Exposure to acute waterborne cadmium caused severe damage on lipid metabolism of freshwater fish, revealed by nuclear lipid droplet deposition in hepatocytes of rare minnow.

Cadmium (Cd) is a widely distributed aquatic toxic heavy metal with the potential to disrupt fish metabolism; however, more research is needed to clarify the underlying mechanisms. In the present study, rare minnows (Gobiocypris rarus) were used to detect the effects of cadmium on freshwater fish lipid metabolism and its underlying mechanism by histopathological observation, measurement of serum and liver biochemical indexes, and analysis of gene expression in terms of lipid oxidation, synthesis and transport. Here, severe damage, such as cytoplasmic lipid droplet (LD) accumulation, ectopic deposition of LDs, and the appearance of nuclear LDs (nLDs), was detected after exposure to 2.0 mg/L or higher concentrations (2.5 and 2.8 mg/L CdCl2) for 96 h. Other damage included abnormal increases in rough endoplasmic reticulum (RER) lamellae in a fingerprint or concentric circle pattern and necrosis of hepatocytes, and which was observed in the livers of fish exposed to 2.0 mg/L CdCl2.. Both hepatic and serum lipids, such as triglycerides and total cholesterol, were significantly increased after exposure to 2.0 mg/L CdCl2, as was serum lipase (LPS). Hepatic lipase and lipoprotein lipase remained unchanged, in accordance with the unchanged hepatic mRNA transcripts of PPARɑ. Furthermore, the mRNA transcripts of both SCD and SQLE were significantly decreased. Moreover, hepatic and serum low-density and high-density lipoprotein cholesterol showed significant changes, which were accompanied by a significant increase and decrease in hepatic APOAI and APOB100 mRNA levels, respectively. All the results indicate the presence of severe damage to hepatic lipid metabolism and that disrupted lipid transport may play a key role in the accumulation of hepatic LDs. In addition, the hepatic nLDs of nonmammalian vertebrates and their location across the nuclear envelope are intriguing, suggesting that large-size nLDs are a common marker for severe liver damage.

Novel 1H-pyrazolo[3,4-d]pyrimidin-6-amino derivatives as potent selective Janus kinase 3 (JAK3) inhibitors. Evaluation of their improved effect for the treatment of rheumatoid arthritis.

Selective JAK3 inhibitors have been shown to have a potential benefit in the treatment of autoimmune disorders. Here we report the identification of a series of pyrazolopyrimidine derivatives as potent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Most of these compounds (13k, 13n and 13 t), displayed stronger anti-JAK3 kinase activity and selectivity than tofacitinib. Furthermore, the most active inhibitor 13t (IC50 = 0.1 nM), also exhibited favourable selectivity for JAK3 in a panel of 9 kinases which contain the same cysteine. In a series of cytokinestimulated cellular analysis, compound 13 t, could potently block the JAK3-STAT signaling pathway. Further biological studies, including cellular antiproliferative activity assays and a rat adjuvant-induced arthritis model for in vivo evaluation, also indicated its efficacy and low toxicity in the treatment of rheumatoid arthritis. The results of these experimental explorations suggested that 13t is a promising lead compound for the development of selective JAK3 inhibitor with therapeutic potential in rheumatoid arthritis.

Differential Impact of Cigarette Smoking on Prognosis in Women and Men Undergoing Percutaneous Coronary Intervention.

We sought to compare the effects of smoking on clinical outcomes in women and men with coronary artery disease undergoing percutaneous coronary intervention (PCI). We prospectively followed up 10 369 patients undergoing elective PCI. All patients were stratified according to smoking status and sex. The impacts of smoking on long-term major adverse cardiovascular events (MACEs, the composite of all-cause death, myocardial infarction, or target vessel revascularization) were assessed. Among 7773 men and 2596 women undergoing PCI, the prevalence of cigarette smoking was 66.7% (n = 5185) and 11.0% (n = 286; P < .001). During the 3 years of follow-up (median: 20.6 months), smoking increased MACE in both men and women (men 10.8% vs 8.1%, P < .001; women 23.2% vs 6.4%; P < .001). After adjusting for baseline characteristics, smoking had a greater effect on MACE in women (hazard ratio [HR]: 3.68, 95% confidence interval [CI]: 1.86-7.28; P < .001) compared with men (HR: 1.35, 95% CI: 1.03-1.77; P = .005, interaction P = .026). There was a lower prevalence of smoking in women compared to men among patients undergoing PCI. However, smoking confers a higher excess risk for MACE among women compared with men.

Structure-based design and synthesis of pyrimidine-4,6-diamine derivatives as Janus kinase 3 inhibitors.

Janus kinases (JAKs) play a key role in the proliferation, apoptosis and differentiation of immune cells, and JAKs are considered as an attractive target for the treatment of inflammatory and autoimmune diseases. Here we show the design and optimization of pyrimidine-4,6-diamine derivatives as selectivity JAK3 inhibitors. Compound 11e, which might interact with unique cysteine (Cys909) residue in JAK3, exhibited excellent JAK3 inhibitory activity (IC50 = 2.1 nM) and high JAK kinase selectivity. In cellular assay, 11e showed moderate potency inhibiting IL-2-stimulated T cell proliferation. The data supports the further development of novel JAKs inhibitors.

Structure-based design and synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amino derivatives as Janus kinase 3 inhibitors.

Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1H-pyrazolo[3,4-d]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound 12a, which exhibited potent JAK3 inhibitory activity (IC50 of 6.2 nM) as well as excellent JAK kinase selectivity (>60-fold). In cellular assay, 12a exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50 of 9.4 µM). Further, compound 12a showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors.

InP/ZnS QDs exposure induces developmental toxicity in rare minnow (Gobiocypris rarus) embryos.

We investigated the in vivo toxicity of InP/ZnS quantum dots (QDs) in Chinese rare minnow (Gobiocypris rarus) embryos. The 72 h post-fertilization (hpf) LC50 (median lethal concentration) was 1678.007 nmol/L. Rare minnows exposed to InP/ZnS QDs exhibited decreased spontaneous movement, decreased survival and hatchability rates, and an increased malformation rate. Pericardial edema, spinal curvature, bent tails and vitelline cysts were observed. Embryonic Wnt8a and Mstn mRNA levels were significantly up-regulated after InP/ZnS QDs treatment at 48 hpf (200 nmol/L) (p < 0.05). The superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels at 96 hpf (800 nmol/L) had an increasing trend. Hsp70 mRNA expression was significantly changed at 48 hpf (200 nmol/L), but compared with the blank control, the different InP/ZnS QDs treatments did not significantly change the Olive tail moments (p > 0.05). Thus, InP/ZnS QDs caused teratogenic effects and death during the development of Chinese rare minnow embryos, but InP/ZnS QDs did not cause significant genetic toxicity during Chinese rare minnow development.

Characterization and expression analyses of somatolactin-α and -ß genes in rare minnows (Gobiocypris rarus) following waterborne cadmium exposure.

Using reverse transcription-polymerase chain reaction (RT-PCR) and RACE (rapid amplification of cDNA ends), somatolactin-α (rmSLα) and -ß (rmSLß) were identified from the pituitary gland of rare minnows (Gobiocypris rarus). The full-length cDNAs of these two genes were 1288 and 801 bp, encoding prepeptides of 250 and 228 amino acids residues, respectively. rmSLß can be detected in the brain (including the pituitary), ovary, testis, and gill, while rmSLα was mainly expressed in the brain. On the other hand, rmSLα was expressed in all the fetal developmental stages; however, rmSLß can just be detected in the stages since from 14 h post-fertilization (hpf). After exposure to acute waterborne cadmium (Cd), rmSLα was distinctly upregulated in juvenile rare minnows at all detected time points, from 24 to 96 h and 10 days, while rmSLß was significantly altered only in 96 h or 10-day treatment groups. As for adults, acute Cd exposure caused alterations of both rmSLα and rmSLß in the brain (containing the pituitary) at the 24 h; subchronic waterborne Cd treatment led to upregulation of rmSLα, while decrease of mSLß in the brain. Alteration of rmSL transcripts following waterborne Cd exposure further confirmed the endocrine disruption of this heavy metal. Besides, exposure to as low as 5 µg/L Cd caused alteration of rmSLα, which suggested that rmSLα might be a potential biomarker for risk assessment of aquatic Cd.

Effects of subchronic exposure to waterborne cadmium on H-P-I axis hormones and related genes in rare minnows (Gobiocypris rarus).

The H (hypothalamic)-P (pituitary)-I (interrenal) axis is critical in the stress response and other activities of fish. To further investigate cadmium (Cd) toxicity on the H-P-I axis and to identify its potential regulatory genes in fish, the adult female rare minnows (Gobiocypris rarus) were exposed to subchronic (5weeks) levels of waterborne Cd in the present study. This kind of treatment caused dose-dependent decline in fish growth, with significance in the high dose group (100µg/L). Correspondingly, low dose (5-50µg/L) waterborne Cd disrupted the endocrine system of H-P-I axis just at the secretion level, while high dose Cd disrupted both the secretion and synthesis of cortisol and its downstream signals in rare minnows, revealed by the significantly upregulation and positive correlation of corticosteroidogenic genes including MC2R, StAR, CYP11A1, and CYP11B1 in the kidney (including the interrenal tissue) (P<0.05), and the significant alteration of Glcci1, Hsp90AA and Hsp90AB in the hepatopancreas, gill and intestine as well (P<0.05). The expression of Glcci1 was significantly decreased in hepatopancreas, gill and intestine of tested fish following treatment, and its positive correlation with GR (Glucocorticoid receptor) suggested its potential regulation on the cortisol and/or H-P-I axis in fish. The expression of FKBP5 in the intestine was positively and significantly correlated with that of Hsp90AA (P<0.05), and the Hsp90AB transcript in the hepatopancreas was positively correlated with that of Hsp90AA (P<0.05), which indicated that Hsp90AA and Hsp90AB were more likely to serve as cofactors of GR and FKBP5 in response to Cd exposure.

Transcriptome profiling analysis of rare minnow (Gobiocypris rarus) gills after waterborne cadmium exposure.

Rare minnow (Gobiocypris rarus) is a widely used experimental fish in risk assessments of aquatic pollutants in China. Cadmium (Cd) is one of the most toxic heavy metals in the world; however, few studies have used fish gills, a multi-functional organ. In this study, we characterized the differential expression of adult female rare minnow gills after sub-chronic waterborne Cd (75µg/L CdCl2) exposure for 35d. A total of 452 genes (209 up-regulated and 243 down-regulated) were identified by gene expression profiling using RNA-Seq before and after treatment. Of these differentially expressed genes, 75, 21, and 54 differentially expressed genes are related to ion transport, oxidation-reduction processes, and the immune response, respectively. The results of GO and KEGG enrichment analyses, together with the altered transcript levels of major histocompatibility complex (MHC) class I and class II molecules and the significant increases in the levels of serum tumor necrosis factor α (TNF-α), interleukin 1ß (IL1ß) and nuclear factor-κB (NF-κB), indicated a disruption of the immune system, particularly the induction of inflammation and autoimmunity. The significant down-regulation of coagulation factor XIII A1 polypeptide (F13A1), tripartite motif-containing protein 21 (TRIM21), and Golgi-associated plant pathogenesis-related protein (GAPr) during both acute (≤96h) and sub-chronic (35d) waterborne Cd exposure, as well as their dosage dependence, suggested that these three genes could be used as sensitive biomarkers for aquatic Cd risk assessment.

The secretion, synthesis, and metabolism of cortisol and its downstream genes in the H-P-I axis of rare minnows (Gobiocypris rarus) are disrupted by acute waterborne cadmium exposure.

The H (hypothalamic)-P (pituitary)-I (interrenal) axis plays a critical role in the fish stress response and is regulated by several factors. Cadmium (Cd) is one of the most toxic heavy metals in the world, but its effects on the H-P-I axis of teleosts are largely unknown. Using rare minnow (Gobiocypris rarus) as an experimental animal, we found that Cd only disrupted the secretion and synthesis of cortisol. Neither hormones at the H or P level nor the expressions of their receptor genes (corticotropin-releasing hormone receptor (CRHR) and melanocortin receptor 2 (MC2R)) were affected. Steroidogenic acute regulator (StAR), CYP11A1 and CYP11B1, which encode the key enzymes in the cortisol synthesis pathway, were significantly up-regulated in the kidney (including the head kidney). The level of 11ß-HSD2, which is required for the conversion of cortisol to cortisone, was increased in the kidney, intestine, brain, and hepatopancreas, whereas the expression of 11ß-HSD1, which encodes the reverse conversion enzyme, was increased in the gill, kidney and almost unchanged in other tissues. The enzyme activity concentration of 11ß-HSD2 was increased in the kidney as well. The level of glucocorticoid receptor (GR) decreased in the intestine, gill and muscle, and the key GR regulator FK506 binding protein5 (FKBP5) was up-regulated in the GR-decreased tissues, whereas the level of nuclear receptor co-repressor 1 (NCoR1), another GR regulator remained almost unchanged. Thus, GR, FKBP5 and 11ß-HSD2 may be involved in Cd-induced cortisol disruption.

Neuroprotective effects of Ilexonin A following transient focal cerebral ischemia in rats.

Ilexonin A is a compound isolated from the root of a plant commonly used in traditional Chinese medicine. The aim of the present study was to investigate the possible protective mechanism of Ilexonin A in rats subjected to occlusion of the middle cerebral artery (MCAO). Transient focal cerebral ischemia was induced by 2 h of MCAO, followed by reperfusion. Ilexonin A at doses of 20, 40 and 80 mg/kg were administered via intraperitoneal injection immediately following ischemia/reperfusion. The expression levels of glial fibrillary acidic protein (GFAP), ionized calcium­binding adapter molecule­1 (Iba­1), vascular endothelial growth factor (VEGF), fetal liver kinase­1 (Flk­1) and Nestin were examined using immunostaining and Western blot analysis of the peri­infarct region following ischemia/reperfusion. Ilexonin A significantly decreased the infarct volume and improved neurological deficits in a dose­dependent manner. The expression levels of VEGF, Flk­1 and Nestin were significantly increased in the rats treated with Ilexonin A, compared with the rats administered with saline. Following treatment with Ilexonin A, a higher number of GFAP­positive astrocytes were found in the Ilexonin A­treated rats at 1, 3 and 7 days, compared with the rats exposed to ischemia only, however, there were fewer astrocytes at 14 days, compared with the ischemia group. Ilexonin A significantly decreased the protein expression of Iba­1. The results of the present study suggested that the protective effects of Ilexonin A were associated with revascularization, neuronal regeneration, and the regulation of astrocyte and microglia cell activation.

Transradial Coronary Intervention Versus Coronary Artery Bypass Grafting for Unprotected Left Main and/or Multivessel Disease in Patients With Acute Coronary Syndrome.

The overall safety and efficacy of transradial coronary intervention (TRI) versus coronary artery bypass grafting (CABG) for patients with unprotected left main (UPLM) disease and/or multivessel coronary disease (MVD) presenting with acute coronary syndrome (ACS) have not been established. Consecutive patients with ACS undergoing TRI with drug-eluting stent (n = 1431) or CABG (n = 651) for UPLM and/or MVD were included. A propensity-score matching was performed to adjust for differences in baseline characteristics between the 2 cohorts, yielding 524 pairs of matched patients. Median clinical follow-up was 32 months. After propensity-score adjustment, no significant difference was observed between the TRI and CABG groups in all-cause mortality (4.0% vs 5.2%; P = .375). Transradial coronary intervention was favored by a significant increase in the incidence of stroke in the CABG group (0.4% vs 1.9%; P = .020), whereas a significantly increased target vessel revascularization rate (16.8% vs 6.3%; P < .0001) observed in the TRI group favored CABG. Composite outcome (death/myocardial infarction/stroke) was comparable between the TRI and the CABG groups (8.0% vs 11.5%; P = .061). Clinical outcomes of TRI on UPLM and/or MVD for patients with ACS are comparable to CABG in composite safety outcomes with the advantage to TRI for avoiding a stroke.

Molecular characterization of Beclin 1 in rare minnow (Gobiocypris rarus) and its expression after waterborne cadmium exposure.

Beclin 1 plays an important role in autophagy and apoptosis which are well documented in mammals. However, relevant reports are rare in fish. This study characterized Beclin 1 of the rare minnow Gobiocypris rarus (rmBeclin 1), which encodes a peptide of 447 amino acids using RT-PCR and RACE. The deduced peptide showed 96.4 and 80.8% similarity to Beclin 1 of common carp and human, respectively. Semiquantitative RT-PCR revealed that rmBeclin 1 was ubiquitously expressed in all tested tissues of male and female fish in all developmental stages, even unfertilized eggs. RT-qPCR revealed that rmBeclin 1 mRNA transcripts were significantly up-regulated in gills after a 12 h treatment with waterborne CdCl2 but were decreased thereafter. However, rmBeclin 1 expression was decreased in the brain, but it was not significantly changed in other tissues. Subchronic CdCl2 exposure significantly increased rmBeclin 1 in the brain, but it distinctly decreased rmBeclin 1 in the gill and hepatopancreas. A dose-dependent effect was not observed in mature fish treated for 96 h, but a dose-dependent effect existed in immature fish treated for 10 days. Longer treatment (10 day) caused a significantly higher expression of rmBeclin 1 in the larvae groups. These data suggest that alterations in rmBeclin 1 after CdCl2 exposure are tissue-specific and time-related and that the dose-dependent effect was restricted to a certain concentration range and exposure time.

Efficacy of coenzyme Q10 in mitigating spinal cord injury-induced osteoporosis.

Spinal cord injury (SCI)­induced osteoporosis may cause mild trauma to bone and increase the risk of bone fracture. The present study aimed to investigate the efficacy of coenzyme Q (CoQ10) on SCI­induced osteoporosis in rats. SCI was induced by surgical transection of the cord at the T10­12 level. Animals were treated with CoQ10 (10 mg/kg; intragastrically) daily from 12 h after the surgery and over 10 subsequent days. At the end of the experimental period, blood was collected from the animals and femurs and tibiae were removed for evaluation using biochemical assays. Treatment with CoQ10 prevented SCI­induced bone loss by rescuing the decreased levels of bone mineral density and bone mineral content observed in the SCI rats. Furthermore, CoQ10 administration reduced bone malondialdehyde levels with a concomitant increase in superoxide dismutase levels, thus alleviating SCI­induced oxidative injury. In addition, serum inflammatory cytokine levels were markedly increased in rats post­SCI, which was attenuated by treatment with CoQ10. Finally, the osteoclast­specific genes receptor activator of nuclear factor kappa­B ligand and cathepsin K were significantly upregulated and the osteoblast­specific gene core­binding factor alpha 1 in the femur was downregulated following SCI, which was effectively restored following treatment with CoQ10. The results suggested that CoQ10 treatment may be effective in attenuating SCI­induced osteoporosis.

Rationale and design of the RT-AF study: Combination of rivaroxaban and ticagrelor in patients with atrial fibrillation and coronary artery disease undergoing percutaneous coronary intervention.

OBJECTIVE: Optimal antithrombotic strategy for patients with concomitant coronary artery disease and atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) is still controversial, and the role of novel antithrombotic agents has nerve been tested. Therefore, the aim of this study is to evaluate and overall safety and efficacy profile of the combination of rivaroxaban and ticagrelor in this particular population. DESIGN: The RT-AF study is an open-label, randomized, active-controlled, multicenter clinical trial with up to 420 subjects enrolled in 5 centers. Eligible patients, who have a history or new onset paroxysmal, persistent, or permanent non-valvular AF, referred to the study centers with indications for PCI will be randomly assigned to receive triple therapy (including warfarin, clopidogrel and aspirin) or dual therapy (rivaroxaban and ticagrelor). All subjects will have clinical follow-up at discharge, at 30 days, 6 months and 12 months. The primary end point is major or clinically relevant non-major bleeding events at 12 months. The major secondary end point is the composite efficacy outcome of death, myocardial infarction, stent thrombosis and ischemic stroke. CONCLUSION: The study will be sufficiently powered to provide data primarily regarding the safety of dual therapy with rivaroxaban and ticagrelor over the traditional triple therapy in patients with AF undergoing PCI at 12 months. It will also provide important information regarding the efficacy of the two different antithrombotic regimens. (ClinicalTrials.gov identifier: NCT02334254).

[Expression of CysLTR-1 and CysLTR-2 in adenoid tissues from children with adenoid hypertrophy].

OBJECTIVE: To examine the expression of cysteinyl leukotriene receptor-1 (CysLTR-1) and cysteinyl leukotriene receptor-2 (CysLTR-2) in the adenoid tissues from children with adenoid hypertrophy (AH) and to explore the role of leukotrienes in the pathogenesis of AH. METHODS: Sixty children with AH who were treated by adenoidectomy and/or tonsillectomy were classified into two groups: simple AH and AH plus allergic rhinitis (n=30 each). Twenty children who underwent tonsillectomy due to recurrent purulent tonsillitis were selected as the control group. The expression of CysLTR-1 and CysLTR-2 in the excised tonsil and/or adenoid tissues was determined by immunofluorescence histochemical labeling and integrated optical density measurement. RESULTS: The expression of CysLTR-1 and CysLTR-2 in the adenoid and tonsil tissues increased significantly in both the simple AH group and AH plus allergic rhinitis group compared with the control group (P<0.01). The expression of CysLTR-1 and CysLTR-2 in the AH plus allergic rhinitis group increased more significantly compared with the simple AH group (P<0.01). CONCLUSIONS: CysLTR-1 and CysLTR-2 are highly expressed in the adenoid tissues from children with AH, suggesting that leukotrienes are involved in the pathogenesis of AH.

Design, synthesis, and structure-activity relationship of novel LSD1 inhibitors based on pyrimidine-thiourea hybrids as potent, orally active antitumor agents.

Histone lysine specific demethylase 1 (LSD1) was reported to be overexpressed in several human cancers and recognized as a promising anticancer drug target. In the current study, we designed and synthesized a novel series of pyrimidine-thiourea hybrids and evaluated their potential LSD1 inhibitory effect. One of the compounds, 6b, containing a terminal alkyne appendage, was shown to be the most potent and selective LSD1 inhibitor in vitro and exhibited strong cytotoxicity against LSD1 overexpressed gastric cancer cells. Compound 6b also showed marked inhibition of cell migration and invasion as well as significant in vivo tumor suppressing and antimetastasis role, without significant side effects by oral administration. Our findings indicate that the pyrimidine-thiourea-based LSD1 inactivator may serve as a leading compound targeting LSD1 overexpressed cancers.

Can HPV vaccine have other health benefits more than cancer prevention? A systematic review of association between cervical HPV infection and preterm birth.

Although the association between high-risk human papillomavirus (HPV) infection and cervical dysplasia as well as cervical cancer is well established, studies on the relationship between HPV infection and risk of preterm birth (PTB) have yielded inconclusive and inconsistent results. Therefore, we conducted a meta-analysis to investigate the association between HPV infection and PTB. The electronic database was searched until July 1, 2014. Relevant studies reporting the association between HPV infection and the risk of PTB were included and for further evaluation. Statistical analysis was performed using Revmen 5.3 and Stata 10.0. Six observational cohort studies and 2 case-control studies were included. A significant association between HPV infection and PTB was observed (odds ratio=2.12, 95% CI 1.51-2.98, P<0.001, random effect model). Stratification according to diagnostic methods indicated that both positive HPV DNA status and abnormal cervical cytology were associated with increased risk of PTB. Moreover, our data suggested a higher risk of PTB in Caucasian HPV-infected population, while no significant association was observed in the Asian population. Although the causality remains unclear, findings from our meta-analysis indicate that HPV infection might increase the risk of PTB. In the future, prospective cohorts with larger samples sizes are warranted to ascertain the causality and pathophysiological studies are required to explore the possible biological mechanisms involved.

Alternative messenger RNA splicing of autophagic gene Beclin 1 in human B-cell acute lymphoblastic leukemia cells.

Beclin 1 is a key factor for initiation and regulation of autophagy, which is a cellular catabolic process involved in tumorigenesis. To investigate the role of alternative splicing of Beclin1 in the regulation of autophagy in leukemia cells, Beclin1 mRNA from 6 different types of cell lines and peripheral blood mononuclear cells from 2 healthy volunteers was reversely transcribed, subcloned, and screened for alternative splicing. New transcript variants were analyzed by DNA sequencing. A transcript variant of Beclin 1 gene carrying a deletion of exon 11, which encoded a C-terminal truncation of Beclin 1 isoform, was found. The alternative isoform was assessed by bioinformatics, immunoblotting and subcellular localization. The results showed that this variable transcript is generated by alternative 3' splicing, and its translational product displayed a reduced activity in induction of autophagy by starvation, indicating that the spliced isoform might function as a dominant negative modulator of autophagy. Our findings suggest that the alternative splicing of Beclin 1 might play important roles in leukemogenesis regulated by autophagy.

Contemporary management and attainment of cholesterol targets for patients with dyslipidemia in China.

AIMS: It is well-established that lipid disorder is an important cardiovascular risk factor, and failure to reach optimal lipid levels significantly contributes to the residual cardiovascular risks. However, limited information is available on the management and the attainment of recommended cholesterol targets in real-world practice in China. METHODS AND RESULTS: A nationally representative sample of 12,040 patients with dyslipidemia from 19 provinces and 84 hospitals across China were consecutively enrolled in this survey. Risk stratification and individual cholesterol target was established for all participants. This survey identified a high-risk cohort, with over 50% of patients had hypertension, 37.5% had coronary artery disease, and more than 30% had peripheral artery disease. Thirty-nine percent of all participants received lipid lowering medications. And the majority of them (94.5%) had statins (42.5% with atorvastatin, 29.0% with simvastatin, and 15.2% with rosuvastatin). However, the overall attainment for low-density lipoprotein cholesterol (LDL-C) target is low (25.8%), especially, in female (22.2%), and in patients with increased body mass index (BMI) (38.3% for BMI<18.5, 28.1% for BMI 18.5-24.9, 26.0% for BMI 25.0-29.9, and 17.4% for BMI ≥ 30, P<0.0001). Subgroup analysis also showed the attainment is significantly lower in patients who were stratified into high (19.9%) and very high (21.1%) risk category. In logistic regression analysis, eight factors (BMI, gender, coronary artery disease, systolic and diastolic blood pressure, hypertension, family history of premature coronary artery disease and current smoking) were identified as independent predictors of LDL-C attainment. CONCLUSIONS: Despite the proven benefits of lipid-lowering therapies, current management of dyslipidemia continues to be unsatisfied. A considerable proportion of patients failed to achieve guideline-recommended targets in China, and this apparent treatment gap was more pronounced among patients with increased BMI, higher risk stratification and women.