Microvascular disease, modifiable risk factor profiles and incident arrhythmias in type 2 diabetes.

BACKGROUND: To assess the roles of diabetic microvascular disease and modifiable risk factors and their combination in the development of arrhythmias. METHODS: We included participants with type 2 diabetes (T2D) who were free of arrhythmias during recruitment in the UK Biobank study. The associations of microvascular disease states (defined by the presence of retinopathy, peripheral neuropathy or chronic kidney disease), four modifiable arrhythmic risk factors (body mass index, smoking, systolic blood pressure and glycosylated haemoglobin) and their joint associations with incident arrhythmias were examined. RESULTS: Among the 25 632 participants with T2D, 1705 (20.1%) of the 8482 with microvascular disease and 2017 (11.8%) of the 17 150 without microvascular disease developed arrhythmias during a median follow-up of 12.3 years. Having any of the three microvascular diseases was associated with a 48% increase in the hazard of developing arrhythmias. Incorporating microvascular disease states into a model alongside 11 traditional risk factors significantly enhanced arrhythmia prediction. Furthermore, individuals with microvascular disease who had optimal levels of zero to one, two, three or four arrhythmic risk factors showed an HR of 2.05 (95% CI 1.85, 2.27), 1.67 (95% CI 1.53, 1.83), 1.35 (95% CI 1.22, 1.50) and 0.91 (95% CI 0.73, 1.13), respectively, compared with those without microvascular disease. CONCLUSIONS: Although microvascular disease, a non-traditional risk factor, was associated with incident arrhythmias in individuals with T2D, having optimal levels of risk factors may mitigate this risk.

Microvascular Disease, Cardiovascular Health, and Risk of Coronary Heart Disease in Type 2 Diabetes: A UK Biobank Study.

CONTEXT: The interplay between cardiovascular health metrics (CVHMs) and microvascular disease (MVD) in relation to the risk of incident coronary heart disease (CHD) among individuals with type 2 diabetes mellitus (T2DM) remains to be evaluated. OBJECTIVE: To investigate the role of MVD and CVHMs in the development of CHD among T2DM. DESIGN: We included 19,664 participants with T2DM from the UK Biobank who had data on CVH metrics (CVHMs) and were free of CHD during recruitment. CVHMs were defined based on five behavioral (body mass index, diet, sleep duration, smoking, and regular exercise) and three biological factors (glycemic control, hyperlipidemia, and hypertension). MVD was defined as the presence of retinopathy, peripheral neuropathy, and chronic kidney disease. HR and 95% CI of CHD were estimated by multivariable Cox regression models. RESULTS: There were 3,252 incident cases of CHD recorded after a median follow-up of 12.3 years. After multivariable adjustment, each MVD was separately associated with risk of CHD, and those who had 1 or ≥2 MVD had a 27% and an 87% increased risk of developing CHD, respectively. Each of the unfavorable CVHMs was associated with a higher risk of CHD. As compared with MVD-free participants who had ideal CVHMs, those who had ≥2 MVD and had poor CVHMs were at particularly high risk of incident CHD (HR=4.58; 95% CI: 3.58, 5.86), similarly when considering behavioral CVH or biological CVH separately. On an additive scale, there was a positive statistically significant interaction between number of MVD and CVHMs. CONCLUSIONS: Coexistence of multiple MVDs was associated with a substantially higher risk of CHD among individuals with T2DM. Such an association may be amplified by unfavorable CVHMs.

Design, synthesis, and evaluation of fluoroquinolone derivatives as microRNA-21 small-molecule inhibitors.

MicroRNA-21 (miRNA-21) is highly expressed in various tumors. Small-molecule inhibition of miRNA-21 is considered to be an attractive novel cancer therapeutic strategy. In this study, fluoroquinolone derivatives A1-A43 were synthesized and used as miRNA-21 inhibitors. Compound A36 showed the most potent inhibitory activity and specificity for miRNA-21 in a dual-luciferase reporter assay in HeLa cells. Compound A36 significantly reduced the expression of mature miRNA-21 and increased the protein expression of miRNA-21 target genes, including programmed cell death protein 4 (PDCD4) and phosphatase and tensin homology deleted on chromosome ten (PTEN), at 10 µM in HeLa cells. The Cell Counting Kit-8 assay (CCK-8) was used to evaluate the antiproliferative activity of A36; the results showed that the IC50 value range of A36 against six tumor cell lines was between 1.76 and 13.0 µM. Meanwhile, A36 did not display cytotoxicity in BEAS-2B cells (lung epithelial cells from a healthy human donor). Furthermore, A36 significantly induced apoptosis, arrested cells at the G0/G1 phase, and inhibited cell-colony formation in HeLa cells. In addition, mRNA deep sequencing showed that treatment with A36 could generate 171 dysregulated mRNAs in HeLa cells, while the expression of miRNA-21 target gene dual-specificity phosphatase 5 (DUSP5) was significantly upregulated at both the mRNA and protein levels. Collectively, these findings demonstrated that A36 is a novel miRNA-21 inhibitor.

Discovery of Potent PROTACs Targeting EGFR Mutants through the Optimization of Covalent EGFR Ligands.

Drug resistance caused by epidermal growth factor receptor (EGFR) mutation has largely limited the clinical use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) for the treatment of non-small-cell lung cancer (NSCLC). Herein, to overcome the intractable problem of drug resistance, proteolysis targeting chimeras (PROTACs) targeting EGFR mutants were developed by optimizing covalent EGFR ligands. Covalent or reversible covalent pyrimidine- or purine-containing PROTACs were designed, synthesized, and evaluated. As a consequence, covalent PROTAC CP17, with a novel purine-containing EGFR ligand, was discovered as a highly potent degrader against EGFRL858R/T790M and EGFRdel19, reaching the lowest DC50 values among all reported EGFR-targeting PROTACs. Furthermore, CP17 exhibited excellent cellular activity against the H1975 and HCC827 cell lines with high selectivity. Mechanism investigation indicated that the lysosome was involved in the degradation process. Importantly, the covalent binding strategy was proven to be an effective approach for the design of PROTACs targeting EGFRL858R/T790M, which laid the practical foundation for further development of potent EGFR-targeting PROTACs.

The efficacy and safety of intravenous tranexamic acid in hip fracture surgery: A systematic review and meta-analysis.

OBJECTIVE: The present meta-analysis was conducted to compare the efficacy and safety of intravenous application of tranexamic acid (TXA) with placebo in patients with hip fracture undergoing hip surgeries. METHODS: PubMed, EMBASE and Cochrane Library were searched from inception until March 2018. A combined searching strategy of subject words and random words was adopted. Only randomized clinical trials were included. The comparisons regarding transfusion rate, total blood loss, intraoperative blood loss, postoperative blood loss, postoperative haemoglobin and postoperative thromboembolic complications were conducted. The meta-analysis was performed using Review Manager 5.3, and the bias evaluation was based on the Cochrane Handbook 5.1.0. RESULTS: Ten randomized controlled trials published from 2007 to 2018 were included in the meta-analysis. The results showed that there were significant differences in the two groups concerning transfusion rate of allogeneic blood [risk ratio (RR) = 0.66, 95% confidence interval (CI): 0.56 to 0.78, P = 0.003], total blood loss [mean difference (MD) = -273.00, 95% CI: -353.15 to -192.84, P < 0.00001], intraoperative blood loss (MD = -76.63, 95% CI: -139.55 to -13.71, P = 0.02), postoperative blood loss (MD = -125.29, 95% CI: -221.96 to -28.62, P = 0.01) and postoperative haemoglobin (MD = 0.80, 95% CI: 0.38 to 1.22, P = 0.0002). Nonsignificant differences were found in the incidence of thromboembolic events (RR = 1.38, 95% CI: 0.74 to 2.55, P = 0.31). CONCLUSIONS: This meta-analysis of the available evidence implies that the intravenous route of TXA shows an ability to reduce transfusion requirements and total blood loss, not increasing the incidence of thromboembolic events in patients undergoing hip surgeries. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: The result of this meta-analysis shows that the utilization of intravenous TXA in patients with hip fracture undergoing hip surgeries possesses great potential in reducing blood loss and allogeneic blood transfusion safely.

Methylation of sodium iodide symporter promoter correlated with aggressiveness and metastasis in papillary thyroid carcinoma: a meta-analysis.

BACKGROUND: Methylation of sodium iodide symporter promoter has been reported to increase the incidence of papillary thyroid carcinoma (PTC). In this meta-analysis stratified via methylation of sodium iodide symporter promoter, we evaluate the relationship between methylation of sodium iodide symporter promoter and PTC. The association between methylation with aggressiveness and metastasis potential of PTC is also discussed. METHODS: We searched electronic databases for original articles and references of included studies both in English and Chinese from 1966 to 2014. Two reviewers selected the case-control study and extracted data from relevant literature independently. RESULTS: Seven articles, including 360 cases and 268 controls, were involved in this meta-analysis. The prevalence of PTC in patients with methylated sodium iodide symporter promoter was significantly higher than those with non-methylated promoter (OR=7.36, 95% CI: 4.25-12.74, P<0.001). Stratified analysis showed that PTC patients with multiple lesions, capsule invasion and lymphatic metastasis had significantly higher rates of methylation (OR=2.22, 95% CI: 1.12-4.41, P=0.02; OR=2.14, 95% CI: 1.12-4.08, P=0.02; OR=3.56, 95% CI: 1.97-6.46, P<0.0001). But no relationship was found among the methylation of sodium iodide symporter and age, gender and size of tumor. CONCLUSIONS: The methylation of sodium iodide symporter promoter is related with PTC and its aggressive and metastatic potential. Due to the limited sample size, more clinical researches should be taken in the future.

pParse: a method for accurate determination of monoisotopic peaks in high-resolution mass spectra.

Determining the monoisotopic peak of a precursor is a first step in interpreting mass spectra, which is basic but non-trivial. The reason is that in the isolation window of a precursor, other peaks interfere with the determination of the monoisotopic peak, leading to wrong mass-to-charge ratio or charge state. Here we propose a method, named pParse, to export the most probable monoisotopic peaks for precursors, including co-eluted precursors. We use the relationship between the position of the highest peak and the mass of the first peak to detect candidate clusters. Then, we extract three features to sort the candidate clusters: (i) the sum of the intensity, (ii) the similarity of the experimental and the theoretical isotopic distribution, and (iii) the similarity of elution profiles. We showed that the recall of pParse, MaxQuant, and BioWorks was 98-98.8%, 0.5-17%, and 1.8-36.5% at the same precision, respectively. About 50% of tandem mass spectra are triggered by multiple precursors which are difficult to identify. Then we design a new scoring function to identify the co-eluted precursors. About 26% of all identified peptides were exclusively from co-eluted peptides. Therefore, accurately determining monoisotopic peaks, including co-eluted precursors, can greatly increase peptide identification rate.

[Iron and ferritin changes in multiple organs failure after trauma].

OBJECTIVE: To investigate the changes of iron content in serum and liver, ferritin content in serum, percentage of myeloperoxidase (MPO) positive granulocyte in rabbits after different serious trauma and to explore the relationship between these changes and multiple organ failure (MOF). METHODS: Rabbit trauma models were established. Iron content in serum and liver, ferritin content in serum and the percentage of MPO positive granulocyte were measured at different time after trauma. RESULTS: After trauma, iron content in serum decreased sharply in early period (12-36h) and increased gradually to normal level in mild traumatic group after 60 h. Iron content in serum remained lower level in severe traumatic and death group 60 h after trauma. Iron content in liver obviously increased in death group. The changes of ferritin content in serum in mild traumatic were not obvious. Ferritin contents in serum in severe injury group and death group were slightly higher in early period and decreased in later period. The percentage of MPO positive granulocyte increased in early period after trauma. The percentage began to decrease 6 d after trauma and returned to normal level in mild traumatic group. The percentage obviously was significantly lower than normal levels in severe traumatic group and death group 6 d after trauma. Some rabbits died 60 h-6 d after severe trauma, and the pathological changes in the other organs were consistent with MOF. CONCLUSION: Trauma can cause the serum iron, ferritin levels and percentage of MPO positive granulocyte changes. Severe trauma can cause uncompensated changes of these indicators, which could be the main mechanisms of MOF and death.

Effects of trace element supplementation on the inflammatory response in a rabbit model of major trauma.

Patients with a severe trauma exhibit a strong oxidative stress, an intense inflammatory response, and long-lasting hypermetabolism, all of which are proportional to the severity of injury. In this study, we investigated the impact of trace element (TE) supplementation on the inflammatory response in an animal model of major trauma. New Zealand White rabbits were randomly assigned as a control group (n=5) and an experimental group (n=70) that, after receiving a major trauma, was subdivided into Trauma-Control (n=35) and Trauma-TE (n=35) groups. Systemic inflammatory response syndrome (SIRS) was observed in 40 out of 70 rabbits with a trauma, with a higher incidence in the Trauma-Control group (88.6%; 31/35) than the Trauma-TE group (28.6%; 10/35) (p<0.01). The mortality rate was significantly different between the Trauma-Control and the Trauma-TE groups; (34% vs. 8%; p<0.01). There were significant post-trauma alterations in the levels of (1) serum and spleen zinc (Zn), copper (Cu), selenium (Se), and manganese (Mn), (2) serum AST and ALT, (3) serum interleukin-6/10, and (4) nuclear factor kappa binding (NF-kappaB) activity and the expression. TE supplementation: (1) improved blood urea nitrogen (BUN), and creatinine (Cr) levels, (2) stabilized IL-6/10 production, (3) decreased NF-kappaB p(65) production. Appropriate TE supplementation can improve the TE status, mitigate SIRS, and reduce the mortality due to multiple organ dysfunction syndromes (MODS)/multiple organ failure (MOF) after major trauma.

A strategy for precise and large scale identification of core fucosylated glycoproteins.

Core fucosylation (CF) patterns of some glycoproteins are more sensitive and specific than evaluation of their total respective protein levels for diagnosis of many diseases, such as cancers. Global profiling and quantitative characterization of CF glycoproteins may reveal potent biomarkers for clinical applications. However, current techniques are unable to reveal CF glycoproteins precisely on a large scale. Here we developed a robust strategy that integrates molecular weight cutoff, neutral loss-dependent MS(3), database-independent candidate spectrum filtering, and optimization to effectively identify CF glycoproteins. The rationale for spectrum treatment was innovatively based on computation of the mass distribution in spectra of CF glycopeptides. The efficacy of this strategy was demonstrated by implementation for plasma from healthy subjects and subjects with hepatocellular carcinoma. Over 100 CF glycoproteins and CF sites were identified, and over 10,000 mass spectra of CF glycopeptide were found. The scale of identification results indicates great progress for finding biomarkers with a particular and attractive prospect, and the candidate spectra will be a useful resource for the improvement of database searching methods for glycopeptides.

pFind 2.0: a software package for peptide and protein identification via tandem mass spectrometry.

This paper describes the pFind 2.0 software package for peptide and protein identification via tandem mass spectrometry. Firstly, the most important feature of pFind 2.0 is that it offers a modularized and customized platform for third parties to test and compare their algorithms. The developers can create their own modules following the open application programming interface (API) standards and then add it into workflows in place of the default modules. In addition, to accommodate different requirements, the package provides four automated workflows adopting different algorithm modules, executing processes and result reports. Based on this design, pFind 2.0 provides an automated target-decoy database search strategy: The user can just specify a certain false positive rate (FPR) and start searching. Then the system will return the protein identification results automatically filtered by such an estimated FPR. Secondly, pFind 2.0 is also of high accuracy and high speed. Many pragmatic preprocessing, peptide-scoring, validation, and protein inference algorithms have been incorporated. To speed up the searching process, a toolbox for indexing protein databases is developed for high-throughput applications and all modules are implemented under a new architecture designed for large-scale parallel and distributed searching. An experiment on a public dataset shows that pFind 2.0 can identify more peptides than SEQUEST and Mascot at the 1% FPR. It is also demonstrated that this version of pFind 2.0 has better usability and higher speed than its previous versions. The software and more detailed supplementary information can both be accessed at http://pfind.ict.ac.cn/.

[Therapeutic options and prognosis of synchronous multiple primary colorectal carcinomas].

OBJECTIVE: To investigate the therapeutic principles and prognosis of synchronous primary colorectal carcinomas (SCC). METHODS: The data of 66 SCC patients surgically treated from 1984 to 2003 were retrospectively reviewed. RESULTS: The synchronous primary colorectal carcinomas were diagnosed and resected simultaneously in 65 patients except one that was misdiagnosed. Thirty patients underwent combined resection, 35 patients segmental resection. Sixty-two patients received radical resection, while three patients had palliative resection due to hepatic metastasis. The overall postoperative 3-, 5-, 10-year survival rates were 70.3%, 60.0%, 40.6%, respectively. In the patients who had simultaneous radical resection, the 3-, 5-, 10-year survival rates were 76.0%, 65.9%, 46.4% respectively. CONCLUSION: The extent of resection should be individually determined by the lesion location, extent and distance between the lesions, as well as the patient's general condition. More extensive bowel resection, such as total or subtotal colectomy are suggested for those patients with hereditary nonpolyposis colorectal carcinoma syndrome in order to reduce or avoid the risk of metachronous colorectal carcinoma. The postoperative survival in patients with synchronous primary colorectal carcinoma is similar to those with solitary lesion.