Epileptic encephalopathies are severe epilepsy disorders with strong genetic bases. We performed targeted next‐generation sequencing (NGS) in 70 patients with epileptic encephalopathies. The likely ...pathogenicity of variants in candidate genes was evaluated by American College of Medical Genetics and Genomics (ACMG) scoring taken together with the accepted clinical presentation. Thirty‐three candidate variants were detected after population filtration and computational prediction. According to ACMG, 21 candidate variants, including 18 de novo variants, were assessed to be pathogenic/likely pathogenic with clinical concordance. Twelve variants were initially assessed as uncertain significance by ACMG, among which 3 were considered causative and 3 others were considered possibly causative after analysis of clinical concordance. In total, 24 variants were identified as putatively causative, among which 19 were novel findings. SCN1A mutations were identified in 50% of patients with Dravet syndrome. TSC1/TSC2 mutations were detected in 66.7% of patients with tuberous sclerosis. STXBP1 mutations were the main findings in patients with West syndrome. Mutations in SCN2A, KCNT1, KCNQ2 and CLCN4 were identified in patients with epileptic infantile with migrating focal seizures; among them, KCNQ2 and CLCN4 were first identified as potential causative genes. Only one CHD2 mutation was detected in patients with Lennox‐Gastaut syndrome. This study highlighted the utility of targeted NGS in genetic diagnoses of epileptic encephalopathies and a comprehensive evaluation of the pathogenicity of variants based on ACMG scoring and assessment of clinical concordance. Epileptic encephalopathies differ in genetic causes, and the genotype‐phenotype correlations would provide insights into the underlying pathogenic mechanisms.
We identified 24 causative mutations (19 novel) in a cohort of 70 EE patients and delineated new phenotype associated with CLCN4 and KCNQ2.
Objectives
Nasopharyngeal cancer (NPC) is an endemic disease in Taiwan. Prognostic factors the anatomical TNM stage are important for its prognostic stratification. An elevated ...neutrophil‐to‐lymphocyte ratio (NLR) has been reported to be associated with poor prognosis in various solid tumours. In this study, we analysed the prognostic impact of the NLR in NPC in Taiwan.
Design
Single‐institution retrospective study.
Setting
Medical centre.
Participants
One hundred and eighty patients with NPC treated at the Far Eastern Memorial Hospital, Taiwan, from January 2007 to December 2013.
Main outcome measures
The association between the clinical or haematological presentations and the prognosis.
Results
The majority of the 180 patients included in this study were men (80%) and were <65 years old (91.7%). A neck mass (55.6%) was the most common clinical presentation, followed by nasal (39.4%) and aural (30.6%) symptoms. In addition, the majority (75.4%) of patients had advanced stage (III and IV) disease. Patients with a high NLR (≧3.6) had significantly lower progression‐free survival, overall survival and disease‐specific survival rates. The association between high NLR and poor prognosis was more pronounced in patients with advanced disease than in those with early‐stage NPC. The results of a multivariate analysis revealed that advanced age, clinical symptoms including headache, diplopia and facial numbness, advanced disease stage, and high NLR were independent prognostic factors.
Conclusion
A high NLR is an independent poor prognostic factor of NPC in Taiwan.
In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of ...protection. These immune markers were measured at the time of second vaccination and 4 weeks later, with values reported in standardized World Health Organization international units. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. Vaccine recipients with postvaccination 50% neutralization titers 10, 100, and 1000 had estimated vaccine efficacies of 78% (95% confidence interval, 54 to 89%), 91% (87 to 94%), and 96% (94 to 98%), respectively. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines.
Gastric cancer is one of the most common malignant cancers, with poor prognosis and high mortality rates worldwide. Therefore, development of an effective therapeutic method without side effects is ...an urgent need. It has been reported that cationic antimicrobial peptides can selectively bind to negatively charged prokaryotic and cancer cell membranes and exert cytotoxicity without causing severe drug resistance. In the current study, we prepared a series of peptide fragments derived from bovine lactoferrin and evaluated their anticancer potency toward the gastric cancer cell line AGS. Cell viability assay revealed that a 25-AA peptide fragment, lactoferricin B25 (LFcinB25), exhibited the most potent anticancer capability against AGS cells. Lactoferricin B25 selectively inhibited AGS cell growth in a dose-dependent manner, exhibiting a half-maximal inhibitory concentration (IC50) value of 64μM. Flow cytometry showed a notable increment of the sub-G1 populations of the cell cycle, indicating the induction of apoptosis by LFcinB25. Western blot analysis further revealed that upon LFcinB25 treatment for 2 to 6h, apoptosis-related caspases-3, 7, 8, 9, and poly(ADP-ribose) polymerase (PARP) were cleaved and activated, whereas autophagy-related LC3-II and beclin-1 were concomitantly increased. Thus, both apoptosis and autophagy are involved in the early stage of LFcinB25-induced cell death of AGS cells. However, upon treatment with LFcinB25 for 12 to 24h, LC3-II began to decrease, whereas cleaved beclin-1 increased in a time-dependent manner, suggesting that consecutive activation of caspases cleaved beclin-1 to inhibit autophagy, thus enhancing apoptosis at the final stage. These findings provide support for future application of LFcinB25 as a potential therapeutic agent for gastric cancer.
Summary
Background
Deregulation of mammalian target of rapamycin (mTOR) signalling is common in human hepatocellular carcinoma (HCC).
Aim
To determine the maximum tolerated dose (MTD) of the oral ...mTOR inhibitor everolimus in advanced HCC patients.
Methods
Patients with locally advanced or metastatic HCC (Child‐Pugh class A or B) were enrolled in an open‐label phase 1 study and randomly assigned to daily (2.5–10 mg) or weekly (20–70 mg) everolimus in a standard 3 + 3 dose‐escalation design. MTD was based on the rate of dose‐limiting toxicities (DLTs). Secondary endpoints included safety, pharmacokinetics and tumour response. In a post hoc analysis, serum hepatitis B virus (HBV) DNA levels were quantified.
Results
Thirty‐nine patients were enrolled. DLTs occurred in five of 21 patients in the daily and two of 19 patients in the weekly cohort. Daily and weekly MTDs were 7.5 mg and 70 mg respectively. Grade 3/4 adverse events with a ≥10% incidence were thrombocytopenia, hypophosphataemia and alanine transaminase (ALT) elevation. In four hepatitis B surface antigen (HBsAg)‐seropositive patients, grade 3/4 ALT elevations were accompanied by significant (>1 log) increases in serum HBV levels. The incidence of hepatitis flare (defined as ALT increase >100 IU/mL from baseline) in HBsAg‐seropositive patients with and without detectable serum HBV DNA before treatment was 46.2% and 7.1% respectively (P < 0.01, Fisher exact test). Disease control rates in the daily and weekly cohorts were 71.4% and 44.4% respectively.
Conclusions
The recommended everolimus dosing schedule for future hepatocellular carcinoma studies is 7.5 mg daily. Prophylactic anti‐viral therapy should be mandatory for HBsAg‐seropositive patients (ClinicalTrials.gov NCT00390195).
In biology, polymorphism is a well-known phenomenon by which a discrete biomacromolecule can adopt multiple specific conformations in response to its environment. The controlled incorporation of ...polymorphism into noncovalent aqueous assemblies of synthetic small molecules is an important step toward the development of bioinspired responsive materials. Herein, we report on a family of carboxylic acid functionalized water-soluble benzene-1,3,5-tricarboxamides (BTAs) that self-assemble in water to form one-dimensional fibers, membranes, and hollow nanotubes. Interestingly, one of the BTAs with the optimized position of the carboxylic group in the hydrophobic domain yields nanotubes that undergo reversible temperature-dependent dynamic reorganizations. SAXS and Cryo-TEM data show the formation of elongated, well-ordered nanotubes at elevated temperatures. At these temperatures, increased dynamics, as measured by hydrogen–deuterium exchange, provide enough flexibility to the system to form well-defined nanotube structures with apparently defect-free tube walls. Without this flexibility, the assemblies are frozen into a variety of structures that are very similar at the supramolecular level, but less defined at the mesoscopic level.
Chronic inflammation plays an important role in cancer development and progression. Cyclooxygenases-2 (COX-2) is a key enzyme in generating prostaglandins causing inflammation, is often found to be ...overexpressed in prostate cancer (PCa) and is correlated with PCa cell invasion and metastasis. We aim to investigate the molecular mechanism of how COX-2 promotes PCa cell invasion and metastasis and to evaluate the effect of COX-2 inhibitors in a selected model of PCa progression. Our results showed that the expression of COX-2 and Interleukin 1β (IL-1β) was upregulated in highly invasive PCa cells and was correlated with the activated levels of membrane-anchored serine protease matriptase. The expression levels of COX-2 were increased and were correlated with matriptase levels in PCa specimens. Moreover, results showed that COX-2 overexpression or a COX-2 product Prostaglandin E
(PGE
) caused an increase in matriptase activation and PCa cell invasion, whereas COX-2 silencing antagonized matriptase activation and cell invasion. In addition, the inhibition of COX-2-mediated matriptase activation by Celebrex and sulindac sulfide suppressed the androgen-independent and COX2-overexpressing PCa PC-3 cell invasion, tumor growth and lung metastasis in an orthotopic xenograft model. Our results indicate that COX-2/matriptase signaling contributes to the invasion, tumor growth and metastasis of COX-2-overexpressing and androgen-independent PCa cells.
We report the discovery of tidal structures around the intermediate-aged (∼700-800 Myr), nearby (∼85 pc) star cluster Coma Berenices. The spatial and kinematic grouping of stars is determined with ...the Gaia DR2 parallax and proper motion data, by a clustering analysis tool, StarGO, to map 5D parameters (X, Y, Z, ) onto a 2D neural network. Leading and trailing tails, each with an extension of ∼50 pc are revealed for the first time around this disrupting star cluster. The cluster members, totaling , are clearly mass-segregated, and exhibit a flat mass function with ∼ 0.79 0.16, in the sense of dN/dm ∝ m− , where N is the number of member stars and m is stellar mass, in the mass range of m = 0.25-2.51 M☉. Within the tidal radius of ∼6.9 pc, there are 77 member candidates with an average position, i.e., the cluster center, of R.A. = 186 8110, and decl. = 25 8112, and an average distance of 85.8 pc. Additional 120 member candidates reside in the tidal structures, i.e., outnumbering those in the cluster core. The expansion of escaping members lead to an anisotropy in the velocity field of the tidal tails. Our analysis also serendipitously uncovers an adjacent stellar group, part of which has been cataloged in the literature. We identify 218 member candidates, 10 times more than previously known. This star group is some 65 pc away from, and ∼400 Myr younger than, Coma Ber, but is already at the final stage of disruption.
Colistin and polymyxin B remain part of the last line of antibiotics for multidrug-resistant Gram-negative bacteria, such as carbapenem-resistant
Current joint EUCAST-CLSI recommendations are for ...broth microdilution (BMD) to be performed for MIC testing of colistin. Commercial susceptibility testing methods were evaluated and compared against the reference BMD, using a susceptibility breakpoint of ≤2 mg/liter for both colistin and polymyxin B. Seventy-six
were included, of which 21 were
positive (18
isolates, 2
isolates, and 1
isolate). Rates of essential agreement (EA) of colistin test results between BMD and Vitek 2, Sensititre, and Etest were 93.4%, 89.5%, and 75.0%, respectively. Rates of EA of polymyxin B test results between BMD and Vitek 2, Sensititre, and Etest were 96.1%, 96.1%, and 48.7%, respectively. A positive MIC correlation with a categorical agreement of >90% was achieved for Sensititre (colistin Spearman's ρ = 0.863, and polymyxin B Spearman's ρ = 0.877) and Vitek 2 (polymyxin B only Spearman's ρ = 0.8917). Although a positive MIC correlation (Spearman's ρ = 0.873) with the reference method was achieved for colistin testing with Vitek 2, categorical agreement was <90%, with very major error rates of 36%. Correlation with the Etest MIC was lower, with very major error rates of 12% (colistin) and 26.1% (polymyxin B). MicroScan (colistin) categorical agreement was 88.2%, with a very major error rate of 4%. Colistin MICs for 15 of the 21
-positive isolates were >2 mg/liter, and polymyxin MICs for 17 of them were >2 mg/liter by broth microdilution. The use of a lower breakpoint of ≤1 mg/liter further improves detection of
for all testing methods. However, further data on the correlation between MICs and clinical outcome are required to determine the most suitable breakpoint to guide clinical management.
We study galaxy mergers using a high-resolution cosmological hydro/N- body simulation with star formation and compare the measured merger timescales with theoretical predictions based on the ...Chandrasekhar formula. In contrast to Navarro et al., our numerical results indicate that the commonly used equation for the merger timescale given by Lacey and Cole systematically underestimates the merger timescales for minor mergers and overestimates those for major mergers. This behavior is partly explained by the poor performance of their expression for the Coulomb logarithm, image. The two alternative forms image and image for the Coulomb logarithm can account for the mass dependence of merger timescale successfully, but both of them underestimate the merger timescale by a factor 2. Since image represents the mass dependence slightly better, we adopt this expression for the Coulomb logarithm. Furthermore, we find that the dependence of the merger timescale on the circularity parameter epsilon is much weaker than the widely adopted power law image, whereas image provides a good match to the data. Based on these findings, we present an accurate and convenient fitting formula for the merger timescale of galaxies in cold dark matter models.
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