A Review of Traditional and Emerging Residual Chlorine Quenchers on Disinfection By-Products: Impact and Mechanisms.

Disinfection by-products (DBPs) are the most common organic contaminants in tap water and are of wide concern because of their highly developmental toxic, cytotoxic, and carcinogenic properties. Typically, to control the proliferation of pathogenic microorganisms, a certain concentration of residual chlorine is retained in the factory water, which reacts with the natural organic matter and the disinfection by-products that have been formed, thus affecting the determination of DBPs. Therefore, to obtain an accurate concentration, residual chlorine in tap water needs to be quenched prior to treatment. Currently, the most commonly used quenching agents are ascorbic acid, sodium thiosulfate, ammonium chloride, sodium sulfite, and sodium arsenite, but these quenching agents can cause varying degrees of DBPs degradation. Therefore, in recent years, researchers have attempted to find emerging chlorine quenchers. However, no studies have been conducted to systematically review the effects of traditional quenchers and new ones on DBPs, as well as their advantages, disadvantages, and scope of application. For inorganic DBPs (bromate, chlorate, and chlorite), sodium sulfite has been proven to be the ideal chlorine quencher. For organic DBPs, although ascorbic acid caused the degradation of some DBPs, it remains the ideal quenching agent for most known DBPs. Among the studied emerging chlorine quenchers, n-acetylcysteine (NAC), glutathione (GSH), and 1,3,5-trimethoxybenzene are promising for their application as the ideal chlorine quencher of organic DBPs. The dehalogenation of trichloronitromethane, trichloroacetonitrile, trichloroacetamide, and bromochlorophenol by sodium sulfite is caused by nucleophilic substitution reaction. This paper takes the understanding of DBPs and traditional and emerging chlorine quenchers as a starting point to comprehensively summarize their effects on different types of DBPs, and to provide assistance in understanding and selecting the most suitable residual chlorine quenchers during DBPs research.

Preparation of a ternary amorphous solid dispersion using hot-melt extrusion for obtaining a stable colloidal dispersion of amorphous probucol nanoparticles.

In our previous reports, ternary amorphous solid dispersions (ASDs) of probucol (PBC)/polymer/surfactant were prepared by spray-drying and cryo-grinding, and colloidal dispersions of amorphous PBC nanoparticles were obtained by dispersing the ternary ASD into water. In this study, hot-melt extrusion, which is a practical method for preparing ASD formulations, was utilized to obtain ternary ASDs and colloidal dispersions of amorphous PBC nanoparticles. Polyvinylpyrrolidone K12 (PVP) with a relatively low Tg (below 100 °C) was used as a polymer, while poloxamer P407 (P407), which is chemically stable during the hot-melt extrusion process, was utilized as a surfactant. Ternary ASDs were successfully produced with high weight ratios of PVP and P407. A hydrogen bond between the PBC hydroxyl proton and PVP carbonyl oxygen in the ternary ASD was detected using solid-state NMR spectroscopy, suggesting that amorphous PBC was stabilized mainly by PVP. Stable colloidal dispersions of amorphous PBC nanoparticles were obtained from the PBC/PVP/P407 ASD at a weight ratio of 1:4:2. The mean particle size was below 200 nm and the amorphous state of PBC remained stable upon storage at 25 °C for 14 d. Solution-state 1H NMR and zeta-potential measurements suggested that P407 mainly stabilized the colloidal dispersion of amorphous PBC nanoparticles by steric hindrance at the solid/liquid interface. The findings of this study demonstrate that hot-melt extrusion can form practical ternary ASDs that provide colloidal dispersion of amorphous drug nanoparticles. Thus, this study advocates for the use of hot-melt extrusion in the design of an amorphous formulation for a variety of poorly water-soluble drugs.

Inhibition of macrophage-derived foam cells by Adipsin attenuates progression of atherosclerosis.

Phagocytosis of oxidized low-density lipoprotein (OxLDL) by macrophages yields "foam cells" and serves as a hallmark of atherosclerotic lesion. Adipsin is a critical component of the complement activation pathway. Recent evidence has indicated an obligatory role for Adipsin in pathological models including ischemia-reperfusion and sepsis. Adipsin levels are significantly decreased in patients with asymptomatic carotid atherosclerosis, implying the role for Adipsin as a potential marker of asymptomatic carotid atherosclerosis. This study was designed to evaluate the role for Adipsin in atherosclerosis and the mechanisms involved using both in vivo and in vitro experiments. ApoE-/-/AdipsinTg mice were constructed and were fed a high-fat diet for 12 weeks. Compared with ApoE-/- mice, area of the sclerotic plaques was reduced, along with lower macrophage deposition within the plaque in ApoE-/-/AdipsinTg mice. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were stimulated with oxLDL (50 µg/ml). Adenovirus vectors containing the Adipsin gene were transfected into macrophages. Lipid accumulation was observed by Oil red O staining. Western blot and reverse transcription-polymerase chain reaction data revealed that Adipsin overexpression inhibited oxLDL-induced lipid uptake and foam cell formation and upregulation of CD36 and PPARγ in Ad-Adipsin-transfected macrophages. In addition, the PPARγ-specific agonist GW1929 reversed Adipsin overexpression-evoked inhibitory effect on lipid uptake. These results demonstrate unequivocally that Adipsin inhibits lipid uptake in a PPARγ/CD36-dependent manner and prevents the formation of foam cells, implying that Adipsin may be a potential therapeutic target against atherosclerosis.

Efficacy and Safety of Endoscopic Submucosal Dissection for Dysplasia in Ulcerative Colitis Patients: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Ulcerative colitis (UC) is associated with an increased risk of colorectal cancer. Current guidelines recommend endoscopic resection if the lesion is visible with distinct margins and a complete resection can be achieved. However, submucosal fibrosis due to chronic inflammation may increase the procedural risk and reduce the complete resection rate. The aim of this study is to assess the efficacy and safety of endoscopic submucosal dissection (ESD) for dysplasia in UC patients. MATERIALS AND METHODS: A systematic search of databases was performed until May 30, 2021. Studies that reported the resection rates and complication rates of ESD for dysplasia in UC patients were included. A random-effects model was used to generate conservative estimates of the prevalence of the outcome variables. All data analyses were performed using software Stata (version 15). RESULTS: 8 studies were enrolled in the meta-analysis, with a total of 203 dysplastic lesions in 192 UC patients. The mean lesion size was 26.7 mm. About 83% of the lesions were located in the left-side colon, and 90% of the lesions were nonpolypoid, and about 71% of the lesions had submucosal fibrosis. The mean procedural time of ESD was 83 minutes. The en bloc resection rate, complete resection rate, and curative resection rate were 94%, 84%, and 81%, respectively, with a local recurrence rate of 5%. The pooled prevalence of bleeding and perforation were 8% and 6%, respectively. The rates of metachronous tumors and additional surgery after ESD were 6% and 10%, respectively. CONCLUSION: Despite some limitations, our study suggests that ESD is an effective and safe treatment for dysplasia in UC patients. However, randomized controlled multicenter studies with less heterogeneity and longer follow-up are needed to better assess the clinical outcomes of ESD in UC patients.

Sirt6-Mediated Endothelial-to-Mesenchymal Transition Contributes Toward Diabetic Cardiomyopathy via the Notch1 Signaling Pathway.

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) is an important source of myofibroblasts that directly affects cardiac function in diabetic cardiomyopathy (DCM) via an unknown underlying mechanism. Sirt6 is a member of the Sirtuin family of NAD(+)-dependent enzymes that plays an important role in glucose and fatty acid metabolism. In this study, we investigated whether Sirt6 participates in EndMT during the development of T2DM and the possible underlying regulatory mechanisms. METHODS: Endothelium-specific Sirt6 knockout (Sirt6-KOEC) mice (C57BL/6 genetic background) were generated using the classic Cre/loxp gene recombination system. T2DM was induced in eight-week-old male mice by feeding with a high-fat diet for three weeks followed by i.p. injection with 30 mg/kg of streptozotocin. The weight, lipids profiles, insulin, food intake and water intake of experimental animals were measured on a weekly basis. Cardiac microvascular endothelial cells (CMECs) were obtained from adult male mice; the isolated cells were cultured with high glucose (HG; 33 mmol/L) and palmitic acid (PA; 500 µmol/L) in DMEM for 24 h, or with normal glucose (NG; 5 mmol/L) as the control. RESULTS: Sirt6 expression is significantly downregulated in CMECs treated with HG+PA. Additionally, Sirt6-KOEC was found to worsen DCM, as indicated by aggravated perivascular fibrosis, cardiomyocyte hypertrophy, and decreased cardiac function. In vitro, Sirt6 knockdown exacerbated the proliferation, and migration of CMECs exposed to HG+PA. Mechanistically, Sirt6 knockdown significantly enhanced Notch1 activation in CMECs treated with HG+PA, whereas Notch1 adenoviral interference significantly blunted the effects of Sirt6 knockdown on CMECs. CONCLUSION: This study is the first to demonstrate that Sirt6 participates in EndMT via the Notch1 signaling pathway in CMECs stimulated with HG+PA. Therefore, the findings of this study suggest that Sirt6 could provide a potential treatment strategy for DCM.

LncRNA GAS5 is upregulated in polycystic ovary syndrome and regulates cell apoptosis and the expression of IL-6.

BACKGROUND: GAS5 contains a hormone response element that can induce cell apoptosis in breast cancer. It is known that cell apoptosis and hormone response play crucial roles in polycystic ovary syndrome (PCOS), indicating the potential involvement of GAS5 in PCOS. This study was performed to investigate the potential involvement of GAS5 and IL-6 (a critical player in PCOS) in PCOS. METHODS: Research subjects of this study included 60 PCOS patients and 60 healthy controls. The expression levels of GAS5 and IL-6 in plasma of both patients and controls were measured by qPCR and ELISA, respectively. Cell transfections were performed to analyze the interaction between GAS5 and IL-6. Cell apoptosis was analyzed by cell apoptosis assay. RESULTS: GAS5 was upregulated in plasma of PCOS patients. The expression levels of GAS5 were positively correlated with the expression levels of IL-6. Altered expression levels of GAS5 and IL-6 distinguished PCOS patients from healthy controls. In cells of a granulosa-like tumor cell line (KGN), overexpression of GAS5 led to upregulated IL-6, while silencing of GAS5 played an opposite role. Cell apoptosis analysis showed that overexpression of GAS5 significantly decreased apoptosis rate of KGN cells. Silencing of GAS5 increased the rate of KGN cell apoptosis. CONCLUSIONS: GAS5 is upregulated in PCOS and regulates cell apoptosis and the expression of IL-6.

MiR-214-3p regulates the viability, invasion, migration and EMT of TNBC cells by targeting ST6GAL1.

MiR-214-3p is concerned with the outcomes of various tumors, such as liver cancer, bladder cancer, etc. However, the role and target of miR-214-3p in triple negative breast cancer (TNBC) is not fully understood. This study took this as the entry point, with a view to find a potential target for TNBC. The expressions of miR-214-3p in TNBC tissues and cell lines were detected, and the effects of miR-214-3p inhibitor on the viability, migration, invasion and epithelial mesenchymal transition (EMT) of TNBC cells were further analyzed. The potential target of miR-214-3p were predicted and verified, as well as the effects of target silencing on the TNBC cells were also measured. MiR-214-3p was abnormally elevated in both TNBC tissues and cell lines, especially in MDA-MB-468 cells. Low-expression of miR-214-3p restrained the survival, migration, invasion and EMT of TNBC cells. ST6GAL1 was the target gene of miR-214-3p, and its expression level increased with the low-expression of miR-214-3p. ST6GAL1 expression was abnormally reduced in both TNBC tissues and cell lines. The silence of ST6GAL1 promoted the viability, migration, invasion and EMT of TNBC cells, which could be reversed by miR-214-3p inhibitor. The down-regulation of miR-214-3p could suppress the viability, migration, invasion and EMT of TNBC cells though targeting ST6GAL1, which might be a potential target for future treatment of TNBC. Up-regulation of miR-214-3p could promote the EMT of non-TNBC cells.

Inhibition of miR­214 attenuates the migration and invasion of triple­negative breast cancer cells.

Triple­negative breast cancer (TNBC) is a subtype of breast cancer. MicroRNA (miR)­214 is closely associated with controlling the development of tumor cells; therefore, in the present study, the target gene and effects of miR­214 on TNBC cells were explored. Luciferase activity was examined by luciferase reporter assay. The viability, invasion and migration of MDA­MB­231 TNBC cells were measured using Cell Counting kit­8, Transwell and wound­healing assays, respectively. The expression levels of various factors were determined using reverse transcription­quantitative polymerase chain reaction and western blotting. The results demonstrated that the expression levels of miR­214 were higher and the levels of α1­antitrypsin (α1­AT) were lower in TNBC tissues compared with in normal tissues. Subsequently, α1­AT was revealed to be a target of miR­214. Furthermore, inhibition of miR­214 decreased cell viability, invasion and migration, enhanced the expression of E­cadherin and tissue inhibitor of metalloproteinases­2, and reduced the expression of metastatic tumour antigen 1 and matrix metalloproteinase­2. Inhibition of miR­214 also significantly downregulated the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR), and markedly downregulated that of phosphoinositide 3­kinase (PI3K); however, the expression levels of total PI3K, Akt and mTOR remained stable in all groups. Taken together, these findings indicated that α1­AT may be a target of miR­214. Downregulation of miR­214 markedly suppressed the viability, migration and invasion of MDA­MB­231 cells, and inhibited the PI3K/Akt/mTOR pathway. These findings suggested that miR­214 targeting α1­AT may be a potential mechanism underlying TNBC development.

Silence of α1-Antitrypsin Inhibits Migration and Proliferation of Triple Negative Breast Cancer Cells.

BACKGROUND α1-antitrypsin (α1-AT) is highly expressed in many tumors. However, to the best of our knowledge, its relationship to triple negative breast cancer (TNBC) has not yet been studied. Thus, in this research we first explored the influence of α1-AT silencing on the abilities of migration and invasion, and then further study its molecular mechanism in TNBC cells. MATERIAL AND METHODS The viability of MDA-MB-231 cells were detected using cell counting kit-8 (CCK-8). The abilities of migration and invasion were examined by Transwell assay. The metastasis-related factors were tested respectively by quantitative real-time PCR (qRT-PCR) and western blot assays. RESULTS Our study results showed that α1-AT level in TNBC tissues was higher than non-triple negative breast cancer (n-TNBC) and adjacent normal breast tissues. The high expression of α1-AT was linked to type of cancer, tumor size, TNM stage and metastasis, but was not correlated with α1-AT expression and age. si-α1-AT suppressed the viability, migration, and invasion of cells. While si-α1-AT upregulated E-cadherin and the tissue inhibitor of metalloproteinases-2 (TIMP-2) levels, it downregulated metastasis associated 1 (MTA1), matrix metallopeptidase 2 (MMP2), phosphorylated-mammalian target of rapamycin (p-mTOR), phosphorylated-protein kinase B (p-Akt), and phosphorylated-phosphatidylinositol 3 kinase (p-PI3K) levels. We also found that the PI3K/Akt/mTOR pathway activator reversed the role of si-α1-AT in metastasis-related factors. CONCLUSIONS α1-AT was highly expressed in TNBC tissues, and its silencing suppressed the abilities of migration and invasion in TNBC cells and downregulated the PI3K/Akt/mTOR pathway. Thus, α1-AT may have a potential therapeutic effect on TNBC.

Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition.

Mitophagy eliminates dysfunctional mitochondria and thus plays a cardinal role in diabetic cardiomyopathy (DCM). We observed the favourable effects of melatonin on cardiomyocyte mitophagy in mice with DCM and elucidated their underlying mechanisms. Electron microscopy and flow cytometric analysis revealed that melatonin reduced the number of impaired mitochondria in the diabetic heart. Other than decreasing mitochondrial biogenesis, melatonin increased the clearance of dysfunctional mitochondria in mice with DCM. Melatonin increased LC3 II expression as well as the colocalization of mitochondria and lysosomes in HG-treated cardiomyocytes and the number of typical autophagosomes engulfing mitochondria in the DCM heart. These results indicated that melatonin promoted mitophagy. When probing the mechanism, increased Parkin translocation to the mitochondria may be responsible for the up-regulated mitophagy exerted by melatonin. Parkin knockout counteracted the beneficial effects of melatonin on the cardiac mitochondrial morphology and bioenergetic disorders, thus abolishing the substantial effects of melatonin on cardiac remodelling with DCM. Furthermore, melatonin inhibited Mammalian sterile 20-like kinase 1 (Mst1) phosphorylation, thus enhancing Parkin-mediated mitophagy, which contributed to mitochondrial quality control. In summary, this study confirms that melatonin rescues the impaired mitophagy activity of DCM. The underlying mechanism may be attributed to activation of Parkin translocation via inhibition of Mst1.

SPHK1 promotes metastasis of thyroid carcinoma through activation of the S1P/S1PR3/Notch signaling pathway.

Thyroid carcinoma is characterized by an aggressive behavior, lack of effective targeted therapies and a high rate of relapse. Sphingosine kinase 1 (SPHK1) has been reported to be a critical regulatory factor in the progression of thyroid carcinoma, but the correlation between SPHK1 and clinical prognosis of patients with thyroid carcinoma has remained to be fully elucidated. The present study aimed to systematically assess the roles of SPHK1 in thyroid carcinoma metastasis and further investigate the possible underlying mechanisms. First, the expression of SPHK1 was detected in tissue samples from 53 thyroid carcinoma patients and in thyroid carcinoma cell lines by reverse transcription-quantitative polymerase chain reaction analysis. Furthermore, the level of phospho-(p)-SPHK1 was immunohistochemically detected in human thyroid carcinoma tissue samples. The activity of SPHK1 was measured with a commercial SPHK1 Activity Assay kit. A sphingosine-1-phosphate (S1P) competitive ELISA kit was used to determine the extracellular S1P levels. The metastatic potential was assessed by a Transwell assay. In addition, the association between SPHK1 and clinicopathological features of the patients was analyzed. The results indicated that the expression of SPHK1 in thyroid carcinoma samples was significantly higher than in paired adjacent normal thyroid tissues. High levels of SPHK1 were positively correlated with poor overall survival and progression-free survival. Downregulation of SPHK1 by lentiviral vector expressing SPHK1 small interfering (si)RNA evidently repressed Notch signaling and reduced the migration and invasion of thyroid carcinoma cells in vitro and in a NOD/SCID mouse model. Furthermore, inhibition of SPHK1 by siRNA or treatment with SPHK1 inhibitor 5C sensitized thyroid carcinoma to cisplatin and doxorubicin. In addition, it was demonstrated that silencing of SPHK1 effectively inhibits processes associated with thyroid carcinoma metastasis through the Notch signaling pathway, and SPHK1 may therefore represent a potential therapeutic target in thyroid carcinoma. In conclusion, the present study indicated that high levels of p-SPHK1 were positively correlated with high levels of S1P which in turn promoted thyroid carcinoma metastasis via the S1P/S1P receptor 3/Notch signaling pathway, suggesting possible prognostic markers and therapeutic targets.

Nicorandil alleviates myocardial injury and post-infarction cardiac remodeling by inhibiting Mst1.

BACKGROUND: Cardiomyocyte autophagy and apoptosis are crucial events underlying the development of cardiac abnormalities and dysfunction after myocardial infarction (MI). A better understanding of the cell signaling pathways involved in cardiac remodeling may support the development of new therapeutic strategies for the treatment of heart failure (HF) after MI. METHODS: A cardiac MI injury model was constructed by ligating the left anterior descending (LAD) coronary artery. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of nicorandil on MI-induced injury. RESULTS: Nicorandil reduced cardiac enzyme release, mitigated left ventricular enlargement and cardiac dysfunction after MI, as evaluated by echocardiography and hemodynamic measurements. According to the results of the western blot analysis and immunofluorescence staining, nicorandil enhanced autophagic flux and reduced apoptosis in cardiomyocytes subjected to hypoxic injury. Interestingly, nicorandil increased Mst1 and p-Mst1 levels in cardiomyocytes subjected to MI injury. Mst1 knockout abolished the protective effects of nicorandil on cardiac remodeling and dysfunction after MI. Mst1 knockout also abolished the beneficial effects of nicorandil on cardiac enzyme release and cardiomyocyte autophagy and apoptosis. CONCLUSIONS: Nicorandil alleviates post-MI cardiac dysfunction and remodeling. The mechanisms were associated with enhancing autophagy and inhibiting apoptosis through Mst1 inhibition.

OSM mitigates post-infarction cardiac remodeling and dysfunction by up-regulating autophagy through Mst1 suppression.

The incidence and prevalence of heart failure (HF) in the world are rapidly rising possibly attributed to the worsened HF following myocardial infarction (MI) in recent years. Here we examined the effects of oncostatin M (OSM) on postinfarction cardiac remodeling and the underlying mechanisms involved. MI model was induced using left anterior descending coronary artery (LAD) ligation. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated MI. Our results revealed that OSM alleviated left ventricular remodeling, promoted cardiac function, restored mitochondrial cristae density and architecture disorders after 4weeks of MI. Enhanced autophagic flux was indicated in cardiomyocytes transduced with Ad-GFP -LC3 in the OSM treated group as compared with the MI group. OSM receptor Oß knockout blocked the beneficial effects of OSM in postinfarction cardiac remodeling and cardiomyocytes autophagy. OSM pretreatment significantly alleviated left ventricular remodeling and dysfunction in Mst1 transgenic mice, while it failed to reverse further the postinfarction left ventricular dilatation and cardiac function in the Mst1 knockout mice. Our data revealed that OSM alleviated postinfarction cardiac remodeling and dysfunction by enhancing cardiomyocyte autophagy. OSM holds promise as a therapeutic target in treating HF after MI through Oß receptor by inhibiting Mst1 phosphorylation.

Polydatin protects cardiomyocytes against myocardial infarction injury by activating Sirt3.

Myocardial infarction (MI), which is characterized by chamber dilation and left ventricular (LV) dysfunction, represents a major cause of morbidity and mortality worldwide. Polydatin (PD), a monocrystalline and polyphenolic drug isolated from a traditional Chinese herb (Polygonum cuspidatum), alleviates mitochondrial dysfunction. We investigated the effects and underlying mechanisms of PD in post-MI cardiac dysfunction. We constructed an MI model by left anterior descending (LAD) coronary artery ligation using wild-type (WT) and Sirt3 knockout (Sirt3-/-) mice. Cardiac function, cardiomyocytes autophagy levels, apoptosis and mitochondria biogenesis in mice that underwent cardiac MI injury were compared between groups. PD significantly improved cardiac function, increased autophagy levels and decreased cardiomyocytes apoptosis after MI. Furthermore, PD improved mitochondrial biogenesis, which is evidenced by increased ATP content, citrate synthase (CS) activity and complexes I/II/III/IV/V activities in the cardiomyocytes subjected to MI injury. Interestingly, Sirt3 knockout abolished the protective effects of PD administration. PD inhibited apoptosis in cultured neonatal mouse ventricular myocytes subjected to hypoxia for 6h to simulate MI injury. PD increased GFP-LC3 puncta, and reduced the accumulation of protein aggresomes and p62 in cardiomyocytes after hypoxia. Interestingly, the knock-down of Sirt3 nullified the PD-induced beneficial effects. Thus, the protective effects of PD are associated with the up-regulation of autophagy and improvement of mitochondrial biogenesis through Sirt3 activity.

Atmospheric metallic and arsenic pollution at an offshore drilling platform in the Bo Sea: A health risk assessment for the workers.

To investigate the ambient metal pollution at the offshore drilling platform in the Bo Sea, which few studies have focused on, PM2.5 samples were collected and ten heavy metals, as well as As, were analyzed. High concentration levels of metals were observed, and the heavy metal pollution was quite serious compared to air quality standards and other marine areas. Back trajectories and wind dependent and PCA analyses showed that the marine sources included ship traffic emissions and corrosive stainless steels from the equipment at the platform as well as industrial emissions from stainless steel production and coal combustion sources, which were transported from the surrounding mainland. Both contributed greatly to the ambient metallic particles at the offshore platform. The Hazard Index values of the metals, which were much less than 1, the Carcinogenic Risk data, which were lower than the EPA's acceptable range, and the fact that the metal concentrations did not the exceed the permissible exposure limits of OSHA, indicated that the health risks from the ambient metallic particles for the oil-drilling workers were not significant.

Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Helicobacter pylori is one of the most common gastric pathogens, affecting at least half the world's population, and is strongly associated with gastritis, peptic ulcer, gastric adenocarcinoma, and lymphoma. We aimed to assess the efficacy, safety, and immunogenicity of a three-dose oral recombinant H pylori vaccine in children in China. METHODS: We did this randomised, double-blind, placebo-controlled, phase 3 trial at one centre in Ganyu County, Jiangsu Province, China. Healthy children aged 6-15 years without past or present H pylori infection were randomly assigned (1:1), via computer-generated randomisation codes in blocks of ten, to receive the H pylori vaccine or placebo. Participants, their guardians, and study investigators were masked to treatment allocation. The primary efficacy endpoint was the occurrence of H pylori infection within 1 year after vaccination. We did analysis in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT02302170. FINDINGS: Between Dec 2, 2004, and March 19, 2005, we randomly assigned 4464 participants to either the vaccine group (n=2232) or the placebo group (n=2232), of whom 4403 (99%) participants completed the three-dose vaccination schedule and were included in the per-protocol efficacy analysis. We extended follow-up to 3 years. We recorded 64 events of H pylori infection within the first year (14 events in 2074·3 person-years at risk in the vaccine group vs 50 events in 2089·6 person-years at risk in the placebo group), resulting in a vaccine efficacy of 71·8% (95% CI 48·2-85·6). 157 (7%) participants in the vaccine group and 161 (7%) participants in the placebo group reported at least one adverse reaction. Serious adverse events were reported in five (<1%) participants in the vaccine group and seven (<1%) participants in the placebo group, but none was considered to be vaccination related. INTERPRETATION: The oral recombinant H pylori vaccine was effective, safe, and immunogenic in H pylori-naive children. This vaccine could substantially reduce the incidence of H pylori infection; however, follow up over a longer period is needed to confirm the protection of the vaccine against H pylori-associated diseases. FUNDING: Chongqing Kangwei Biological Technology.

OSM Enhances Angiogenesis and Improves Cardiac Function after Myocardial Infarction.

Oncostatin M (OSM) has been reported to stimulate angiogenesis by upregulating VEGF and bFGF, implying that it could be a therapeutic strategy in treating ischemic diseases. The present study was aimed at investigating whether OSM could improve cardiac function via prompting angiogenesis following myocardial infarction (MI). Wild type (WT) and Oß knock-out (Oß (-/-)) mice were, respectively, randomized into sham group, MI + vehicle group, and MI + OSM group. WT mice displayed significantly impaired cardiac function after MI. OSM treatment attenuated cardiac dysfunction in WT MI mice, while Oß deletion abrogated the protective effects. Besides, OSM attenuated heart hypertrophy and pulmonary congestion evidenced by decreased heart weight/body weight and lung weight/body weight ratio. Further, reduction of apoptosis and fibrosis in infarct border zone was observed in OSM treated WT MI mice compared with vehicle. Moreover, in WT mice subjected to MI, OSM treatment significantly increased capillary density along with upregulation of p-Akt and angiogenic factors VEGF and bFGF in comparison with vehicle, and this phenomenon was not found in Oß (-/-) mice. In conclusion, OSM treatment preserved cardiac function, inhibited apoptosis and fibrosis, and stimulated angiogenesis via upregulating VEGF and bFGF in infarct border zone of ischemic myocardium, indicating that OSM could be a novel therapeutic target for MI.

Notch3/Akt signaling contributes to OSM-induced protection against cardiac ischemia/reperfusion injury.

Oncostatin M (OSM) exhibits many unique biological activities by activating the Oß receptor. However, its role in myocardial ischemia/reperfusion injury (I/R injury) in mice remains unknown. We investigated whether Notch3/Akt signaling is involved in the regulation of OSM-induced protection against cardiac I/R injury. The effects of OSM were assessed in mice that underwent myocardial I/R injury by OSM treatment or by genetic deficiency of the OSM receptor Oß. We investigated its effects on cardiomyocyte apoptosis and mitochondrial biogenesis and whether Notch3/Akt signaling was involved in the regulation of OSM-induced protection against cardiac I/R injury. The mice underwent 30 min of ischemia followed by 3 h of reperfusion and were randomized to be treated with Notch3 siRNA (siNotch3) or lentivirus carrying Notch3 cDNA (Notch3) 72 h before coronary artery ligation. Myocardial infarct size, cardiac function, cardiomyocyte apoptosis and mitochondria morphology in mice that underwent cardiac I/R injury were compared between groups. OSM alleviated cardiac I/R injury by inhibiting cardiomyocyte apoptosis through promotion of Notch3 production, thus activating the PI3K/Akt pathway. OSM enhanced mitochondrial biogenesis and mitochondrial function in mice subjected to cardiac I/R injury. In contrast, OSM receptor Oß knock out exacerbated cardiac I/R injury, decreased Notch3 production, enhanced cardiomyocyte apoptosis, and impaired mitochondrial biogenesis in cardiac I/R injured mice. The mechanism of OSM on cardiac I/R injury is partly mediated by the Notch3/Akt pathway. These results suggest a novel role of Notch3/Akt signaling that contributes to OSM-induced protection against cardiac I/R injury.

Self-interaction of the cucumber mosaic virus 2b protein plays a vital role in the suppression of RNA silencing and the induction of viral symptoms.

The cucumber mosaic virus (CMV) 2b protein is an RNA silencing suppressor protein that can also play direct and indirect roles in symptom induction. Previous work has shown that a hybrid virus, FRad35(2b) -CMV (renamed here as CMV-FRad2b-Pro), generated by replacement of the 2b gene of strain Fny-CMV with that from Rad35-CMV, displays markedly lower pathogenicity than Fny-CMV on Nicotiana species. However, the replacement of proline with leucine at position 55 of the 2b protein of CMV-FRad2b-Pro (protein Rad2b-Pro) created a virus (CMV-FRad2b-Leu) that induced severe symptoms. Infection of Arabidopsis thaliana mutants defective in the expression of DICER-like (DCL) endoribonucleases 2 and 4, which mediate antiviral RNA silencing, as well as of dcl3 and dcl2/3/4 triple-mutant plants, indicated that Rad2b-Pro was a weaker RNA silencing suppressor than the protein Rad2b-Leu. This was confirmed in Nicotiana benthamiana using agroinfiltration assays, showing that, compared with either Rad2b-Leu or the Fny2b protein, Rad2b-Pro was ineffective at inhibiting local or systemic silencing of expression of a green fluorescent protein reporter gene. Transgenic expression of Rad2b-Leu, but not of Rad2b-Pro, in Arabidopsis induced symptom-like phenotypes and rescued the accumulation of the 2b-deletion mutant Fny-CMVΔ2b. Bimolecular fluorescent complementation indicated that, in planta, Rad2b-Leu, but not Rad2b-Pro, self-interacts. Thus, self-interaction is crucial to the ability of the 2b protein to suppress silencing and induce a symptom-like phenotype, and is dependent on the properties of the residue at position 55.

Dynamic nature of nonculprit coronary artery lesion morphology in STEMI: a serial IVUS analysis from the HORIZONS-AMI trial.

OBJECTIVES: The authors sought to report the temporal stability of an untreated, nonculprit lesion phenotype in patients presenting with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The temporal stability of the untreated, nonculprit lesion phenotype has been studied using intravascular ultrasound-virtual histology (IVUS) in patients with stable ischemic heart disease, but not in STEMI patients. METHODS: As part of a formal substudy of the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, baseline and 13-month follow-up IVUS was performed in 99 untreated nonculprit lesions in 63 STEMI patients. Lesions were classified as pathological intimal thickening (PIT), IVUS-derived thin-cap fibroatheroma (TCFA), thick-cap fibroatheroma (ThCFA), fibrotic plaque, or fibrocalcific plaque. RESULTS: The frequency of TCFA increased from 41% at baseline to 54% at follow-up, whereas ThCFAs decreased from 41% to 34% and PIT decreased from 16% to 8%. Among the 41 lesions classified at baseline as TCFA, at follow-up, 32 (78%) were still classified as TCFA, whereas 9 (22%) were classified as ThCFAs or fibrotic plaques. An additional 21 lesions at follow-up were newly classified as TCFA, developing from either PIT or ThCFA. TCFA at baseline that evolved into non-TCFAs trended toward a more distal location than TCFA that did not change (p = 0.12). In lesions classified as TCFA, the minimum lumen area (MLA) decreased from 8.1 (interquartile range [IQR]: 7.4 to 8.8) mm(2) at baseline to 7.8 (IQR: 7.2 to 8.4) mm(2) at follow-up, p < 0.05; this was associated with an increase in percent necrotic core at the MLA site (14% [IQR: 12 to 16] to 19% [IQR: 17 to 22], p < 0.0001) and over the entire length of the lesion (14% [IQR: 12 to 16] to 18% [IQR: 17 to 20], p < 0.0001). CONCLUSIONS: Untreated nonculprit lesions in STEMI patients frequently have TCFA morphology that does not change during 13-month follow-up and is accompanied by a decrease in MLA and an increase in necrotic core. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966).