Association of lifestyles and multimorbidity with mortality among individuals aged 60 years or older: Two prospective cohort studies.

Lifestyles are associated with all-cause mortality, yet limited research has explored the association in the elderly population with multimorbidity. We aim to investigate the impact of adopting a healthy lifestyle on reducing the risk of all-cause mortality in older individuals with or without multimorbidity in both China and UK. This prospective study included 29,451 and 173,503 older adults aged 60 and over from Chinese Longitudinal Healthy Longevity Survey (CLHLS) and UK Biobank. Lifestyles and multimorbidity were categorized into three groups, respectively. Cox proportional hazards regression was used to estimate the Hazard Ratios (HRs), 95% confidence intervals (95% CIs), and dose-response for all-cause mortality in relation to lifestyles and multimorbidity, as well as the combination of both factors. During a mean follow-up period of 4.7 years in CLHLS and 12.14 years in UK Biobank, we observed 21,540 and 20,720 deaths, respectively. For participants with two or more conditions, compared to those with an unhealthy lifestyle, adopting a healthy lifestyle was associated with a 27%-41% and 22%-42% reduction in mortality risk in the CLHLS and UK Biobank, respectively; Similarly, for individuals without multimorbidity, this reduction ranged from 18% to 41%. Among participants with multimorbidity, individuals with an unhealthy lifestyle had a higher mortality risk compared to those maintaining a healthy lifestyle, with HRs of 1.15 (95% CI: 1.00, 1.32) and 1.27 (95% CI: 1.16, 1.39) for two conditions, and 1.24 (95% CI: 1.06, 1.45) and 1.73 (95% CI: 1.56, 1.91) for three or more conditions in CLHLS and UK Biobank, respectively. Adherence to a healthy lifestyle can yield comparable mortality benefits for older individuals, regardless of their multimorbidity status. Furthermore, maintaining a healthy lifestyle can alleviate the mortality risks linked to a higher number of diseases.

Association of Combined Healthy Lifestyle Factors With Incident Dementia in Participants With and Without Multimorbidity: A Large Population-Based Prospective Cohort Study.

BACKGROUND: The effect of a healthy lifestyle on dementia associated with multimorbidity is not well understood. Our objective is to examine whether the adoption of a healthy lifestyle could potentially reduce the elevated risk of dementia in individuals with and without multimorbidity. METHODS: We utilized data from the UK Biobank cohort. A comprehensive healthy lifestyle score, ranging from 0 to 6, was generated. Cox proportional hazards models were used to examine the associations between multimorbidity, the healthy lifestyle score, and the incidence risk of dementia. RESULTS: Over a median follow-up period of 12.5 years, 5 852 all-cause dementia were recorded. Multimorbidity including cardiovascular, metabolic, neuropsychiatric, and inflammation-related diseases was associated with a higher risk of subsequent dementia. Each additional chronic disease was associated with a hazard ratio (HR) of 1.38 (95% CI: 1.33, 1.44). Compared to individuals without multimorbidity and a healthy lifestyle score of 5-6, patients with multimorbidity and a lifestyle score of 0-1 had a significantly higher risk of dementia (HR: 3.13; 95% CI: 2.64, 3.72), but the risk was markedly attenuated among those with multimorbidity and a lifestyle score of 5-6. Among patients with 3 or more diseases, the HR for dementia was 0.53 (95%CI: 0.42, 0.68) when comparing a lifestyle score of 5-6 to 0-1. And we observed more pronounced association between them among people younger than 60 years old. CONCLUSIONS: Adherence to a combination of healthy lifestyle factors, especially at a young age, was associated with a significantly lower risk of dementia among participants with multimorbidity.

Efficacy and safety of hepatitis B vaccine: an umbrella review of meta-analyses.

BACKGROUND: There is a lack of synthesis of literature to determine hepatitis B vaccine (HepB) strategies for hepatitis B virus (HBV) supported by quality evidence. We aimed to explore the efficacy and safety of HepB strategies among people with different characteristics. RESEARCH DESIGN AND METHODS: PubMed, Cochrane Library, Embase, and Web of Science were searched for meta-analyses comparing the efficacy and safety of HepB up to July 2023. RESULTS: Twenty-one meta-analyses comparing 83 associations were included, with 16 high quality, 4 moderate, and 1 low quality assessed by AMSTAR 2. Highly suggestive evidence supports HepB booster and HepB with 1018 adjuvant (HBsAg-1018) for improved seroprotection, and targeted and universal HepB vaccination reduced HBV infection Suggestive evidence indicated that targeted vaccination decreased the rate of hepatitis B surface antibody positivity and booster doses increased seroprotection in people aged 10-20. Weak evidence suggests potential local/systemic reaction risk with nucleotide analogs or HBsAg-1018. Convincing evidence shows HLA-DPB1*04:01 and DPB1*04:02 increased, while DPB1*05:01 decreased, hepatitis B antibody response. Obesity may reduce HepB seroprotection, as highly suggested. CONCLUSION: Targeted vaccination could effectively reduce HBV infection, and adjuvant and booster vaccinations enhance seroprotection without significant reaction. Factors such as obesity and genetic polymorphisms may affect the efficacy.

Unsaturated Fatty Acids in Mental Disorders: An Umbrella Review of Meta-Analyses.

Unsaturated fatty acids might be involved in the prevention of and improvement in mental disorders, but the evidence on these associations has not been comprehensively assessed. This umbrella review aimed to appraise the credibility of published evidence evaluating the associations between unsaturated fatty acids and mental disorders. In this umbrella review, systematic reviews and meta-analyses of studies comparing unsaturated fatty acids (including supplementation, dietary intake, and blood concentrations) in participants with mental disorders with healthy individuals were included. We reanalyzed summary estimates, between-study heterogeneity, predictive intervals, publication bias, small-study effects, and excess significance bias for each meta-analysis. Ninety-five meta-analyses from 29 systematic reviews were included, encompassing 43 studies on supplementation interventions, 32 studies on dietary factors, and 20 studies on blood biomarkers. Suggestive evidence was only observed for dietary intake, in which higher intake of fish was associated with reduced risk of depression (RR: 0.78; 95% CI: 0.69, 0.89) and Alzheimer disease (RR: 0.74; 95% CI: 0.63, 0.87), and higher intake of total PUFAs might be associated with a lower risk of mild cognitive impairment (RR: 0.71; 95% CI: 0.61, 0.84). Evidence showed that PUFA supplementation was favorable but had weak credibility in anxiety, depression, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), dementia, mild cognitive impairment, Huntington's disease, and schizophrenia (P-random effects <0.001-0.040). There was also weak evidence on the effect of decreased circulating n-3 (É·-3) PUFAs among patients on risk of ADHD, ASD, bipolar disorder, and schizophrenia (P-random effects <10-6-0.037). Our results suggest that higher levels of unsaturated fatty acids may relieve symptoms or reduce the risk of various mental disorders; however, the strength of the associations and credibility of the evidence were generally weak. Future high-quality research is needed to identify whether PUFA interventions should be prioritized to alleviate mental disorders.

miR-370-3p as a Novel Biomarker Promotes Breast Cancer Progression by Targeting FBLN5.

miRNAs play a crucial part in multiple biological processes of cell proliferation, migration, apoptosis, and chemoresistance. In cancer, miRNAs can be divided into oncogenes or tumor suppressors on the basis of their functions in the carcinogenic process. The purpose of this study was to explore the roles and clinical diagnostic value of miR-370-3p in breast cancer. Our results demonstrated that miR-370-3p significantly promoted proliferation, metastasis, and stemness of breast cancer in vitro and in vivo. In particular, clinical data revealed that high expression of serum miR-370-3p and exosomal miR-370-3p from breast cancer patients was remarkably correlated with lymphatic metastasis and tumor node metastasis (TNM) stages. Mechanistically, miR-370-3p inhibited FBLN5 expression and activated the NF-κB signaling pathway to promote breast cancer cell proliferation, migration, and stemness. FBLN5 expression was significantly decreased in breast cancer cells and tumor tissues of breast cancer patients. Our research identified that miR-370-3p promoted breast cancer progression by inhibiting FBLN5 expression and activating the NF-κB signaling pathway. Serum exosomal miR-370-3p would provide a potential biomarker for the diagnosis of breast cancer.

Exosomes: A rising star in breast cancer (Review).

Exosomes are nano­sized extracellular vesicles composed of lipid bilayers. They originate from different types of cells and contain various biological molecules. Exosomes can release their contents and exert their corresponding biological functions. In addition, exosomes play important roles in clinical applications. Exosomes and their contents play key roles in the development of breast cancer, including promoting tumorigenesis, metastasis, angiogenesis, immune escape, and treatment resistance. Exosomes can also be used as biomarkers for cancer diagnosis, prognosis and treatment. In this review, we propose that exosomes are important in clinical applications for breast cancer and their roles cannot be neglected.

Exosomal miR-1910-3p promotes proliferation, metastasis, and autophagy of breast cancer cells by targeting MTMR3 and activating the NF-κB signaling pathway.

Exosomes are key mediators of intercellular communication and play a role in the pathogenesis and progression of cancer. Exosomes in circulating body fluids serve as molecular markers for cancer diagnosis. This study aimed to investigate the role of exosomal microRNA (miR)-1910-3p in breast cancer and determine its clinical diagnostic value. MiR-1910-3p promoted proliferation and migration of breast cancer cells in vitro and in vivo. In vitro, exosomes enriched in miR-1910-3p transferred miR-1910-3p to mammary epithelial cells and breast cancer cells, promoting proliferation and migration, inhibiting apoptosis, and inducing autophagy. In vivo, exosomes enriched in miR-1910-3p promoted the proliferation and migration of breast cancer cells. MiR-1910-3p downregulated myotubularin-related protein 3, activated the NF-κB and wnt/ß-catenin signaling pathway, and promoted breast cancer progression. Serum miR-1910-3p in exosomes was an effective diagnostic marker that improved the sensitivity of breast cancer diagnosis when used in combination with the traditional tumor marker CA153. In conclusion, breast cancer cell-derived exosomes promoted the growth, metastasis, and autophagy of breast cancer cells by transferring miR-1910-3p. MiR-1910-3p in serum exosomes may serve as a novel molecular marker for breast cancer diagnosis.

Mouse bone marrow mesenchymal stem cells with distinct p53 statuses display differential characteristics.

Mesenchymal stem cells (MSCs) affect diverse aspects of tumor progression, such as angiogenesis, tumor growth and metastasis. Bone marrow MSCs (BM­MSCs) are fibroblast­like cells with multipotent differentiation ability, that localize to areas of tissue damage, including wounds and solid tumors. The tumor suppressor gene, p53, is functionally involved in cell cycle control, apoptosis and genomic stability, and is mutated and inactivated in most human cancers. The present study aimed to investigate the role of p53 in the biology of BM­MSCs. In the present study, p53 wild­type (p53+/+), knockdown (p53+/­) and knockout (p53­/­) mouse BM­MSCs (mBM­MSCs) were observed to be similar in appearance and in the expression of cell surface biomarkers, but expressed differential p53 protein levels. The p53+/­ and p53­/­ mBM­MSCs demonstrated an increased proliferation rate compared with mBM­MSCs derived from p53+/+ mice. mBM­MSCs from all three groups, representing distinct p53 statuses, were unable to form tumors over a 3­month period in vivo. The adipogenic and osteogenic differentiation of mBM­MSCs was increased in the absence of p53. The colony formation and migratory abilities of p53+/­ and p53­/­ mBM­MSCs were markedly enhanced, and the expression levels of stem cell­associated proteins were significantly increased compared with p53+/+. The expression levels of microRNA (miR)­3152 and miR­337 were significantly increased in p53+/­ and p53­/­ mBM­MSCs, whereas the expression levels of miR­221, miR­155, miR­1288 and miR­4669 were significantly decreased. The expression levels of tumor necrosis factor­α and interferon­Î³­inducible protein­10 were significantly upregulated in the supernatant of p53+/­ and p53­/­ mBM­MSCs. Ubiquitin protein ligase E3 component n­recognin 2, RING­finger protein 31 and matrix metalloproteinase 19 were highly expressed in p53+/­ and p53­/­ mBM­MSCs. The results of the present study indicated that p53 may serve an important role in the biology of mBM­MSCs, and may provide novel insights into the role of cells with different p53 statuses in cancer progression.

Genetic Diversity of Carbapenem-Resistant Enterobacteriaceae (CRE) Clinical Isolates From a Tertiary Hospital in Eastern China.

The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) is increasing globally, with different molecular mechanisms described. Here we studied the molecular mechanisms of carbapenem resistance, including clonal and plasmid dissemination, of 67 CRE isolates collected between 2012 and 2016 from a tertiary hospital in Eastern China, an CRE endemic region. Species identification and susceptibility testing were performed using the BD Phoenix Automated Microbiology System. Isolates were characterized by PCR (for carbapenemases, ESBLs, AmpC and porin genes), multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and conjugation transfer experiments. Selected bla KPC-2 -harboring plasmids were subjected to next-generation sequencing using the Illumina Miseq platform. Among the 67 CRE isolates, 42 Klebsiella pneumoniae, 10 Serratia marcescens, 6 Enterobacter cloacae, 2 Raoultella ornithinolytica, 2 K. oxytoca, 1 K. aerogenes, and 4 Escherichia coli isolates were identified. Six different carbapenemases were detected, including bla KPC-2 (n = 45), bla KPC-3 (n = 1), bla NDM-1 (n = 6), bla NDM-5 (n = 1), bla IMP-4 (n = 2), and bla VIM-1 (n = 2); bla OXA-48-like genes were not detected. One E. cloacae strain possessed both bla NDM-1 and bla KPC-3, while two E. cloacae isolates harbored bla NDM-1 and bla VIM-1. ESBLs (CTX-M, SHV, and TEM) and/or AmpC (CMY, DHA, and ACT/MIR) genes were also identified in 59 isolates, including 13 strains that lacked carbapenemases. Several insertions or stop codon mutations were found within porin genes of K. pneumoniae, E. coli and S. marcescens isolates, both with and without carbapenemases. The 42 K. pneumoniae isolates belonged to 12 different sequence types (ST), with ST11 being the most common, while the 6 E. cloacae isolates comprised 4 different STs. The 10 S. marcescens all shared the same PFGE pulsotype, suggestive of clonal spread. Complete plasmid sequencing and PCR screening revealed both intra-strain and inter-species spread of a common bla KPC-2-harboring plasmid in our hospital. Taken together, our study revealed extensive genetic diversity among CRE isolates form a single Chinese hospital. CRE isolates circulating in the hospital differ significantly in their species, STs, porin genes, carbapenemase genes, and their plasmid content, highlighting the complex dissemination of CRE in this endemic region.

The interaction of MMP-2/B7-H3 in human osteoporosis.

The immune costimulatory molecule B7-H3 has been shown to be involved in the regulation of murine bone formation. However, the role of B7-H3 in bone metabolic diseases remains unknown. In our study, matrix metalloproteinase 2 (MMP-2) and soluble B7-H3 (sB7-H3) were found to be correlatively up-regulated in the sera of osteoporosis patients. Furthermore, our results showed that MG63 cells treated with MMP-2 inhibitors produced lower amounts of sB7-H3 while cells with recombinant MMP-2 had an increased membrane B7-H3 (mB7-H3) shedding. Therefore, elevated MMP-2 levels resulted in an elevation of serum sB7-H3 and reduction of osteoblastic mB7-H3. B7-H3 knockdown in MG63 cells significantly decreased osteoblastic markers and substantially decreased the number of mineralized nodules after 21days. Thus, B7-H3-deficient MG63 cells exhibited impaired bone formation. These results suggest that mB7-H3 is required for the later phases of osteoblast differentiation and that MMP-2/B7-H3 plays a negative regulatory role in osteoporosis.

Reduced serum B7-H3 levels in patients with ankylosing spondylitis.

This study aimed to investigate molecule B7-H3 expression profiles of patients with ankylosing spondylitis (AS) and the clinical significance of B7-H3 in the pathogenesis of AS. Serum B7-H3 levels were measured by ELISA in patients with AS and healthy controls. The expression of B7-H3 protein and mRNA on CD14+ monocytes of peripheral blood mononuclear cells (PBMCs) and serum levels of T cell-associated cytokines were also analyzed. The serum B7-H3 levels in AS patients were significantly lower than in healthy controls. The expression of B7-H3 protein and mRNA on CD14+ monocytes of PBMCs and serum levels of TNF-α, IL-6, and IL-17A in AS patients were significantly higher than in controls. The reduced serum B7-H3 level was highly negatively correlated with AS Disease Activity Score (ASDAS), TNF-α, and IL-17A. Upregulated B7-H3 protein may play a role in the pathogenesis of AS by binding its receptor on T cells.

The alteration and clinical significance of Th1/Th2/Th17/Treg cells in patients with multiple myeloma.

Immunological T cells and associated cytokines have been shown to be involved in the pathogenesis of multiple myeloma (MM). However, the abnormal immune imbalance of T lymphocyte subsets on MM remains unknown. We investigate the proportions of T helper 1 (Th1)/Th2/Th17/T regulatory (Treg) cells in peripheral blood mononuclear cells (PBMCs) by flow cytometry (FCM), and serum levels of relevant cytokines in MM patients and controls were detected by enzyme-linked immunosorbent assay (ELISA). The messenger RNA (mRNA) expression of T-bet, STAT6, RORgammat, and Foxp3 was measured by real-time quantitative polymerase chain reaction (PCR). The CD4+ Th1 and CD4+ Th17 cells in patients with MM were significantly higher than those in health controls as well as the expression of T-bet and RORgammat mRNA. Furthermore, serum levels of interferon gamma (IFN-γ), IL-6, and IL-17A in MM group were greatly increased and significantly associated with each other. Significant differences on Th cells, cytokines, and transcription factors were observed on MM patients. The imbalance of T lymphocyte subsets was thought to contribute to the pathogenesis and underlying mechanisms of MM.

Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis.

Toll-like receptor (TLR)4-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study investigated the expression and biological role of TLR4 in human breast cancer metastasis. MCF-7 and MDA-MB-231 are human breast cancer cell lines with low and high metastatic potential, respectively. Using lipopolysaccharide (LPS) to stimulate MCF-7 and MDA-MB-231 cells, expression of TLR4 mRNA and protein increased compared with that in control cells. TLR4 activation notably up-regulated expression of matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor(VEGF) mRNA and their secretion in the supernatants of both cell lines. LPS enhanced invasion of MDA-MB-231 cells by transwell assay and MCF-7 cells by wound healing assay. LPS triggered increased expression of TLR4 downstream signaling pathway protein myeloid differentiation factor 88(MyD88) and resulted in interleukin (IL)-6 and IL-10 higher production by human breast cancer cells. Stimulation of TLR4 with LPS promoted tumorigenesis and formed metastatic lesions in liver of nude mice. Moreover, expression of TLR4 and MyD88 as well as invasiveness and migration of the cells could be blocked by TLR4 antagonist. Combined with clinicopathological parameters, TLR4 was overexpressed in human breast cancer tissue and correlated with lymph node metastasis. These findings indicated that TLR4 may participate in the progression and metastasis of human breast cancer and provide a new therapeutic target.

Toll-like receptor 2 promotes invasion by SGC-7901 human gastric carcinoma cells and is associated with gastric carcinoma metastasis.

Toll-like receptors (TLRs) play a key role in cancer metastasis. The biological role of TLR2 in invasion and metastasis in gastric carcinoma cells and gastric carcinoma is not clear; therefore, we aimed to investigate the biological role of TLR2 in invasion by SGC-7901 human gastric carcinoma cells and to determine whether TLR2 is associated with gastric carcinoma metastasis. RT-PCR, real-time PCR, flow cytometry, and western blotting showed that TLR2 activation significantly increased TLR2 expression at the mRNA and protein levels and notably promoted the transcription of genes related to angiogenesis and invasion, such as VEGF-C and MMP-9. The invasive capacity of SGC-7901 cells was strikingly advanced by TLR2 stimulation on Transwell invasion assay. IL-6 in the supernatants of cultured SGC-7901 cells was increased under the condition of TLR2 stimulation and reduced after TLR2 blockade by ELISA. Combined with clinicopathological parameters, the expression of TLR2 protein examined by immunohistochemical analysis was higher in gastric carcinoma tissues than in adjacent non-cancerous tissues (p<0.001). There was a significant relationship between TLR2 expression and lymph node metastasis (p<0.01), distant metastasis (p<0.01). There was no significant correlation between gastric carcinoma and age (p>0.05), sex (p>0.05), or degree of differentiation (p>0.05). These findings indicate that TLR2 may participate in the progression and metastasis of human gastric carcinoma and provide a new therapeutic target against metastasis of gastric carcinoma.

Reduced expression of Toll-like receptor 4 inhibits human breast cancer cells proliferation and inflammatory cytokines secretion.

BACKGROUND: Tumor cell expression of Toll-like receptors (TLRs) can promote inflammation and cell survival in the tumor microenvironment. Toll-like receptor 4 (TLR4) signaling in tumor cells can mediate tumor cell immune escape and tumor progression, and it is regarded as one of the mechanisms for chronic inflammation in tumorigenesis and progression. The expression of TLR4 in human breast cancer cell line MDA-MB-231 and its biological function in the development and progression of breast cancer have not been investigated. We sought to characterize the expression of TLR1-TLR10 in the established human breast cancer cell line MDA-MB-231, and to investigate the biological roles of TLR4 in breast cancer cells growth, survival, and its potential as a target for breast cancer therapy. METHODS: TLRs mRNA and protein expressions were detected in human breast cancer cell line MDA-MB-231 by RT-PCR, real-time PCR and flow cytometry (FCM). RNA interference was used to knockdown the expression of TLR4 in MDA-MB-231. MDA-MB-231 transfected with the vector pGenesil-1 and the vector containing a scrambled siRNA were as controls. Recombinant plasmids named TLR4AsiRNA, TLR4BsiRNA and TLR4CsiRNA specific to TLR4 were transfected into human breast cancer cell line MDA-MB-231 with Lipfectamine 2000 reagent. TLR4 mRNA and protein expressions were investigated by RT-PCR, real-time PCR, FCM and immunofluorescence after silence. MTT analysis was performed to detect cell proliferation and FCM was used to detect the secretion of inflammatory cytokines in supernatant of transfected cells. RESULTS: The human breast cancer cell line MDA-MB-231 was found to express TLR1-TLR10 at both the mRNA and protein levels. TLR4 was found to be the highest expressed TLR in MDA-MB-231. TLR4AsiRNA, TLR4BsiRNA and TLR4CsiRNA were found to significantly inhibit TLR4 expression in MDA-MB-231 at both mRNA and protein levels as compared to vector control(vector transfected cells). TLR4AsiRNA mediated the strongest effect. Knockdown of TLR4 gene in MDA-MB-231 resulted in a dramatic reduction of breast cancer cell viability. The cytokines which were secreted by the TLR4 silenced cells, such as IL-6 and IL-8, also decreased significantly as compared with vector control. No significant difference was observed in siRNA control (Recombinant plasmid named ScrambledsiRNA transfected cells) compared to vector control. CONCLUSIONS: These studies identified the expression levels of multiple TLRs in human breast cancer cell line MDA-MB-231 and demonstrated that knockdown of TLR4 could actively inhibit proliferation and survival of breast cancer cells. Taken together, our results suggest RNAi-directed targeting of TLR4 may be a beneficial strategy for breast cancer therapy.