First Affiliated Hospital of Sichuan Medical University

OBJECTIVE: To determine the effects of longer term modest salt reduction on blood pressure, hormones, and lipids. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane Hypertension Group Specialised Register, Cochrane Central Register of Controlled Trials, and reference list of relevant articles. INCLUSION CRITERIA: Randomised trials with a modest reduction in salt intake and duration of at least four weeks. DATA EXTRACTION AND ANALYSIS: Data were extracted independently by two reviewers. Random effects meta-analyses, subgroup analyses, and meta-regression were performed. RESULTS: Thirty four trials (3230 participants) were included. Meta-analysis showed that the mean change in urinary sodium (reduced salt v usual salt) was -75 mmol/24 h (equivalent to a reduction of 4.4 g/day salt), and with this reduction in salt intake, the mean change in blood pressure was -4.18 mm Hg (95% confidence interval -5.18 to -3.18, I(2)=75%) for systolic blood pressure and -2.06 mm Hg (-2.67 to -1.45, I(2)=68%) for diastolic blood pressure. Meta-regression showed that age, ethnic group, blood pressure status (hypertensive or normotensive), and the change in 24 hour urinary sodium were all significantly associated with the fall in systolic blood pressure, explaining 68% of the variance between studies. A 100 mmol reduction in 24 hour urinary sodium (6 g/day salt) was associated with a fall in systolic blood pressure of 5.8 mm Hg (2.5 to 9.2, P=0.001) after adjustment for age, ethnic group, and blood pressure status. For diastolic blood pressure, age, ethnic group, blood pressure status, and the change in 24 hour urinary sodium explained 41% of the variance between studies. Meta-analysis by subgroup showed that in people with hypertension the mean effect was -5.39 mm Hg (-6.62 to -4.15, I(2)=61%) for systolic blood pressure and -2.82 mm Hg (-3.54 to -2.11, I(2)=52%) for diastolic blood pressure. In normotensive people, the figures were -2.42 mm Hg (-3.56 to -1.29, I(2)=66%) and -1.00 mm Hg (-1.85 to -0.15, I(2)=66%), respectively. Further subgroup analysis showed that the decrease in systolic blood pressure was significant in both white and black people and in men and women. Meta-analysis of data on hormones and lipids showed that the mean change was 0.26 ng/mL/h (0.17 to 0.36, I(2)=70%) for plasma renin activity, 73.20 pmol/L (44.92 to 101.48, I(2)=62%) for aldosterone, 187 pmol/L (39 to 336, I(2)=5%) for noradrenaline (norepinephrine), 37 pmol/L (-1 to 74, I(2)=12%) for adrenaline (epinephrine), 0.05 mmol/L (-0.02 to 0.11, I(2)=0%) for total cholesterol, 0.05 mmol/L (-0.01 to 0.12, I(2)=0%) for low density lipoprotein cholesterol, -0.02 mmol/L (-0.06 to 0.01, I(2)=16%) for high density lipoprotein cholesterol, and 0.04 mmol/L (-0.02 to 0.09, I(2)=0%) for triglycerides. CONCLUSIONS: A modest reduction in salt intake for four or more weeks causes significant and, from a population viewpoint, important falls in blood pressure in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. Salt reduction is associated with a small physiological increase in plasma renin activity, aldosterone, and noradrenaline and no significant change in lipid concentrations. These results support a reduction in population salt intake, which will lower population blood pressure and thereby reduce cardiovascular disease. The observed significant association between the reduction in 24 hour urinary sodium and the fall in systolic blood pressure, indicates that larger reductions in salt intake will lead to larger falls in systolic blood pressure. The current recommendations to reduce salt intake from 9-12 to 5-6 g/day will have a major effect on blood pressure, but a further reduction to 3 g/day will have a greater effect and should become the long term target for population salt intake.

BACKGROUND: A reduction in salt intake lowers blood pressure (BP) and, thereby, reduces cardiovascular risk. A recent meta-analysis by Graudal implied that salt reduction had adverse effects on hormones and lipids which might mitigate any benefit that occurs with BP reduction. However, Graudal's meta-analysis included a large number of very short-term trials with a large change in salt intake, and such studies are irrelevant to the public health recommendations for a longer-term modest reduction in salt intake. We have updated our Cochrane meta-analysis. OBJECTIVES: To assess (1) the effect of a longer-term modest reduction in salt intake (i.e. of public health relevance) on BP and whether there was a dose-response relationship; (2) the effect on BP by sex and ethnic group; (3) the effect on plasma renin activity, aldosterone, noradrenaline, adrenaline, cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides. SEARCH METHODS: We searched MEDLINE, EMBASE, Cochrane Hypertension Group Specialised Register, Cochrane Central Register of Controlled Trials, and reference list of relevant articles. SELECTION CRITERIA: We included randomised trials with a modest reduction in salt intake and duration of at least 4 weeks. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers. Random effects meta-analyses, subgroup analyses and meta-regression were performed. MAIN RESULTS: Thirty-four trials (3230 participants) were included. Meta-analysis showed that the mean change in urinary sodium (reduced salt vs usual salt) was -75 mmol/24-h (equivalent to a reduction of 4.4 g/d salt), the mean change in BP was -4.18 mmHg (95% CI: -5.18 to -3.18, I (2)=75%) for systolic and -2.06 mmHg (95% CI: -2.67 to -1.45, I (2)=68%) for diastolic BP. Meta-regression showed that age, ethnic group, BP status (hypertensive or normotensive) and the change in 24-h urinary sodium were all significantly associated with the fall in systolic BP, explaining 68% of the variance between studies. A 100 mmol reduction in 24 hour urinary sodium (6 g/day salt) was associated with a fall in systolic BP of 5.8 mmHg (95%CI: 2.5 to 9.2, P=0.001) after adjusting for age, ethnic group and BP status. For diastolic BP, age, ethnic group, BP status and the change in 24-h urinary sodium explained 41% of the variance between studies. Meta-analysis by subgroup showed that, in hypertensives, the mean effect was -5.39 mmHg (95% CI: -6.62 to -4.15, I (2)=61%) for systolic and -2.82 mmHg (95% CI: -3.54 to -2.11, I (2)=52%) for diastolic BP. In normotensives, the mean effect was -2.42 mmHg (95% CI: -3.56 to -1.29, I (2)=66%) for systolic and -1.00 mmHg (95% CI: -1.85 to -0.15, I (2)=66%) for diastolic BP. Further subgroup analysis showed that the decrease in systolic BP was significant in both whites and blacks, men and women. Meta-analysis of hormone and lipid data showed that the mean effect was 0.26 ng/ml/hr (95% CI: 0.17 to 0.36, I (2)=70%) for plasma renin activity, 73.20 pmol/l (95% CI: 44.92 to 101.48, I (2)=62%) for aldosterone, 31.67 pg/ml (95% CI: 6.57 to 56.77, I (2)=5%) for noradrenaline, 6.70 pg/ml (95% CI: -0.25 to 13.64, I (2)=12%) for adrenaline, 0.05 mmol/l (95% CI: -0.02 to 0.11, I (2)=0%) for cholesterol, 0.05 mmol/l (95% CI: -0.01 to 0.12, I (2)=0%) for LDL, -0.02 mmol/l (95% CI: -0.06 to 0.01, I (2)=16%) for HDL, and 0.04 mmol/l (95% CI: -0.02 to 0.09, I (2)=0%) for triglycerides. AUTHORS' CONCLUSIONS: A modest reduction in salt intake for 4 or more weeks causes significant and, from a population viewpoint, important falls in BP in both hypertensive and normotensive individuals, irrespective of sex and ethnic group. With salt reduction, there is a small physiological increase in plasma renin activity, aldosterone and noradrenaline. There is no significant change in lipid levels. These results provide further strong support for a reduction in population salt intake. This will likely lower population BP and, thereby, reduce cardiovascular disease. Additionally, our analysis demonstrates a significant association between the reduction in 24-h urinary sodium and the fall in systolic BP, indicating the greater the reduction in salt intake, the greater the fall in systolic BP. The current recommendations to reduce salt intake from 9-12 to 5-6 g/d will have a major effect on BP, but are not ideal. A further reduction to 3 g/d will have a greater effect and should become the long term target for population salt intake.

Biofilm is a natural form of bacterial growth ubiquitously in environmental niches. The biofilm formation results in increased resistance to negative environmental influences including resistance to antibiotics and antimicrobial agents. Quorum sensing (QS) is cell-to-cell communication mechanism, which plays an important role in biofilm development and balances the environment when the bacteria density becomes high. Due to the prominent points of biofilms implicated in infectious disease and the spread of multi-drug resistance, it is urgent to discover new antibacterial agents that can regulate biofilm formation and development. Accumulated evidences demonstrated that natural products from plants had antimicrobial and chemo-preventive properties in modulation of biofilm formation in the last two decades. This review will summarize recent studies on the discovery of natural anti-biofilm agents from plants with clear-cut mechanisms or identified molecular addresses, as well as some herbs with unknown mechanisms or unidentified bioactive ingredients. We also focus on the progression of techniques on the extraction and identification of natural anti-biofilm substances. Besides, anti-biofilm therapeutics undergoing clinical trials are discussed. These newly discovered natural anti-biofilm agents are promising candidates which could provide novel strategies for biofilm-associated infections.

Diabetes mellitus is a metabolic disease characterized by long-term hyperglycaemia, which leads to microangiopathy and macroangiopathy and ultimately increases the mortality of diabetic patients. Endothelial dysfunction, which has been recognized as a key factor in the pathogenesis of diabetic microangiopathy and macroangiopathy, is characterized by a reduction in NO bioavailability. Oxidative stress, which is the main pathogenic factor in diabetes, is one of the major triggers of endothelial dysfunction through the reduction in NO. In this review, we summarize the four sources of ROS in the diabetic vasculature and the underlying molecular mechanisms by which the pathogenic factors hyperglycaemia, hyperlipidaemia, adipokines and insulin resistance induce oxidative stress in endothelial cells in the context of diabetes. In addition, we discuss oxidative stress-targeted interventions, including hypoglycaemic drugs, antioxidants and lifestyle interventions, and their effects on diabetes-induced endothelial dysfunction. In summary, our review provides comprehensive insight into the roles of oxidative stress in diabetes-induced endothelial dysfunction.

miRNAs (microRNAs) participate in many diseases including cardiovascular disease. In contrast with our original hypothesis, miRNAs exist in circulating blood and are relatively stable due to binding with other materials. The aim of the present translational study is to establish a method of determining the absolute amount of an miRNA in blood and to determine the potential applications of circulating cell-free miR-1 (microRNA-1) in AMI (acute myocardial infarction). The results revealed that miR-1 is the most abundant miRNA in the heart and is also a heart- and muscle-specific miRNA. In a cardiac cell necrosis model induced by Triton X-100 in vitro, we found that cardiac miR-1 can be released into the culture medium and is stable at least for 24 h. In a rat model of AMI induced by coronary ligation, we found that serum miR-1 is quickly increased after AMI with a peak at 6 h, in which an increase in miR-1 of over 200-fold was demonstrated. The miR-1 level returned to basal levels at 3 days after AMI. Moreover, the serum miR-1 level in rats with AMI had a strong positive correlation with myocardial infarct size. To verify further the relationship between myocardial size and miR-1 level, an IP (ischaemic preconditioning) model was used. The results showed that IP significantly reduced circulating miR-1 levels and myocardial infract size induced by I/R (ischaemia/reperfusion) injury. Finally, the levels of circulating cell-free miR-1 were significantly increased in patients with AMI and had a positive correlation with serum CK-MB (creatine kinase-MB) levels. In conclusion, the results suggest that serum miR-1 could be a novel sensitive diagnostic biomarker for AMI.

Objective: Insomnia is a major health challenge in the general population, but the results of the gender differences in the epidemiology of insomnia have been mixed. This is a meta-analysis to examine the gender difference in the prevalence of insomnia among the general population. Methods: Two reviewers independently searched relevant publications in PubMed, EMBASE, PsycINFO, Web of Science from their inception to 16 April 2019. Studies that reported the gender-based prevalence of insomnia according to the international diagnostic criteria were included for analyses using the random-effects model. Results: Eventually 13 articles were included in the meta-analysis. The pooled prevalence of insomnia in the general population was 22.0% [ n = 22,980, 95% confidence interval (CI): 17.0–28.0%], and females had a significantly higher prevalence of insomnia compared with males (OR = 1.58, 95% CI: 1.35, 1.85, Z = 5.63, p < 0.0001). Subgroup analyses showed that greater gender difference was associated with the use of case-control study design and consecutive sampling method. Meta-regression analyses also revealed that higher proportion of females and better study quality were significantly associated with greater gender difference. Conclusions: This meta-analysis found that the prevalence of insomnia in females was significantly higher than males in the included studies. Due to the negative effects of insomnia on health, regular screening, and effective interventions should be implemented in the general population particularly for females.

The rapid development of nanotechnology offers a variety of potential therapeutic strategies for cancer treatment. High atomic element nanomaterials are often utilized as radiosensitizers due to their unique photoelectric decay characteristics. Among them, gold nanoparticles (GNPs) are one of the most widely investigated and are considered to be an ideal radiosensitizers for radiotherapy due to their high X-ray absorption and unique physicochemical properties. Over the last few decades, multi-disciplinary studies have focused on the design and optimization of GNPs to achieve greater dosing capability and higher therapeutic effects and highlight potential mechanisms for radiosensitization of GNPs. Although the radiosensitizing potential of GNPs has been widely recognized, its clinical translation still faces many challenges. This review analyses the different roles of GNPs as radiosensitizers in cancer radiotherapy and summarizes recent advances. In addition, the underlying mechanisms of GNP radiosensitization, including physical, chemical and biological mechanisms are discussed, which may provide new directions for the optimization and clinical transformation of next-generation GNPs.

Non-small cell lung cancer (NSCLC) is the leading cause of death by cancer worldwide. Despite developments in therapeutic approaches for the past few decades, the 5-year survival rate of patients with NSCLC remains low. NSCLC tumor is a complex, heterogeneous microenvironment, comprising blood vessels, cancer cells, immune cells, and stroma cells. Vascular endothelial growth factors (VEGFs) are a major mediator to induce tumor microvasculature and are associated with the progression, recurrence, and metastasis of NSCLC. Current treatment medicines targeting VEGF/VEGF receptor (VEGFR) pathway, including neutralizing antibodies to VEGF or VEGFR and receptor tyrosine kinase inhibitors, have shown good treatment efficacy in patients with NSCLC. VEGF is not only an important angiogenic factor but also an immunomodulator of tumor microenvironment (TME). VEGFs can suppress antigen presentation, stimulate activity of regulatory T (Treg) cells, and tumor-associated macrophages, which in turn promote an immune suppressive microenvironment in NSCLC. The present review focuses on the angiogenic and non-angiogenic functions of VEGF in NSCLC, especially the interaction between VEGF and the cellular components of the TME. Additionally, we discuss recent preclinical and clinical studies to explore VEGF/VEGFR-targeted compounds and immunotherapy as novel approaches targeting the TME for the treatment of NSCLC.

Although emerging evidence suggests that low levels of vitamin D may contribute to the development of autoimmune disease, the relationship between vitamin D reduction and autoimmune thyroid disease (AITD), which includes Graves' disease (GD) and Hashimoto thyroiditis (HT), is still controversial. The aim was to evaluate the association between vitamin D levels and AITD through systematic literature review. We identified all studies that assessed the association between vitamin D and AITD from PubMed, Embase, CENTRAL, and China National Knowledge Infrastructure (CNKI) databases. We included studies that compared vitamin D levels between AITD cases and controls as well as those that measured the odds of vitamin D deficiency by AITD status. We combined the standardized mean differences (SMD) or the odds ratios (OR) in a random effects model. Twenty case-control studies provided data for a quantitative meta-analysis. Compared to controls, AITD patients had lower levels of 25(OH)D (SMD: -0.99, 95% CI: -1.31, -0.66) and were more likely to be deficient in 25(OH)D (OR 2.99, 95% CI: 1.88, 4.74). Furthermore, subgroup analyses result showed that GD and HT patients also had lower 25(OH)D levels and were more likely to have a 25(OH)D deficiency, suggesting that low levels of serum 25(OH)D was related to AITD.

BACKGROUND: Gene expression can be posttranscriptionally regulated by a complex network of proteins. N1-methyladenosine (m1A) is a newly validated RNA modification. However, little is known about both its influence and biogenesis in tumor development. METHODS: This study analyzed TCGA data of patients with five kinds of gastrointestinal (GI) cancers. Using data from cBioPortal, molecular features of the nine known m1A-related enzymes in GI cancers were investigated. Using a variety of bioinformatics approach, the impact of m1A regulators on its downstream signaling pathway was studied. To further confirm this regulation, the effect of m1A writer ALKBH3 knockdown was studied using RNA-seq data from published database. RESULTS: Dysregulation and multiple types of genetic alteration of putative m1A-related enzymes in tumor samples were observed. The ErbB and mTOR pathways with ErbB2, mTOR, and AKT1S1 hub genes were identified as being regulated by m1A-related enzymes. The expression of both ErbB2 and AKT1S1 was decreased after m1A writer ALKBH3 knockdown. Furthermore, Gene Ontology analysis revealed that m1A downstream genes were associated with cell proliferation, and the results showed that m1A genes are reliably linked to mTOR. CONCLUSION: This study demonstrated for the first time the dysregulation of m1A regulators in GI cancer and its signaling pathways and will contribute to the understanding of RNA modification in cancer.

BACKGROUND: Glucocorticoids (GCs) show powerful treatment effect on rheumatoid arthritis (RA). However, the clinical application is limited by their nonspecific distribution after systemic administration, serious adverse reactions during long-term administration. To achieve better treatment, reduce side effect, we here established a biomimetic exosome (Exo) encapsulating dexamethasone sodium phosphate (Dex) nanoparticle (Exo/Dex), whose surface was modified with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) compound to attain FPC-Exo/Dex active targeting drug delivery system. RESULTS: The size of FPC-Exo/Dex was 128.43 ± 16.27 nm, with a polydispersity index (PDI) of 0.36 ± 0.05, and the Zeta potential was - 22.73 ± 0.91 mV. The encapsulation efficiency (EE) of the preparation was 10.26 ± 0.73%, with drug loading efficiency (DLE) of 18.81 ± 2.05%. In vitro study showed this system displayed enhanced endocytosis and excellent anti-inflammation effect against RAW264.7 cells by suppressing pro-inflammatory cytokines and increasing anti-inflammatory cytokine. Further biodistribution study showed the fluorescence intensity of FPC-Exo/Dex was stronger than other Dex formulations in joints, suggesting its enhanced accumulation to inflammation sites. In vivo biodistribution experiment displayed FPC-Exo/Dex could preserve the bone and cartilage of CIA mice better and significantly reduce inflamed joints. Next in vivo safety evaluation demonstrated this biomimetic drug delivery system had no obvious hepatotoxicity and exhibited desirable biocompatibility. CONCLUSION: The present study provides a promising strategy for using exosome as nanocarrier to enhance the therapeutic effect of GCs against RA.

Diabetic nephropathy (DN) is a chronic low-grade inflammatory disease. Oxidative stress and nuclear factor kappa B (NF- κ B) signaling play an important role in the pathogenesis of DN. Short-chain fatty acids (SCFAs) produced from carbohydrate fermentation in the gastrointestinal tract exert positive regulatory effects on inflammation and kidney injuries. However, it is unclear whether SCFAs can prevent and ameliorate DN. In the present study, we evaluated the role and mechanism of the three main SCFAs (acetate, propionate, and butyrate) in high-fat diet (HFD) and streptozotocin- (STZ-) induced type2 diabetes (T2D) and DN mouse models and in high glucose-induced mouse glomerular mesangial cells (GMCs), to explore novel therapeutic strategies and molecular targets for DN. We found that exogenous SCFAs, especially butyrate, improved hyperglycemia and insulin resistance; prevented the formation of proteinuria and an increase in serum creatinine, urea nitrogen, and cystatin C; inhibited mesangial matrix accumulation and renal fibrosis; and blocked NF- κ B activation in mice. SCFAs also inhibited high glucose-induced oxidative stress and NF- κ B activation and enhanced the interaction between β -arrestin-2 and I- κ B α in GMCs. Specifically, the beneficial effects of SCFAs were significantly facilitated by the overexpression GPR43 or imitated by a GPR43 agonist but were inhibited by siRNA-GPR43 in GMCs. These results support the conclusion that SCFAs, especially butyrate, partially improve T2D-induced kidney injury via GPR43-mediated inhibition of oxidative stress and NF- κ B signaling, suggesting SCFAs may be potential therapeutic agents in the prevention and treatment of DN.

BACKGROUND: Ischemic brain injury is associated with neuroinflammatory response, which essentially involves glial activation and neutrophil infiltration. Transcription factors nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) contribute to ischemic neuroinflammatory processes and secondary brain injury by releasing proinflammatory mediators. Kaempferol-3-O-rutinoside (KRS) and kaempferol-3-O- glucoside (KGS) are primary flavonoids found in Carthamus tinctorius L. Recent studies demonstrated that KRS protected against ischemic brain injury. However, little is known about the underlying mechanisms. Flavonoids have been reported to have antiinflammatory properties. Herein, we explored the effects of KRS and KGS in a transient focal stroke model. METHODOLOGY/PRINCIPAL FINDINGS: Rats were subjected to middle cerebral artery occlusion for 2 hours followed by 22 h reperfusion. An equimolar dose of KRS or KGS was administered i.v. at the beginning of reperfusion. The results showed that KRS or KGS significantly attenuated the neurological deficits, brain infarct volume, and neuron and axon injury, reflected by the upregulation of neuronal nuclear antigen-positive neurons and downregulation of amyloid precursor protein immunoreactivity in the ipsilateral ischemic hemisphere. Moreover, KRS and KGS inhibited the expression of OX-42, glial fibrillary acidic protein, phosphorylated STAT3 and NF-κB p65, and the nuclear content of NF-κB p65. Subsequently, these flavonoids inhibited the expression of tumor necrosis factor α, interleukin 1β, intercellular adhesion molecule 1, matrix metallopeptidase 9, inducible nitric oxide synthase, and myeloperoxidase. CONCLUSION/SIGNIFICANCE: Our findings suggest that postischemic treatment with KRS or KGS prevents ischemic brain injury and neuroinflammation by inhibition of STAT3 and NF-κB activation and has the therapeutic potential for the neuroinflammation-related diseases, such as ischemic stroke.

BACKGROUND: Recurrence and metastasis are the leading causes of tumour-related death in patients with oesophageal squamous cell carcinoma (ESCC). Tumour-infiltrating natural killer cells (NK cells) display powerful cytotoxicity to tumour cells and play a pivotal role in tumour therapy. However, the phenotype and functional regulation of NK cells in oesophageal squamous cell carcinoma (ESCC) remains largely unknown. METHODS: Single cell suspensions from blood and tissue samples were isolated by physical dissociation and filtering through a 70 μm cell strainer. Flow cytometry was applied to profile the activity and function of NK cells, and an antibody chip experiment was used to identify and quantitate cytokine levels. We studied IL-6 and IL-8 function in primary oesophageal squamous carcinoma and NK cell co-cultures in vitro and by a xenograft tumour model in vivo. Western blotting was used to quantitate STAT3 (signal transducer and activator of transcription 3) and p-STAT3 levels. Finally, we performed an IHC array to analyse IL-6/IL-8 (interleukin 6/interleukin 8) expression in 103 pairs of tumours and matched adjacent tissues of patients with ESCC to elucidate the correlation between IL-6 or IL-8 and clinical characteristics. RESULTS: The percentages of NK cells in both peripheral blood and tumour tissues from patients with ESCC were significantly increased in comparison with those in the controls and correlated with the clinical characteristics. Furthermore, the decrease in activating receptors and increase in inhibitory receptors on the surface of tumour-infiltrating NK cells was confirmed by flow cytometry. The level of granzyme B, the effector molecule of tumour-infiltrating NK cells, was also decreased. Mechanistically, primary ESCC cells activated the STAT3 signalling pathway on NK cells through IL-6 and IL-8 secretion, leading to the downregulation of activating receptors (NKp30 and NKG2D) on the surface of NK cells. An ex vivo study showed that blockade of STAT3 attenuated the IL-6/IL-8-mediated impairment of NK cell function. Moreover, the expression of IL-6 or IL-8 in tumour tissues was validated by immunohistochemistry to be positively correlated with tumour progression and poor survival, respectively. CONCLUSIONS: Tumour cell-secreted IL-6 and IL-8 impair the activity and function of NK cells via STAT3 signalling and contribute to oesophageal squamous cell carcinoma malignancy.

OBJECTIVE: To demonstrate whether abnormal glucose metabolism (diabetes and prediabetes) is associated with increased risk for cancer in the Chinese population and to identify factors that modify the risk of cancer among individuals with abnormal glucose metabolism. METHODS: Between 2011 and 2012, 259 657 community-dwelling adults, aged 40 years and older, were recruited from 25 centers across mainland China to participant in the baseline survey of the REACTION study, with follow-up investigations performed 3, 5, and 10 years later. Detailed questionnaires about lifestyles, physical and biochemical measurement, bio-samples including serum, urine, and whole blood for DNA extraction were collected for all the participants. RESULTS: The mean ± standard deviation (SD) age of this cohort was 57 ± 10 years. And the prevalence of pre-existing and newly diagnosed diabetes was 10.32% and 10.57%, respectively. A total of 4511 prevalent cancer cases (988 men and 3523 women) were identified, the prevalence was 1.79. Compared to those with normal glucose metabolism, men with diabetes had a significantly lower adjusted prevalence ratio (PR) of stomach cancer (PR: 0.38, 95% CI: 0.16-0.89), and women with diabetes had significantly higher adjusted PRs of cancer of all sites (PR: 1.36, 95% CI: 1.20-1.56), and cancer of the breast (PR: 1.56, 95% CI: 1.21-2.00), the endometrium (PR: 1.58, 95% CI: 1.16-2.15), and the thyroid (PR: 1.53, 95% CI: 1.03-2.27). CONCLUSION: The multi-center REACTION study has captured a broad range of data on physical, psychological and metabolic function as well as health status, biochemical and lifestyle information in 259 657 adults from the general population across the China.

The prevalence of invasive Fusobacterium nucleatum (Fn) within the serrated neoplasia pathway of the proximal colon has seldom been investigated. We examined the invasive Fn and bacterial biofilms in 35 proximal hyperplastic polyps (HPs), 33 sessile serrated adenomas (SSAs), 48 proximal colorectal cancers (CRCs) and 10 matched metastatic lymph nodes using 16S rRNA fluorescence in situ hybridization (FISH). Samples of normal mucosa, traditional adenomas (TAs), distal HPs, distal CRCs and matched lymph nodes with or without metastases were used as controls. The prevalence of invasive Fn within proximal HPs (65.7%) and SSAs (78.8%) were significantly higher than that of proximal TAs (28.9%) and distal TAs (24.4%; p < 0.05). Invasive Fn was detected in markedly more proximal CRCs (89.6%) than in distal CRCs (42.2%; p < 0.05). Moreover, invasive Fn was detected in a significantly higher proportion of matched metastatic lymph nodes (100%) than that within nonmetastatic lymph nodes (40.0%; p < 0.001). Bacterial biofilms were found on 52.1% of proximal CRCs, 55.6% of distal CRCs and 48.5% of SSAs. Biofilms were positive for Fn in 47.9% of proximal CRCs, 48.9% of distal CRCs and 27.3% of SSAs. However, the presence of Fn in biofilms was not related to invasive Fn within colorectal tissues (p = 0.415). Invasive Fn may play a role in the carcinogenesis of proximal colon developing via the serrated neoplasia pathway, but might have a less important role in the TA-carcinoma sequence. Bacterial biofilms may not contribute to the invasion of Fn into tumor tissues.

Diabetic cardiomyopathy (DCM) is characterized by lipid accumulation, mitochondrial dysfunction, and aseptic inflammatory activation. Mitochondria-derived cytosolic DNA has been reported to induce inflammation by activating cyclic GMP-AMP synthase (cGAS)/the stimulator of interferon genes (STING) pathway in the adipose, liver, and kidney tissues. However, the role of cytosolic mtDNA in the progression of DCM is unclear. In this study, with an obesity-related DCM mouse model established by feeding db/db mice with a high-fat diet (HFD), we observed increased mtDNA in the cytosol and activated cGAS-STING signaling pathway during DCM, as well as the downstream targets, IRF3, NF-κB, IL-18, and IL-1β. In a further study with a palmitic acid (PA)-induced lipotoxic cell model established in H9C2 cells, we revealed that the cytosolic mtDNA was the result of PA-induced overproduction of mitochondrial ROS, which also led to the activation of the cGAS/STING system and its downstream targets. Notably, treatment of extracted mtDNA alone was sufficient to activate the cGAS-STING signaling pathway in cultured H9C2 cells. Besides, both knockdown of STING in PA-induced H9C2 cells and inhibition of STING by C-176 injection in the DCM mouse model could remarkably block the inflammation and apoptosis of cardiomyocytes. In conclusion, our study elucidated the critical role of cytosolic mtDNA-induced cGAS-STING activation in the pathogenesis of obesity-related DCM and provided preclinical validation for using a STING inhibitor as a new potential therapeutic strategy for the treatment of DCM.

Over the past decade, immunotherapy, especially cell-based immunotherapy, has provided new strategies for cancer therapy. Recent clinical studies demonstrated that adopting cell transfer of tumor-infiltrating lymphocytes (TILs) for advanced solid tumors showed good efficacy. TIL therapy is a type of cell-based immunotherapy using the patient's own immune cells from the microenvironment of the solid tumor to kill tumor cells. In this review, we provide a comprehensive summary of the current strategies and challenges in TIL isolation and generation. Moreover, the current clinical experience of TIL therapy is summarized and discussed, with an emphasis on lymphodepletion regimen, the use of interleukin-2, and related toxicity. Furthermore, we highlight the clinical trials where TIL therapy is used independently and in combination with other types of therapy for solid cancers. Finally, the limitations, future potential, and directions of TIL therapy for solid tumor treatment are also discussed.

Major depression is a debilitating disease. To date, the development of biomarkers of major depressive disorder (MDD) remains a challenge. Recently, alterations in the expression of microRNAs (miRNAs) from post-mortem brain tissue and peripheral blood have been linked to MDD. The goals of this study were to detect the differential miRNAs in cerebrospinal fluid (CSF) and serum of MDD patients. First, the relative expression levels of 179 miRNAs (relative high levels in serum) were analyzed by miRNA PCR Panel in the CSF of MDD patients. Then, the differentially altered miRNAs from CSF were further assessed by qRT-PCR in the serum of the same patients. Finally, the serum differentially altered miRNAs were further validated by qRT-PCR in the serum of another MDD patients. The CSF-results indicated that 11 miRNAs in MDD patients were significantly higher than these in control subjects, and 5 miRNAs were significantly lower than these in control subjects. The serum-results from the same patients showed that 3 miRNAs (miR-221-3p, miR-34a-5p, and let-7d-3p) of the 11 miRNAs were significantly higher than these in control subjects, and 1 miRNA (miR-451a) of 5 miRNAs was significantly lower than these in control subjects. The up-regulation of miR-221-3p, miR-34a-5p, let-7d-3p and down-regulation of miR-451a was further validated in another 32 MDD patients. ROC analysis showed that the area under curve of let-7d-3p, miR-34a-5p, miR-221-3p and miR-451a was 0.94, 0.98, 0.97 and 0.94, with specificity of 90.48%, 95.24%, 90.48% and 90.48%, and sensitivity of 93.75%, 96.88%, 90.63% and 84.85%, respectively. In addition, target gene prediction found that the altered miRNAs are involved in affecting some important genes and pathway related to MDD. Our results suggested that differentially altered miRNAs in CSF might be involved in MDD, and serum miR-221-3p, miR-34a-5p, let-7d-3p, and miR-451a might be able to serve as biomarkers for MDD.

The microstructure of porous scaffolds plays a vital role in bone regeneration, but its optimal shape is still unclear. In this study, four kinds of porous titanium alloy scaffolds with similar porosities (65%) and pore sizes (650 μm) and different structures were prepared by selective laser melting. Four scaffolds were implanted into the distal femur of rabbits to evaluate bone tissue growth in vivo. Micro-CT and hard tissue section analyses were performed 6 and 12 weeks after the operation to reveal the bone growth of the porous scaffold. The results show that diamond lattice unit (DIA) bone growth is the best of the four topological scaffolds. Through computational fluid dynamics (CFD) analysis, the permeability, velocity and flow trajectory inside the scaffold structure were calculated. The internal fluid velocity difference of the DIA structure is the smallest, and the trajectory of fluid flow inside the scaffold is the longest, which is beneficial for blood vessel growth, nutrient transport and bone formation. In this study, the mechanism of bone growth in different structures was revealed by in vivo experiments combined with CFD, providing a new theoretical basis for the design of bone scaffolds in the future.