Miracle-dz/UniFAR-FTUs huggingface dataset:
Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions

Background In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Patients and methods Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected. Results Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty-one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had <10 pg mutated genomes/µl with allelic fractions below 0.25%. Patients treated first line with TKIs based exclusively on EGFR positivity in blood had an ORR of 72% and a median PFS of 11 months. Of 105 patients screened after progression to EGFR-TKIs, sensitizing mutations were found in 56.2% and the p.T790M resistance mutation in 35.2%. Conclusions Large-scale EGFR testing in the blood of unselected advanced NSCLC patients is feasible and can be used to select patients for targeted therapy when testing cannot be done in tissue. The characteristics and clinical outcomes to TKI treatment of the EGFR-mutated patients identified are undistinguishable from those positive in tumor.
CYP2C9 Genotype‐Dependent Warfarin Pharmacokinetics: Impact of CYP2C9 Genotype on R‐ and S‐Warfarin and Their Oxidative Metabolites

Multiple factors can impact warfarin therapy, including genetic variations in the drug‐metabolizing enzyme cytochrome P450 2C9 (CYP2C9). Compared with individuals with the wild‐type allele, CYP2C9*1, carriers of the common *3 variant have significantly impaired CYP2C9 metabolism. Genetic variations in CYP2C9, the primary enzyme governing the metabolic clearance of the more potent S‐enantiomer of the racemic anticoagulant warfarin, may impact warfarin–drug interactions. To establish a baseline for such studies, plasma and urine concentrations of R‐ and S‐warfarin and 10 warfarin metabolites were monitored for up to 360 hours following a 10‐mg warfarin dose in healthy subjects with 4 different CYP2C9 genotypes: CYP2C9*1/*1 (n = 8), CYP2C9*1/*3 (n = 9), CYP2C9*2/*3 (n = 3), and CYP2C9*3/*3 (n = 4). Plasma clearance of S‐warfarin, but not R‐warfarin, decreased multiexponentially and in a CYP2C9 gene‐dependent manner: 56%, 70%, and 75% for CYP2C9*1/*3, CYP2C9*2/*3, and CYP2C9*3/*3 genotypes, respectively, compared with CYP2C9*1/*1, resulting in pronounced differences in the S:R ratio that identified warfarin‐sensitive genotypes. CYP2C9 was the primary P450 enzyme contributing to S‐warfarin metabolism and a minor contributor to R‐warfarin metabolism. In the presence of a defective CYP2C9 allele, switching of warfarin metabolism to other oxidative pathways and P450 enzymes for the metabolic elimination of S‐warfarin was not observed. The 10‐hydroxywarfarin metabolites, whose detailed pharmacokinetics are reported for the first time, exhibited a prolonged half‐life with no evidence of renal excretion and displayed elimination rate‐limited kinetics. Understanding the impact of CYP2C9 genetics on warfarin pharmacokinetics lays the foundation for future genotype‐dependent warfarin–drug interaction studies.
National Patterns of Carotid Revascularization Before and After the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST)

Importance The Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) showed greater safety of carotid artery stenting (CAS) in patients younger than 70 years and carotid endarterectomy (CEA) in those older than 70 years. It is unknown how the result of CREST has influenced carotid revascularization choices in the United States. Objective To evaluate national patterns in CAS performance in patients older than 70 years in the post-CREST (2011-2014) compared with the pre-CREST (2007-2010) era. Design, Setting, and Participants All adults older than 70 years undergoing carotid revascularization in the United States from 2007 to 2014 were retrospectively identified from the 2007-2014 National Inpatient Sample using International Classification of Disease, Ninth Revision procedural codes. From 61 324 882 unweighted hospitalizations contained in the 2007-2014 National Inpatient Sample, 494 733 weighted carotid revascularization admissions in adults older than 70 years were identified using International Classification of Disease, Ninth Revision procedural codes. Main Outcomes and Measures The proportion of CAS performed in all age groups over time was estimated and multivariable-adjusted models were used to compare the odds of receiving CAS in the pre-CREST with those in the post-CREST era in adults older than 70 years. Results A total of 41.8% of all patients were women, and mean (SE) age at presentation was 78.1 (0.03) years. A total of 16.3% of CAS and 10.1% of CEA procedures were performed in patients with symptomatic stenosis. The proportion of patients older than 70 years receiving CAS increased from 11.9% in the pre-CREST to 13.8% in the post-CREST era (P = .005). In multivariable models, the odds of receiving CAS increased by 13% in all patients older than 70 years in the post-CREST compared with the pre-CREST period (odds ratio [OR], 1.13, 95% CI, 1.00-1.28, P = .04), including symptomatic women (OR, 1.31, 1.05-1.65, P = .02). Symptomatic stenosis (OR 1.39; 95% CI, 1.27-1.52; P < .001), congestive heart failure (OR, 1.48; 95% CI, 1.35-1.63; P < .001), and peripheral vascular disease (OR, 1.35; 95% CI, 1.27-1.43; P < .001) were associated with higher odds of CAS; comorbid hypertension (OR, 0.70; 95% CI, 0.66-0.74; P < .001), smoking (OR, 0.84; 95% CI, 0.78-0.91; P < .001), and weekend admission (OR, 0.77; 95% CI, 0.68-0.88; P < .001) were negatively associated with the odds of CAS. Conclusions and Relevance Despite concerns for higher periprocedural complications with CAS in elderly patients, the odds of CAS increased in the post-CREST compared with pre-CREST era in patients older than 70 years, including symptomatic women.
Free radical-mediated cytosine C-5 methylation triggers epigenetic changes during carcinogenesis

Abstract The methylation of the C-5 position of deoxycytidine (dC) in the promoter regions of tumor suppressor genes is often observed in cancer cells. We found that various environmental agents, as well as endogenous compounds such as methionine sulfoxide (MetO), generate methyl radicals and modify dC to form 5-methyl-dC in DNA in vitro. We confirmed that both DNA methylation and cancer incidence in the liver were increased by the administration of MetO to oxidatively stressed mice. In this review, we summarize previous reports on methyl radical generation in vitro and in vivo and DNA modifications by methyl radicals, including our discoveries, as well as our recent experimental evidence suggesting that free radical-mediated dC methylation triggers epigenetic changes.
Fucosylated Antigens in Cancer: An Alliance toward Tumor Progression, Metastasis, and Resistance to Chemotherapy

Aberrant glycosylation of tumor cells is recognized as a universal hallmark of cancer pathogenesis. Overexpression of fucosylated epitopes, such as type I (H1, Lewisa, Lewisb, and sialyl Lewisa) and type II (H2, Lewisx, Lewisy, and sialyl Lewisx) Lewis antigens, frequently occurs on the cancer cell surface and is mainly attributed to upregulated expression of pertinent fucosyltransferases (FUTs). Nevertheless, the impact of fucose-containing moieties on tumor cell biology is not fully elucidated yet. Here, we review the relevance of tumor-overexpressed FUTs and their respective synthesized Lewis determinants in critical aspects associated with cancer progression, such as increased cell survival and proliferation, tissue invasion and metastasis, epithelial to mesenchymal transition, epithelial and immune cell interaction, angiogenesis, multidrug resistance, and cancer stemness. Furthermore, we discuss the potential use of enhanced levels of fucosylation as glycan biomarkers for early prognosis, diagnosis, and disease monitoring in cancer patients.
Partitioning the heritability of coronary artery disease highlights the importance of immune-mediated processes and epigenetic sites associated with transcriptional activity

Aims With the availability of genome-wide genotype data from GWAS studies, it is now possible to compute the genetic relatedness among individuals and estimate its contribution (SNP-based heritability) to phenotypic variance using Mixed-Linear-Models (MLMs). The estimated heritability can be partitioned according to biological features to gain insight into the genetic architecture of a disease. Here, we aimed to examine the genetic structure of coronary artery disease (CAD). Methods and results We investigated the genetic structure of CAD using 3,163,082 autosomal genome-wide SNPs (MAF ≥ 0.01) and MLMs in a sample of genetically 'unrelated' 4535 cases and 2977 controls. We find that genome-wide SNPs explain 22% of liability to CAD (55% of narrow-sense heritability) and sex-differences in CAD is not due to common SNPs on autosomal chromosomes. Heritability was proportionally distributed across the allele frequency spectrum and notably enriched among genic SNPs. We identified a number of modules that are significantly associated with CAD including: Dendritic cells stimulation; Basigin interactions; and a Cancer module. Of note, genes involved in inflammation account for one-fifth of SNP-based heritability. Heritability-enrichment analysis showed significant enrichment in epigenetic sites associated with transcriptionally activity; namely, enhancers, H3K9ac/H3K27ac/H3K4me1/H3K4me3 histone modifications, and Fetal DNase I hypersensitivity sites whereas heritability was highly depleted in transcriptionally repressed regions. Conclusions More individual SNP associations will be detected for CAD as sample size increases. The identified modules provide further biological insight for CAD and highlight the importance of immune-mediated processes in CAD pathogenesis. Finally, we showed that genetic liability to CAD is mainly attributed to epigenetic sites associated with transcriptional activity which encourage the design of custom sequencing/genotyping panels based on transcriptionally active regions.
Design of Scheduling Algorithm based on Earliest Departure Time for QoS Requirements in WiMAX Networks

The IEEE 802.16 is a standard for broadband wireless technologies which provides guaranteed quality of service (QoS) with different characteristics. This standard provides four different scheduling services: Unsolicited Grant Service (UGS), real-time Polling Service (rtPS), non-real-time Polling Service (nrtPS), and Best Effort (BE). To get a guaranteed QoS, an effective scheduling algorithm should be designed. This paper presents the design of a scheduling technique based on the earliest departure time (EDT) of the packets which enters to the base station. This algorithm is analyzed in two different ways. First, it aims to provide differentiated service according to the QoS requirements. Second it is designed to provide service differentiation in downlink traffic delivery even in non ideal channel conditions. The simulation results show that the proposed algorithm provides service differentiation, increased throughput and allocates bandwidth with lesser delay for real time services. KeywordsEDT based QoS aware algorithm, EDT based channel aware algorithm, QoS, service classes.
5-Hydroxyethyl-3-tetradecanoyltetramic acid represents a novel treatment for intravascular catheter infections due to Staphylococcus aureus

Objectives: Biofilm infections of intravascular catheters caused by Staphylococcus aureus may be treated with catheter lock solutions (CLSs). Here we investigated the antibacterial activity, cytotoxicity and CLS potential of 5-hydroxyethyl-3-tetradecanoyltetramic acid (5HE-C14-TMA) compared with the related compounds 3-tetradecanoyltetronic (C14-TOA) and 3-tetradecanoylthiotetronic (C14-TTA), which are variants of quorum sensing signalling molecules produced by Pseudomonas aeruginosa. Methods: Antibacterial activity and mechanism of action of 5HE-C14-TMA, C14-TOA and C14-TTA were determined via MIC, bacterial killing, membrane potential and permeability assays. Susceptibility of S. aureus biofilms formed in the presence of plasma in vitro was investigated, MTT cytotoxicity testing was undertaken and cytokine release in human blood upon exposure to 5HE-C14-TMA and/or S. aureus biofilms was quantified. The effectiveness of 5HE-C14-TMA as CLS therapy in vivo was assessed using a rat intravascular catheter biofilm infection model. Results: MICs of 5HE-C14-TMA, C14-TOA and C14-TTA ranged from 2 to 4 mg/L. 5HE-C14-TMA and C14-TTA were bactericidal; all three compounds perturbed the staphylococcal membrane by increasing membrane permeability, depolarized the transmembrane potential and caused ATP leakage. Cytotoxicity and haemolytic activity were compound and target cell type-dependent. 5HE-C14-TMA reduced S. aureus biofilm viability in a dose-dependent manner in vitro and in vivo and did not trigger release of cytokines in human blood, but inhibited the high levels of IL-8 and TNF-&agr; induced by S. aureus biofilms. Conclusions: 5HE-C14-TMA, C14-TOA and C14-TTA are membrane-active agents. 5HE-C14-TMA was the most potent, eradicating S. aureus biofilms at 512–1024 mg/L both in vitro and in vivo as a CLS.
Tardive Dyskinesia Prevalence in the Period of Second-Generation Antipsychotic Use: A Meta-Analysis.

OBJECTIVE Comparison of tardive dyskinesia (TD) prevalence during contemporaneous treatment with first-generation antipsychotics (FGAs) and/or second-generation antipsychotics (SGAs). DATA SOURCES PubMed/MEDLINE/Google Scholar search (January 1, 2000-September 30, 2015) without language restriction using (tardive dyskinesia OR tardive) AND (antipsychotic*) plus specific names of SGAs. STUDY SELECTION Of 8,895 hits, we screened 203 full-text articles for cross-sectional, rating scale-based TD rates during SGA, FGA, or FGA+SGA treatment. Forty-one studies were used for random effects meta-analysis and meta-regression. DATA EXTRACTION Two authors independently extracted data on overall and antipsychotic class-wise TD rates and on TD moderators. RESULTS The global mean TD prevalence was 25.3% (95% CI = 22.7%-28.1%) across all 41 studies (N = 11,493, mean age = 42.8 years, male = 66.4%, schizophrenia-spectrum disorders = 77.1%). TD prevalence varied greatly: Rates were lower with current SGA treatment (20.7%; 95% CI = 16.6%-25.4%, N = 5,103) vs current FGA treatment (30.0%; 95% CI = 26.4%-33.8%, N = 5,062; Q = 9.17, P = .002). This difference remained significant after controlling for moderators: higher age (Z = 2.85, P = .004; number of studies = 39 ) and region (39 studies; Asia vs Europe, Z = 1.55, P = .12; Asia lower than United States, Z = 2.6, P = .009; Asia lower than other regions, Z = 2.42, P = .015). Additional moderators of TD prevalence included longer illness duration (R² = 0.15; P = .03; 21 studies) and frequency of parkinsonism (R² = 0.23, P = .017; number of studies = 19). Particularly low TD prevalence (7.2%; number of studies = 4) was found in the treatment arms with FGA-naive subjects relative to SGA-treated cohorts with likely prior FGA exposure (23.4%; P < .001; 28 studies). Lower TD prevalence of SGA relative to FGA was also confirmed in the subgroup of studies reporting on ≥ 2 antipsychotic classes/combinations; this was found for both SGAs vs FGAs (risk ratio = 0.80; 95% CI = 0.67-0.95, Z = -2.55, P = .011) and FGA + SGA vs FGAs (risk ratio = 0.80, 95% CI = 0.71-0.90, Z = -3.56, P < .001). Reports on TD severity, provided by 10 studies, were of insufficient quality for meta-analysis. CONCLUSIONS Rating scale-based TD remains highly prevalent, with higher rates during FGA than during SGA treatment. However, TD severity was insufficiently reported to allow for interpretation of the clinical impact of identified TD cases with SGAs and FGAs. Reasons for high geographical variation warrant future research.
Establishment and Verification of a Scoring Model for the Differential Diagnosis of Pancreatic Cancer and Chronic Pancreatitis

Objectives The aims of this study were to establish a scoring model for the differential diagnosis of pancreatic cancer (PC) and chronic pancreatitis (CP) and to evaluate its diagnostic efficacy. Methods The data of 502 patients with PC and 210 patients with CP at the Peking Union Medical College Hospital from January 1999 to December 2013 were retrospectively analyzed. Binary logistic regression was applied to establish the prediction model for the differential diagnosis. The model was verified using the method of leave-one-out cross-validation. Results The scoring system was established with 5 variables including age, carbohydrate antigen 19-9 level, splenic vein invasion, irregular dilatation of the pancreatic duct, and nontruncated pancreatic duct stenosis. The score range was from −2 to 3. The area under the receiver operating characteristic curve of the objects was 0.779 (95% confidence interval, 0.744–0.814) (P < 0.01), indicating that the scoring system is good at differentiation of PC with CP. With a score of 1 as the diagnostic cut-off value, the diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rate were 71.3%, 69.0%, 70.0%, 71.4%, and 70.2%, respectively. Conclusions The scoring model may improve the differential diagnosis of PC and CP and be useful in clinical practice.
BNIP3 expression in bovine follicle and corpus luteum

BNIP3 (BCL2/adenovirus E1B nineteen kilodalton interacting protein-3), a member of the BCL2 family, is activated under hypoxic conditions and induces apoptosis or mitochondrial autophagy for adapting cells to hypoxia. The physiological roles of BNIP3 in the mammalian ovary are still unclear. In order to understand the role of BNIP3 in the bovine ovary, we examined its mRNA and protein expressions of BNIP3 in follicular granulosa cells and corpus luteum (CL). BNIP3 mRNA and protein expressions in granulosa cells from large follicles (>10 mm) at the follicular stage were much higher than those in small follicles (2–8 mm). BNIP3 mRNA and protein expressions in the CL peaked at the early luteal stage. In bovine granulosa cells cultured for 6 hr under hypoxia (3% O2) and normoxia (20% O2), BNIP3 mRNA expression was higher under hypoxia. These results of the present study suggest that BNIP3 has some roles in luteal formation in the bovine ovary, and that the highly expressed BNIP3 in the granulosa cells from large follicles at the follicular stage is related to the roles of BNIP3 in the luteal formation.
Large-scale assessment of aortic stenosis: facing the next cardiac epidemic?

Aims Aortic stenosis (AS) is the most frequent valvular disease in developed countries. As society grows older, the prevalence of AS increases. However, the real burden, current aetiology, severity distribution, and echocardiographic patterns of AS are not fully clear. The aim of the present study is to provide an accurate overall picture of AS, focusing on its epidemiology, aetiology, and echocardiographic features. Methods and results A total of 29 502 consecutive echocardiograpies were prospectively included in this multicentre study. The present sample was composed of patients with advanced age (mean 75.2 years) and similar gender distribution. High proportion (7.2%) showed any grade of AS, with important number of patients (2.8%) presenting severe AS, most of them aged 75 years or more. Coexisting valvular disease appeared in almost half of the sample (49.6%), being the most frequently diagnosed aortic regurgitation (AR) (22%) followed by mitral regurgitation (MR) (15.6%). Degenerative aetiology was found in the vast majority (93.4%) of the studies whereas rheumatic is currently infrequent (3.35%). Low flow-low gradient (LFLG) appeared in 24.6% of patients with severe AS. Atrial fibrillation (23.1% vs. 11.6%; P = 0.002), MR (23.3% vs. 15.1%; P = 0.018), and right ventricle dysfunction (13.3% vs. 5.2%; P = 0.003) appeared frequently in LFLG group. Conclusions Burden of AS is higher than previously assumed. Degenerative aetiology is the main cause of AS. Most of the patients are elder with high prevalence of significant co-existing valvular disease. LFLG severe AS is present in an important proportion of patients, showing high grade of left ventricle remodelling.
Trade-Offs Associated with Photoprotective Green Fluorescent Protein Expression as Potential Drivers of Balancing Selection for Color Polymorphism in Reef Corals

Photodamage of symbiotic algae exposed to thermal stress is involved in mass coral bleaching, a major cause of reef decline. Photoprotection is therefore a vital part of coral stress physiology. Corals produce a variety of green fluorescent protein (GFP)-like proteins from which some representatives screen the symbiotic algae from excess light. Different tissue concentrations of these GFP-like proteins distinguish colour morphs that are characteristic for many coral species. The question arises whether these pigmentation differences may diversify the niches that can be occupied by corals along the steep light gradient that structures coral reef communities. We assessed the implications of GFP-like protein expression in two color morphs of the symbiotic coral Hydnophora grandis, both associated with the same Symbiodinium sp. (subclade C40). The colour morphs of this species (high fluorescent, HF; and low fluorescent, LF), characterized by markedly different contents of a cyan fluorescent protein, were exposed to different quantities of blue light (470nm) that matched the major absorption band of the host pigment (473nm). High intensities of blue light caused less photodamage to the symbiotic algae of the HF morph and resulted in higher growth rates of these corals compared to representatives of the LF morph. In contrast, under low intensities of blue light, the HF morph showed lower growth rates than the LF morph, indicating that trade-offs are associated with high levels of fluorescent protein expression under this condition. Both morphs showed highest growth rates at medium light intensities with no obvious influence of the tissue pigmentation. Reef coral colour polymorphism caused by photoprotective GFP-like proteins may therefore be a product of balancing selection in which high pigment contents may be beneficial at the upper and detrimental at the lower end of the depth distribution range of symbiotic corals. Conversely, colour morphs with GFP-like proteins that function to optimize symbiont photosynthesis in low light environments could gain an advantage from the benefits offered by high pigment levels in deeper waters.