A Mendelian randomization study of the effect of selenium on autoimmune thyroid disease.

OBJECTIVE: The impact of selenium on autoimmune thyroid disease (AITD) is a subject of ongoing debate. This study aimed to analyze the causal correlations of selenium with autoimmune thyroiditis (AIT), autoimmune hyperthyroidism (AIH), and Graves' disease (GD) by Mendelian randomization (MR). MATERIALS AND METHODS: Single nucleotide polymorphisms related to selenium, AIT, AIH, and GD were sourced from the IEU Open GWAS project and FinnGen. Exposure-outcome causality was assessed using inverse variance weighted, MR-Egger, and weighted median. Horizontal pleiotropy was examined using the MR-Egger intercept, heterogeneity was evaluated with Cochran's Q test, and the robustness of the results was confirmed via leave-one-out sensitivity analysis. RESULTS: The MR analysis revealed that selenium did not exhibit a causal relationship with AIT (OR 0.993, 95% CI 0.786 to 1.108, p=0.432), AIH (OR 1.066, 95% CI 0.976 to 1.164, p=0.154), or GD (OR 1.052, 95% CI 0.984 to 1.126, p=0.138). Moreover, the MR-Egger intercept and Cochran's Q test demonstrated the absence of horizontal pleiotropy or heterogeneity in these results (p>0.05). Sensitivity analysis affirmed the robustness of these results. CONCLUSIONS: This MR analysis concluded that selenium was not linked to AIT, AIH, or GD risk. Therefore, indiscriminate selenium supplementation is not advisable for AITD patients without concurrent selenium deficiency.

DNA binding properties and cell viabilities of metal complexes derived from (E)-2-hydroxy-N'-((thiophen-2-yl)methylene)benzohydrazone and (E)-N'-((thiophen-2-yl)methylene)isonicotinylhydrazone.

OBJECTIVE: This study aims to investigate the CT-DNA (Calf thymus DNA) binding properties and HeLa cell viabilities of metal complexes derived from (E)-2-hydroxy-N'-((thiophen-2-yl)methylene)benzohydrazone (H2L1) and (E)-N'-((thiophen-2-yl)methylene)isonicotinylhydrazone (HL2). MATERIALS AND METHODS: A series of metal complexes derived from (E)-2-hydroxy-N'-((thiophen-2-yl)methylene)benzohydrazone (H2L1) and (E)-N'-((thiophen-2-yl)methylene)isonicotinylhydrazonewere (HL2) were synthesized, and their structures were characterized through FT-IR, ESI-MS, elemental analysis, molar conductivities and X-ray diffraction. DNA binding properties between CT-DNA and metal complexes were investigated by UV-Vis spectrophotometry and viscosity titration. The toxicological properties of compounds on HeLa cell were measured in vitro. RESULTS: Ligand H2L1 or HL2 exhibits a tridentate and anion ligand and uses oxygen anion, nitrogen atom and sulfur atom to coordinate with metal ions. When coordinated with metal ions, the unit O=C-NH- of each ligand has been enolized and deprotonated into -O-C=N-. The suggested chemical formulas of metal complexes are: [Co(HL1)2], [Ni(HL1)2], [Cu(HL1)2], [Co(L2)2], [Cu(L2)2], [Zn(L2)2], [ScL2(NO3)2(H2O)2], [Pr(L2)2(NO3)] and [Dy(L2)2(NO3)]. Both ligands and their metal complexes can bind strongly to CT-DNA through hydrogen bond and intercalation with Kb of 104~105 L mol-1 compared to ethidium bromide [classical DNA intercalator, Kb(EB-DNA) = 3.068 × 104 L mol-1]; however, the groove pattern cannot be excluded. The coexistence of multiple binding modes may be a common form of drug binding to DNA. HeLa cell shows lower viabilities in the presence of [Ni(HL1)2] and [Cu(HL1)2] (*p < 0.05) compared to the other compounds, with the LC50 of 2.6 µmol L-1 and 2.2 µmol L-1, respectively. CONCLUSIONS: These compounds, especially [Ni(HL1)2] and [Cu(HL1)2], will be promising for anti-tumor drugs, which should be further studied.

Risk factors and etiological characteristics of urinary tract infection in hospitalized continuous ambulatory peritoneal dialysis patients.

OBJECTIVE: This study aimed to explore the risk factors and etiological characteristics of urinary tract infection (UTI) in continuous ambulatory peritoneal dialysis (CAPD) patients. PATIENTS AND METHODS: A total of 90 CAPD patients with UTI comprised the infection group, while 32 CAPD patients without UTI constituted the control group. The risk factors and etiological characteristics of UTI were analyzed. RESULTS: Of the 90 bacterial strains isolated, 30 were Gram-positive (33.3%) and 60 were Gram-negative (66.7%). Urinary stones or urinary tract structural changes were more prevalent in the infection group (71.1%) than in the control group (46.9%) (χ² = 6.076, p = 0.018). The proportion of patients with residual diuresis less than 200 ml was higher in the infection group (50%) than in the control group (15.6%) (χ² = 11.533, p = 0.001). The distribution of primary disease differed between the two groups. Patients in the infection group had higher CAPD vintage, levels of triglycerides, fasting blood glucose, blood creatinine, blood phosphorus, and calcium-phosphorus product than those in the control group. Multivariate binary logistic regression analysis indicated that residual diuresis less than 200 ml (OR = 3.519, p = 0.039) and urinary stones or structural changes (OR = 4.727, p = 0.006) were independent risk factors for UTI. CONCLUSIONS: Urine cultures of CAPD patients with UTI contained a complex distribution of pathogenic bacteria. Urinary stones or structural changes and residual diuresis less than 200 ml were independent risk factors for UTI.

B cells and tertiary lymphoid structures are associated with survival in papillary thyroid cancer.

PURPOSE: The function of B cells in papillary thyroid cancer (PTC) is controversial. The role of B-cell-related tertiary lymphoid structures (TLSs) is still unclear. Whether B cells exert their anti-tumor effect through forming TLS in PTC needs further investigation. METHODS: We detected the percentage of B cells in PTC tissues by multi-parameter flow cytometry. Paraffin-embedded tumor tissues of 125 PTC patients were collected and stained with Haematoxylin-Eosin (H&E) for inflammatory infiltration analysis in combination with clinical features. Multiplexed immunohistochemistry (mIHC) was performed to verify the TLSs in above inflammatory infiltration. Correlation of B cells and TLSs with prognosis was analyzed using the TCGA database. RESULTS: We observed that PTC patients with higher expression of B lineage cell genes had improved survival and the percentage of B cells in the PTC tumor tissues was variable. Moreover, PTC tumor tissues with more B cells were surrounded by immune cell aggregates of varying sizes. We furtherly confirmed the immune cell aggregates as TLSs with different maturation stages. By analyzing PTC data from TCGA database, we found the maturation stages of TLSs were associated with genders and clinical stages among PTC patients. Moreover, patients with high TLSs survived longer and had a better prognosis. CONCLUSION: B cells are associated with the existence of TLSs which have different maturation stages in PTC. Both B cells and TLSs are associated with the survival rate of PTC. These observations indicate that the anti-tumor effects of B cells in PTC are associated with TLSs formation.

Radiomics nomogram integrating intratumoural and peritumoural features to predict lymph node metastasis and prognosis in clinical stage IA non-small cell lung cancer: a two-centre study.

AIM: To investigate the value of a radiomics nomogram integrating intratumoural and peritumoural features in predicting lymph node metastasis and overall survival (OS) in patients with clinical stage IA non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: This study retrospectively enrolled 199 patients (training cohort: 71 patients from Affiliated Tumour Hospital of Nantong University; internal validation cohort: 46 patients from Affiliated Tumour Hospital of Nantong University; external validation cohort: 82 patients from the public database). CT radiomics models were constructed based on four volumes of interest: gross tumour volume (GTV), gross and 3 mm peritumoural volume (GPTV3), gross and 6 mm peritumoural volume (GPTV6), and gross and 9 mm peritumoural volume (GPTV9). The optimal radiomics signature was further combined with independent clinical predictors to develop a nomogram. Univariable and multivariable Cox regression analysis were applied to determine the relationship between factors and OS. RESULTS: GPTV6 radiomics yielded better performance than GTV, GPTV3, and, GPTV9 radiomics in the training (area under the curve [AUC], 0.81), internal validation (AUC, 0.79), and external validation cohorts (AUC, 0.71), respectively. The nomogram integrating GPTV6 radiomics and spiculation improved predictive ability, with AUCs of 0.85, 0.80, and 0.74 in three cohorts, respectively. Pathological lymph node metastasis, nomogram-predicted lymph node metastasis, and pleural indentation were independent risk predictors of OS (p<0.05). CONCLUSIONS: The nomogram integrating GPTV6 radiomics features and independent clinical predictors performed well in predicting lymph node metastasis and prognosis in patients with clinical stage IA NSCLC.

Serum creatinine to bilirubin ratio associated with essential hypertension.

OBJECTIVE: Previous studies have shown that serum bilirubin (BIL) is significantly decreased, and serum creatinine (Cr) level is increased in patients with essential hypertension (EH). In this paper, the ratio of serum Cr to BIL was measured to explore whether the ratio was associated with EH risk. PATIENTS AND METHODS: 80 EH cases were selected as the observation group. 44 cases with normal blood pressure were selected as the control group. Serum Cr and BIL levels were detected, and the ratio values were calculated. RESULTS: Compared with the control group, the Cr to total bilirubin (TBIL) ratio (Cr/TBIL, CTR), Cr to direct bilirubin (DBIL) ratio (Cr/DBIL, CDR) and Cr to indirect bilirubin (IBIL) ratio (Cr/IBIL, CIR) in the EH group were significantly increased (p<0.05). Spearman correlation analysis showed that EH risk was positively correlated with CTR and CIR, while it was negatively correlated with serum BIL (p<0.05). The area under the ROC curve of CTR, CDR and CIR in diagnosing EH were 0.719 (95% CI: 0.631-0.796) (p<0.001), 0.700 (95% CI: 0.611-0.779) (p<0.001) and 0.716 (95% CI: 0.628-0.793) (p<0.001), respectively. Logistic regression analysis showed that CTR, CDR and CIR were independent risk factors for EH (CTR OR: 1.28, 95% CI: 1.11-1.48, p=0.0008), (CDR OR: 1.03, 95% CI: 1.003-1.067, p=0.032), (CIR OR: 1.17, 95% CI: 1.07-1.29, p=0.001). CONCLUSIONS: CTR and CIR are positively correlated with the incidence of EH. With the increase of blood pressure, CTR and CIR increase. CTR and CIR are independent risk factors for the incidence of EH.

Fecal metabolomics reveals products of dysregulated proteolysis and altered microbial metabolism in obesity-related osteoarthritis.

OBJECTIVE: The objective of this exploratory study was to determine if perturbations in gut microbial composition and the gut metabolome could be linked to individuals with obesity and osteoarthritis (OA). METHODS: Fecal samples were collected from obese individuals diagnosed with radiographic hand plus knee OA (n = 59), defined as involvement of at least 3 joints across both hands, and a Kellgren-Lawrence (KL) grade 2-4 (or total knee replacement) in at least one knee. Controls (n = 33) were without hand OA and with KL grade 0-1 knees. Fecal metabolomes were analyzed by a UHPLC/Q Exactive HFx mass spectrometer. Microbiome composition was determined in fecal samples by 16 S ribosomal RNA amplicon sequencing (rRNA-seq). Stepwise logistic regression models were built to determine microbiome and/or metabolic characteristics of OA. RESULTS: Untargeted metabolomics analysis indicated that OA cases had significantly higher levels of di- and tripeptides and significant perturbations in microbial metabolites including propionic acid, indoles, and other tryptophan metabolites. Pathway analysis revealed several significantly perturbed pathways associated with OA including leukotriene metabolism, amino acid metabolism and fatty acid utilization. Logistic regression models selected metabolites associated with the gut microbiota and leaky gut syndrome as significant predictors of OA status, particularly when combined with the rRNA-seq data. CONCLUSIONS: Adults with obesity and knee plus hand OA have distinct fecal metabolomes characterized by increased products of proteolysis, perturbations in leukotriene metabolism, and changes in microbial metabolites compared with controls. These metabolic perturbations indicate a possible role of dysregulated proteolysis in OA.

Juvenile hormone regulates the reproductive diapause through Methoprene-tolerant gene in Galeruca daurica.

Juvenile hormone (JH) signalling plays an important role in regulation of reproductive diapause in insects. However, its underlying molecular mechanism has been unclear. Methoprene-tolerant (Met), as a universal JH receptor, is involved in JH action. To gain some insight into its function in the reproductive diapause of Galeruca daurica, a serious pest on the Inner Mongolia grasslands undergoing obligatory summer diapause at the adult stage, we cloned the complete open-reading frame (ORF) sequences of Met and other 7 JH signalling-related genes, including JH acid methyltransferase (JHAMT), JH esterase (JHE), JH epoxide hydrolase (JHEH), Krüppel homologue 1 (Kr-h1), vitellogenin (Vg), forkhead box O (FOXO) and fatty acid synthase 2 (FAS2), from this species. GdMet encoded a putative protein, which contained three domains typical of the bHLH-PAS family. Expression patterns of these eight genes were developmentally regulated during adult development. Topical application of JH analogue (JHA) methoprene into the 3-day-old and 5-day-old adults induced the expression of GdMet. Silencing GdMet by RNAi inhibited the expression of JHBP, JHE, Kr-h1 and Vg, whereas promoted the FAS2 expression, which enhanced lipid accumulation and fat body development, and finally induced the adults into diapause ahead. Combining with our previous results, we conclude that JH may regulate reproductive diapause through a conserved Met-dependent pathway in G. daurica.

Untargeted analysis of first trimester serum to reveal biomarkers of pregnancy complications: a case-control discovery phase study.

Understanding of causal biology and predictive biomarkers are lacking for hypertensive disorders of pregnancy (HDP) and preterm birth (PTB). First-trimester serum specimens from 51 cases of HDP, including 18 cases of pre-eclampsia (PE) and 33 cases of gestational hypertension (GH); 53 cases of PTB; and 109 controls were obtained from the Global Alliance to Prevent Prematurity and Stillbirth repository. Metabotyping was conducted using liquid chromatography high resolution mass spectroscopy and nuclear magnetic resonance spectroscopy. Multivariable logistic regression was used to identify signals that differed between groups after controlling for confounders. Signals important to predicting HDP and PTB were matched to an in-house physical standards library and public databases. Pathway analysis was conducted using GeneGo MetaCore. Over 400 signals for endogenous and exogenous metabolites that differentiated cases and controls were identified or annotated, and models that included these signals produced substantial improvements in predictive power beyond models that only included known risk factors. Perturbations of the aminoacyl-tRNA biosynthesis, L-threonine, and renal secretion of organic electrolytes pathways were associated with both HDP and PTB, while pathways related to cholesterol transport and metabolism were associated with HDP. This untargeted metabolomics analysis identified signals and common pathways associated with pregnancy complications.

IGHG1 functions as an oncogene in tongue squamous cell carcinoma via JAK1/STAT5 signaling.

The article "IGHG1 functions as an oncogene in tongue squamous cell carcinoma via JAK1/STAT5 signaling, by Y.-L. Zheng, Y.-Y. Li, J.-F. Xie, H.-Q. Ma, published in Eur Rev Med Pharmacol Sci 2020; 24 (12): 6716-6725-DOI: 10.26355/eurrev_202006_21659-PMID: 32633362" has been withdrawn from the authors stating that "the experimental data in the article are wrong". The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/21659.

LncRNA CASC15 promotes migration and invasion in prostate cancer via targeting miR-200a-3p.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "LncRNA CASC15 promotes migration and invasion in prostate cancer via targeting miR-200a-3p, by C. Zhang, G.-X. Wang, B. Fu, X.-C. Zhou, Y. Li, Y.-Y. Li, published in Eur Rev Med Pharmacol Sci 2019; 23 (19): 8303-8309-DOI: 10.26355/eurrev_201910_19141-PMID: 31646560" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19141.

IGHG1 functions as an oncogene in tongue squamous cell carcinoma via JAK1/STAT5 signaling.

OBJECTIVE: We explored the IgG1 heavy chain constant region (IGHG1) roles in tongue squamous cell carcinoma (TSCC) progression, as well as to probe the underlying mechanisms. PATIENTS AND METHODS: The expression patterns of IGHG1 in TSCC tissues and cell lines were tested by Western blotting, quantitative real-time PCR (RT-PCR) and immunohistochemistry (IHC) technologies. The relationship between IGHG1 expression level and the overall survival and clinicopathologic features of patients with TSCC were evaluated to assess the clinical value of IGHG1. The effects of IGHG1 on cell function were determined by Cell-Counting Kit-8 (CCK-8), clone formation, flow cytometry and in vivo tumor formation assays. RESULTS: The expression of IGHG1 in TSCC tissues and cell lines was significantly elevated at both mRNA and protein levels. IGHG1 expression levels closely related to T classification (p=0.008), clinical stage (p=0.011), and node metastasis (p=0.005) in TSCC patients. Upregulation of IGHG1 with lentivirus infection significantly increased Janus kinase 1 (JAK1) expression and the phosphorylation level of signal transducer and activator of transcription 5 (STAT5). In addition, IGHG1 overexpression markedly enhanced cell proliferation, clone formation and tumorigenesis and inhibited cell apoptosis, whereas these effects were abolished when JAK1 was downregulated in SCC15 and SCC4 TSCC cell lines. CONCLUSIONS: Collectively, this study reveals that IGHG1 functions as an oncogene in TSCC via activating JAK1/STAT5 signaling.

PNPLA3 polymorphism influences the association between high-normal TSH level and NASH in euthyroid adults with biopsy-proven NAFLD.

AIM: We aimed to evaluate the association between serum thyroid stimulating hormone (TSH) levels, within the reference range, and the histological severity of nonalcoholic fatty liver disease (NAFLD), and whether this association was modulated by the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism. MATERIALS AND METHODS: We enrolled 327 euthyroid individuals with biopsy-proven NAFLD, who were subdivided into two groups, i.e., a 'strict-normal' TSH group (TSH level 0.4 to 2.5mIU/L; n=283) and a 'high-normal' TSH group (TSH level 2.5 to 5.3mIU/L with normal thyroid hormones; n=44). Logistic regression analyses were performed to assess the association between TSH status and presence of nonalcoholic steatohepatitis (NASH) after stratifying subjects by PNPLA3 genotypes. RESULTS: Compared to strict-normal TSH group, patients with high-normal TSH levels were younger and had a greater prevalence of NASH and higher histologic NAFLD activity score. After stratifying by PNPLA3 genotypes, the significant association between high-normal TSH levels and presence of NASH was restricted only to carriers of the PNPLA3 G risk allele and remained significant even after adjustment for potential confounding factors (adjusted-odds ratio: 3.279; 95% CI: 1.298-8.284; P=0.012). CONCLUSION: In euthyroid individuals with biopsy-proven NAFLD, we found a significant association between high-normal TSH levels and NASH. After stratifying by PNPLA3 rs738409 genotypes, this association was observed only among carriers of the PNPLA3 G risk allele.

MiR-92b inhibited cells EMT by targeting Gabra3 and predicted prognosis of triple negative breast cancer patients.

OBJECTIVE: Triple negative breast cancer (TNBC) is a subtype of breast cancer without the three markers, which has a poor prognosis than other types. Recently, studies have identified that microRNA-92b (miR-92b) acted as potential oncogene in tumor progression, however, the biological roles of miR-92b in TNBC remain unknown. The purpose of this study was to investigate the functions of miR-92b and verify its effect on the regulation of Gabra3 in TNBC. MATERIALS AND METHODS: Dual-Luciferase reporter assay was recruited to confirm whether miR-92b directly binds to the 3'-untranslated region (3'-UTR) of Gabra3 mRNA in TNBC. Transwell assay was employed to analyze the capacities of migration and invasion. Western blot was applied to evaluate the expression of the special proteins that including Gabra3, epithelial-mesenchymal transition (EMT) markers and GAPDH. RESULTS: We demonstrated that miR-92b was remarkably low expressed in TNBC tissues and cell lines, and particularly in inhibiting the migration, invasion and EMT of TNBC cells. On the contrary, Gabra3 was significantly overexpressed in TNBC tissues and cell lines in comparison with the corresponding paracancerous tissues and the normal breast epithelial cell line. The expression of miR-92b had a negative correlation with the expression of Gabra3 in TNBC tissues. Downregulation of Gabra3 could inhibit the migration, invasion and EMT of TNBC cells. MiR-92b mediated the expression of Gabra3 through directly binding to the 3'-UTR of Gabra3 mRNA. In addition, low expression of miR-92b or overexpression of Gabra3 predicted poor prognosis of TNBC patients. CONCLUSIONS: MiR-92b inhibited the migration and invasion-mediated EMT through directly targeting the 3'-UTR of Gabra3 mRNA in triple negative breast cancer. The newly identified miR-92b/Gabra3 axis may make it to be a new target for clinical diagnosis and treatment of TNBC.

MiR-1-3p suppresses cell proliferation and invasion and targets STC2 in gastric cancer.

OBJECTIVE: MiR-1 has been reported to act as an inhibitory microRNA in gastric cancer (GC). This study aimed to investigate the regulatory mechanism by which miR-1-3p blocks the progression of GC by targeting stanniocalcin 2 (STC2). PATIENTS AND METHODS: The expression level of miR-1-3p in GC was assessed via quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Expressions of STC2 were measured by qRT-PCR and Western blot analysis. Proliferation and invasion assays were detected by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) and transwell assays, respectively. Moreover, the dual-luciferase reporter assay was used to confirm the binding sites between miR-1-3p and STC2. RESULTS: MiR-1-3p was significantly down-regulated in GC. Moreover, abnormal expression of miR-1-3p was correlated with GC tumor size. Functionally, overexpression of miR-1-3p inhibited proliferation and invasion in GC by inhibiting stanniocalcin 2 (STC2) expressions. In contrast, STC2 was significantly up-regulated in GC. Furthermore, miR-1-3p negatively regulated STC2 expression in GC. The upregulation of STC2 weakened the inhibitory effect of miR-1-3p in GC. CONCLUSIONS: MiR-1-3p suppressed cell proliferation and invasion by targeting STC2 in GC, providing a novel therapeutic target for GC.

LncRNA CASC15 promotes migration and invasion in prostate cancer via targeting miR-200a-3p.

OBJECTIVE: Prostate cancer (PC) is one of the most ordinary malignant cancers. Recent researches have proved that long noncoding RNAs (lncRNAs) act as an important role in cancers. Our study aims to explore the function of lncRNA CASC15 in the tumor metastasis of PC. PATIENTS AND METHODS: Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) was utilized to detect CASC15 expression in 50 PC patients. Besides, the wound healing assay and transwell assay were performed to identify the biological behavior changes of PC cells after CASC15 was silenced in PC cells. In addition, the potential mechanism was also explored using the luciferase assay. RESULTS: CASC15 expression level was significantly higher in PC tissues and cell lines. Results of wound healing assay and transwell assay revealed that cell migrated ability and invaded ability were suppressed via silence of CASC15 in PC cells. Furthermore, the expression of miR-200a-3p was upregulated via silence of CASC15 in PC cells. Luciferase assay showed that miR-200a-3p was a direct target of CASC15 in PC. In addition, miR-200a-3p expression was negatively correlated with CASC15 expression in PC tissues. Rescue experiments also revealed that the inhibition of PC migration and invasion by silence of CASC15 could be reversed through knockdown of miR-200a-3p. CONCLUSIONS: Our study uncovers that CASC15 could enhance cell migration and invasion of PC cells by sponging miR-200a-3p, which might be applied as a novel therapeutic target for PC patients.

MiRNA-93-5p promotes the biological progression of gastric cancer cells via Hippo signaling pathway.

OBJECTIVE: To clarify the influence of microRNA-93-5p (miRNA-93-5p) on biological behaviors of gastric cancer (GC) cells and its regulatory effect on Hippo pathway. MATERIALS AND METHODS: SGC-7901 and HGC-27 cells were used for establishing miRNA-93-5p overexpression and downregulation model through transfection of miRNA-93-5p mimics or inhibitor, respectively. Relative levels of genes in Hippo pathway were determined in GC cells transfected with miRNA-93-5p mimics or inhibitor by quantitative Real-time polymerase chain reaction (qRT-PCR). Regulatory effects of miRNA-93-5p on proliferative, migratory and invasive abilities of GC cells were evaluated by cell counting kit-8 (CCK-8), colony formation and transwell assay, respectively. RESULTS: MiRNA-93-5p was markedly upregulated by transfection of miRNA-93-5p mimics into SGC-7901 cells, which was downregulated by transfection of miRNA-93-5p inhibitor into HGC-27 cells. Overexpression of miRNA-93-5p accelerated GC cells to proliferate, migrate and invade. Meanwhile, miRNA-93-5p overexpression in GC cells upregulated downstream genes in Hippo pathway, including CDX2, FOXM1 and CTGF. CONCLUSIONS: MiRNA-93-5p enhances proliferative, migratory and invasive abilities of GC cells by activating Hippo pathway, which may serve as a diagnostic and therapeutic target for GC.

Decreased HSP70 expression on serum exosomes contributes to cardiac fibrosis during senescence.

OBJECTIVE: Aging is now considered as an independent risk factor for cardiac fibrosis. However, the mechanisms underlying aging-related cardiac fibrosis remain unknown. Here, we examine the role of serum exosomes in this process. MATERIALS AND METHODS: Experiments were conducted using 6-week-old or 24-week-old male Sprague-Dawley (SD) rats. Cardiac sections were treated with Masson's trichrome stain to evaluate fibrosis. Exosomes were isolated from the serum, characterized and quantified using Western blot, electron microscopy, and qNano analysis, and co-cultured with transforming growth factor-ß1 (TGF-ß1)-induced primary cardiac fibroblasts (CF). Co-cultures were also carried out in the presence of a hot shock protein 70 (HSP70) inhibitor (gefitinib) or inducer (geranylgeranylacetone) to evaluate the role of HSP70 in cardiac fibrosis. RESULTS: Cardiac fibrosis as well as serum exosomes levels were increased during senescence. We observed an increase in fibroblast proliferation and myofibroblast differentiation when CF were co-cultured with exosomes from old rats, compared to those from young mice. Observing a decrease in surface HSP70 expression on the exosomes derived from old rats, we tested the effects of HSP70 inhibition or overexpression on the CF co-cultures. HSP70 inhibition increased fibroblast proliferation and myofibroblast differentiation in CF co-cultures containing exosomes from the young rats, while HSP70 overexpression attenuated fibroblast proliferation and myofibroblast differentiation in CF co-cultures containing exosomes from the old rats. CONCLUSIONS: Using an animal model of cardiac fibrosis, we show a decrease in HSP70 expression on the exosomal surface with aging, which may contribute to cardiac fibrosis.

Risk of bone fracture associated with sodium-glucose cotransporter-2 inhibitor treatment: A meta-analysis of randomized controlled trials.

AIM: To evaluate the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and risk of bone fractures in patients with type 2 diabetes mellitus (T2DM). METHODS: A systematic literature search conducted of PubMed, Embase, the Cochrane Library and Web of Science from inception up to 31 August 2018 identified all eligible randomized controlled trials (RCTs). The following data were extracted from each study: first author; year of publication; sample size; patient characteristics; study design; intervention drug; control drug; follow-up durations; and incident bone-fracture events. A meta-analysis was performed using Review Manager 5.3 software to calculate odds ratios (ORs) and 95% confidence intervals (CI) for dichotomous variables. RESULTS: A total of 30 studies involving 23,372 patients with T2DM were included in our analysis. There were 387 incident bone-fracture cases (245 in the SGLT2 inhibitor group, 142 in the control group). Compared with patients who received placebo, those receiving SGLT2 inhibitor treatment had a pooled OR of bone fracture of 0.86 (95% CI: 0.70-1.06). Also, there was no evidence that individual SGLT2 inhibitors across different doses were associated with any increased risk of bone fracture. After stratification by follow-up duration, an SGLT2 inhibitor treatment period of ≤ 52 weeks appeared to have beneficial effects against bone fracture; however, when the treatment period exceeded 52 weeks, these beneficial effects for preventing bone fracture disappeared. CONCLUSION: Our meta-analysis has indicated that SGLT2 inhibitors do not increase risk of bone fracture compared with placebo in patients with T2DM. However, these findings now need to be confirmed in well-designed RCT studies.