trend than polymorphism types in disease control rate DCR (75.5% vs 57.1%, χ2=2.931, P=0.087). Univariate analysis the median PFS, women were longer than men (6.9 months vs 4.5 months, χ2 =7.077, P=0.008). Non-smokers were longer than smokers (8.0 months vs 2.5 months, χ2 =15.277, P

Background and objective As the first epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in China, icotinib shows promising anticancer activity in vitro and vivo. The phase III clinical study (ICOGEN) showed that icotinib has a good efficacy and tolerability in Chinese patients with advanced non-small cell lung cancer (NSCLC) compared with gefitinib. This retrospective study aims to evaluate the efficacy and tolerability of icotinib monotherapy for advanced NSCLC patients with EGFR mutation and wild-type patients in our hospital. Methods Patients with advanced NSCLC who were treated with icotinib in Zhejiang Cancer Hospital were retrospectively analyzed from August, 2011 to August, 2012. Survival was estimated using Kaplan-Meier analysis and Log-rank tests. Results The clinical data of 49 patients (13 with wild-type and 36 with EGFR mutation) with NSCLC were enrolled in the current study. The patients’ overall objective response rate (ORR) was 58.3% and the disease control rate (DCR) in 36 EGFR mutation patients was 88.9%. The ORR was 7.7% and DCR was 53.8% in the wild-type patients. Median progression-free survival (PFS) with icotinib treatment in EGFR mutation patients was 9.5 months and 2.2 months in wild-type patients (P

The discovery of multiple molecular mechanisms underlying the development, progression, and prognosis of lung cancer, has created new opportunities for targeted therapy. Each subtype is associated with molecular tests that define the subtype and drugs that may have potential therapeutic effect on lung cancer. In 2004, mutations in the epidermal growth factor receptor (epidermal growth factor receptor, EGFR) gene were discovered in non-small cell lung cancers (NSCLC), especially in adenocarcinomas. And they are strongly associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Moreover, in 2007 the existence of the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene was discovered in NSCLC, and the same as EGFR-TKIs, ALK inhibitors are being found to be highly effective in lung cancers. At present, multiple molecular subtype of lung cancer and relevant targeted drugs are undering study. Here, we review the remarkable progress in molecular subtype of lung cancer and the related targeted therapy.

Background and objective The appearance of highly effective and low toxic drugs enables an increasing number of advanced non-small cell lung cancer (NSCLC) patients to receive third-line therapy. No other standard choice for third-line therapy aside from erlotinib is possible. This study respectively explores the efficacy and safety of single chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and doublet chemotherapy in advanced NSCLC third-line treatment. Methods This study included 115 NSCLC patients in the stage IIIb or IV who were retrospectively reviewed to investigate the differences of survival time between different treatments. Univariate and multivariate analyses were conducted based on the Kaplan-Meier method and Cox proportional-hazards model. Results The median progression free survival (PFS) values in the single agent, EGFR-TKIs and doublet groups were 2.30, 3.17 and 2.37 months, respectively (P=0.045). The median overall survival from the initiation of the third-line treatment were 8.00, 10.40 and 7.87 months in the three groups (P=0.110). The rates of stage III-IV toxicities were 33.3%, 18.2% and 68.8% (P

Background/Aims: To investigate whether the invasively obtained central aortic systolic blood pressure (CSBP) predicts chronic kidney disease (CKD) better than brachial systolic blood pressure (SBP), brachial diastolic blood pressure (DBP) and brachial pulse pressure (PP) in the middle-aged Chinese population. Methods: A cross-sectional study was carried out across China in 2009-2010 among the subjects aged 35-64 years. CSBP was measured non-invasively by radial artery applanation tonometry B-pro (A-PULSE CASP and corresponding software). CSBP, SBP, DBP and PP were standardized with Z-score and the odds ratios were calculated with multivariable logistic regression model. Results: Data of 10197 participants were analyzed. The multivariable logistic regression after adjusting for possible confounders showed that a 1-standard deviation increment in each blood pressure measurement was associated with greater risk of CKD in both men and women (P < 0.05). The association of CSBP with CKD was stronger than SBP, DBP and PP in women, while in men the association of CSBP with CKD was stronger only than PP. With CSBP and SBP entering into the multivariable logistic regression models jointly, the odds ratio (95% confidence interval) for CSBP and SBP was 1.57 (1.39-1.79) and 1.22 (1.07-1.38) in women and 1.20 (1.03-1.39) and 1.48 (1.28-1.72) in men, respectively. With CSBP and DBP entering into the multivariable logistic regression models jointly, the odds ratio (95% confidence interval) for CSBP and DBP was 1.68 (1.52-1.84) and 1.15 (1.04-1.27) in women and 1.30 (1.15-1.46) and 1.45 (1.29-1.63) in men, respectively. With CSBP and PP entering into the multivariable logistic regression models jointly, the odds ratio (95% confidence interval) for CSBP and PP was 1.75 (1.58-1.94) and 1.06 (0.96-1.17) in women and 1.58 (1.41-1.77) and 1.04 (0.93-1.17) in men, respectively. Conclusion: CSBP and brachial blood pressure measurements are all predictors of CKD, however the non-invasively obtained CSBP may offer advantages over brachial blood pressure measurements in CKD risk prediction in women.

This study aims to investigate the pre- and postconditioning effects of lipoxin A4 (LXA4) on myocardial damage caused by ischemia/reperfusion (I/R) injury. Seventy-two rats were divided into 6 groups: sham groups (C1 and C2), I/R groups (I/R1 and I/R2), and I/R plus LXA4 preconditioning and postconditioning groups (LX1 and LX2). The serum levels of IL-1β, IL-6, IL-8, IL-10, TNF-α, and cardiac troponin I (cTnI) were measured. The content and the activity of Na+-K+-ATPase as well as the superoxide dismutase (SOD), and malondialdehyde (MDA) levels were determined. Along with the examination of myocardium ultrastructure and ventricular arrhythmia scores (VAS), connexin 43 (Cx43) expression were also detected. Lower levels of IL-1β, IL-6, IL-8, TNF-α, cTnI, MDA content, and VAS and higher levels of IL-10, SOD activity, Na+-K+-ATPase content and activity, and Cx43 expression appeared in LX groups than I/R groups. Besides, H&E staining, TEM examination as well as analysis of gene, and protein confirmed that LXA4 preconditioning was more effective than postconditioning in preventing arrhythmogenesis via the upregulation of Cx43. That is, LXA4 postconditioning had better protective effect on Na+-K+-ATPase and myocardial ultrastructure.

Abstract Background Purifying stem cells is an inevitable process for further investigation and cell-therapy. Sorting side population (SP) cells is generally regarded as an effective method to enrich for progenitor cells. This study was to explore whether sorting SP could enrich for the Musashi1 (Msi1) positive cells from Msi1 high expression cells (Msi1high cells) derived from mouse embryonic stem cells (ESCs) in vitro. Results In this study, Msi1high cell population derived from ESCs were stained by Hoechst 33342, and then the SP and non-SP (NSP) fractions were analyzed and sorted by fluorescence activated cell sorter. Subsequently, the expressions of Msi1 and other markers for neural and intestinal stem cells in SP and NSP were respectively detected. SP and NSP cells were hypodermically engrafted into the backs of NOD/SCID mice to form grafts. The developments of neural and intestinal epithelial cells in these grafts were investigated. SP fraction was identified and isolated from Msi1high cell population. The expression of Msi1 in SP fraction was significantly higher than that in NSP fraction and unsorted Msi1high cells (P< 0.05). Furthermore, the markers for neural cells and intestinal epithelial cells were more highly expressed in the grafts from SP fraction than those from NSP fraction (P< 0.05). Conclusions SP fraction, isolated from Msi1high cells, contains almost all the Msi1-positive cells and has the potential to differentiate into neural and intestinal epithelial cells in vivo. Sorting SP fraction could be a convenient and practical method to enrich for Msi1-positive cells from the differentiated cell population derived from ESCs.

BACKGROUND Loneliness and isolation are associated with multiple cardiovascular diseases (CVDs), but there is a lack of research on whether they were causally linked. We conducted a Mendelian Randomization (MR) study to explore causal relationships between loneliness and isolation and multiple CVDs. METHODS Single nucleotide polymorphisms associated with loneliness and isolation were identified from a genome-wide association study (GWAS) of 455,364 individuals of European ancestry in the IEU GWAS database. Summary data for 15 CVDs were also obtained from the IEU GWAS database. We used three MR methods including inverse variance weighting, MR-Egger, and weighted median estimation to assess the causal effect of exposure on outcomes. Cochran's Q test and MR-Egger intercept test were used to evaluate the heterogeneity and pleiotropy. RESULTS MR analysis showed that loneliness and isolation were significantly associated with essential hypertension (OR = 1.07, 95% CI: 1.03-1.12), atherosclerotic heart disease (OR = 1.04; 95% CI: 1.02-1.06), myocardial infarction (OR = 1.02; 95% CI: 1-1.04) and angina (OR = 1.04; 95% CI =1.02-1.06). No heterogeneity and pleiotropy effects were found in this study. CONCLUSIONS Causal relationship of loneliness and isolation with CVDs were found in this study. [ABSTRACT FROM AUTHOR]