Miracle-dz/UniFAR-FTUs huggingface dataset:
Phase 1B/2 study of the HSP90 inhibitor AUY922 plus trastuzumab in metastatic HER2-positive breast cancer patients who have progressed on trastuzumab-based regimen

This open-label, multicenter, phase 1B/2 trial assessed AUY922 plus trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer previously treated with chemotherapy and anti-HER2 therapy. This study was composed of a dose-escalation part with AUY922 administered weekly at escalating doses with trastuzumab 2 mg/kg/week (phase 1B), followed by a phase 2 part using the same regimen at recommended phase 2 dose (RP2D). The primary objectives were to determine the maximum tolerated dose (MTD) and/or RP2D (phase 1B), and to evaluate preliminary antitumor activity (phase 2) of AUY922 plus trastuzumab at MTD/RP2D. Forty-five patients were treated with AUY922 plus trastuzumab (4 in phase 1B with AUY922 at 55 mg/m2 and 41 in phase 1B/2 with AUY922 at 70 mg/m2 [7 in phase 1B and 34 in phase 2]). One patient in phase 1B (70 mg/m2) experienced a dose-limiting toxicity (grade 3 diarrhea); the RP2D was weekly AUY922 70 mg/m2 plus trastuzumab. Of the 41 patients in the 70 mg/m2 cohort, the overall response rate (complete or partial responses) was 22.0% and 48.8% patients had stable disease. Study treatment-related adverse events occurred in 97.8% of patients; of these, 31.1% were grade 3 or 4. Forty-one patients (91.1%) reported ocular events (82.3% had grade 1 or 2 events). Two patients (4.4%) had ocular events leading to the permanent discontinuation of study treatment. AUY922 at 70 mg/m2 plus trastuzumab standard therapy is well tolerated and active in patients with HER2-positive metastatic breast cancer who progressed on trastuzumab-based therapy.
Temperamental contributions to social behavior: the moderating roles of frontal EEG asymmetry and gender.

OBJECTIVES Infant temperament is thought to provide one of the fundamental bases for social and emotional development. Few studies have examined the direct and indirect influences of early temperament and physiological disposition on later development. METHOD This article presents results of a longitudinal study that took place between the years 1989 and 1996 in which the relations between maternal reports of negative reactivity at 9 months of age and maternal ratings and laboratory observations of social wariness and sociability at 4 years of age (n = 97) were examined. Also examined were the moderating roles of (1) frontal electroencephalogram (EEG) asymmetry as assessed at 9 months of age and (2) the child's gender. RESULTS Negative reactivity predicted social wariness for infants with right frontal EEG asymmetry, but not for those with left frontal EEG asymmetry and for boys but not girls. The only significant predictor of sociability was gender. Specifically, at 4 years of age girls were rated higher on the measure of sociability than were boys. CONCLUSION The findings are discussed in terms of the roles of frontal EEG asymmetry and gender in moderating the impact of temperamental negative reactivity on later social behavior.
Classical cardiovascular risk factors in Trinidadian patients with type 2 diabetes mellitus are not influenced by the level of plasma glycaemia.

The aim of this study is to assess the plasma glycaemia of patients attending the diabetes mellitus outpatients' clinics in Trinidad and to determine how different plasma glycaemia would affect cardiovascular disease (CVD) risk factors. One hundred and ninety-one patients (64 males, 127 females, mean age 56.6 +/- 0.8 yr) with Type 2 diabetes mellitus (mean duration 9.2 +/- 0.6 yr) attending diabetes mellitus clinics from January to April 2000 participated in the study. Anthropometric indices (weight, height, waist and hip circumferences) and blood pressure were measured and overnight fasting blood samples were collected for glycated haemoglobin (HbA1c), glucose, lipids (triglyceride, total cholesterol, LDL-cholesterol, HDL-cholesterol) and creatinine determinations. The patients were categorized into Group 1 ('well controlled'; HbA1c < 7.0%) and Group 2 ('poorly controlled'; HbA1c > 7.0%). Although the majority (85%) of patients were poorly controlled', there were no significant differences in the age, duration of diabetes mellitus, body mass index and waist/hip ratios between the two groups of patients (p > 0.05). Similarly, the blood pressure and lipid (total cholesterol, HDL-cholesterol, LDL-cholesterol) levels did not differ between the two groups (p > 0.05) although triglyceride (1.4 +/- 0.1 vs. 2.2 +/- 0.1 mmol/L) levels were higher in patients in Group 2 compared with Group 1 (p < 0.05). Multiple linear regression analysis indicates that the levels of blood pressure, lipid and anthropometric parameters were not significantly dependent on the plasma glycaemia of the patients (p > 0.05). Analysis of the data has shown that the majority of patients with Type 2 diabetes mellitus attending primary care clinics in Trinidad had poor glycaemic control. The poorly controlled patients had similar levels of CVD risk factors to 'well controlled' patients although the former were potentially at greater risk of progressing to cardiovascular disorder than 'well controlled' patients.
Genome Organization and Pathogenicity of Corynebacterium diphtheriae C7(−) and PW8 Strains

ABSTRACT Corynebacterium diphtheriae is the causative agent of diphtheria. In 2003, the complete genomic nucleotide sequence of an isolate (NCTC13129) from a large outbreak in the former Soviet Union was published, in which the presence of 13 putative pathogenicity islands (PAIs) was demonstrated. In contrast, earlier work on diphtheria mainly employed the C7(−) strain for genetic analysis; therefore, current knowledge of the molecular genetics of the bacterium is limited to that strain. However, genomic information on the NCTC13129 strain has scarcely been compared to strain C7(−). Another important C. diphtheriae strain is Park-Williams no. 8 (PW8), which has been the only major strain used in toxoid vaccine production and for which genomic information also is not available. Here, we show by comparative genomic hybridization that at least 37 regions from the reference genome, including 11 of the 13 PAIs, are considered to be absent in the C7(−) genome. Despite this, the C7(−) strain still retained signs of pathogenicity, showing a degree of adhesion to Detroit 562 cells, as well as the formation of and persistence in abscesses in animal skin comparable to that of the NCTC13129 strain. In contrast, the PW8 strain, suggested to lack 14 genomic regions, including 3 PAIs, exhibited more reduced signs of pathogenicity. These results, together with great diversity in the presence of the 37 genomic regions among various C. diphtheriae strains shown by PCR analyses, suggest great heterogeneity of this pathogen, not only in genome organization, but also in pathogenicity.
Predictors of post-operative atrial fibrillation in patients undergoing isolated coronary artery bypass grafting.

BACKGROUND Post-operative atrial fibrillation (POAF) is the most common cardiac arrhythmia occurring after coronary artery bypass grafting (CABG). Arrhythmia leads to prolonged hospitalisation and may have an impact on both short-term and long-term prognoses. AIM The aim of this paper was to evaluate the incidence of POAF in patients after CABG as well as to identify its predictors. METHODS The study was performed on 791 patients (selected from a group of 1031 patients who underwent CABG in the Clinical Department of Cardiology in the years 2009-2011) who did not suffer from atrial fibrillation (AF) prior to isolated CABG. Data on co-existing diseases, as well as data collected at the time of surgery and in the post-operative period, were evaluated. RESULTS The average age of patients in the examined group was 64.6 ± 9.1 years. Emergency CABG was performed on 38% of patients, whereas 75.1% of patients underwent CABG with the use of extracorporeal circulation. Based on the incidence of POAF, the post-CABG patients were classified into a POAF(+) group that comprised 166 (21%) patients, and a POAF(-) group involving 625 (79%) patients. The first occurrence of arrhythmia during the first three days after surgery was observed in 76.5% of patients. The average age of POAF(+) and POAF(-) patients was 68.7 ± 8.8 years and 63.5 ± 8.9 years, respectively (p < 0.0001). The respective incidence rates of co-existing diseases in patients with POAF and those without POAF were as follows: arterial hypertension, 80.1% vs. 75.8% (p = 0.29); heart failure, 18.7% vs. 21.1% (p = 0.56); type 2 diabetes, 24.1% vs. 26.2% (p = 0.64). Stable angina pectoris was diagnosed in 22.3% of patients with POAF and 15% of patients without POAF (p = 0.034). The following conditions were more frequently observed in patients with POAF compared with those without POAF: low cardiac output syndrome, 28.9% vs. 14.2% (p < 0.0001) and cardiac tamponade, 9% vs. 4.6% (p = 0.044), respectively. Red blood cell transfusions were performed more often in patients with POAF compared to those without POAF (70.5% vs. 55.7%, respectively, p = 0.0008). Multivariate analysis revealed the following potential predictors of POAF: age ≥ 70 years (HR 2.3), preoperative stable angina pectoris (HR 1.7), and post-CABG low cardiac output syndrome (HR 1.8). CONCLUSIONS POAF was diagnosed in 21% of post-CABG patients, and the major predictors were: age ≥ 70 years, preoperative stable angina, as well as low cardiac output syndrome following CABG.
Ion channel sequestration in central nervous system axons

Na+ and K+ channel localization and clustering are essential for proper electrical signal generation and transmission in CNS myelinated nerve fibres. In particular, Na+ channels are clustered at high density at nodes of Ranvier, and Shaker‐type K+ channels are sequestered in juxtaparanodal zones, just beyond the paranodal axoglial junctions. The mechanisms of channel localization at nodes of Ranvier in the CNS during development in both normal and hypomyelinating mutant animals are discussed and reviewed. As myelination proceeds, Na+ channels are initially found in broad zones within gaps between neighbouring oligodendroglial processes, and then are condensed into focal clusters. This process appears to depend on the formation of axoglial junctions. K+ channels are first detected in juxtaparanodal zones, and in mutant mice lacking normal axoglial junctions, these channels fail to cluster. In these mice, despite the presence of numerous oligodendrocytes, Na+ channel clusters are rare, and when present, are highly irregular. A number of molecules have recently been described that are candidates for a role in the neuron‐glial interactions driving ion channel clustering. This paper reviews the cellular and molecular events responsible for formation of the mature node of Ranvier in the CNS.
Preferential development of pre‐B lymphomas with drastically down‐regulated N‐myc in the Eμ‐ret transgenic mice

We established one transgenic mouse line which developed pre‐B leukemic lymphomas by introducing ret cDNA driven by the SV40 promoter and the mouse immunoglobulin (Ig) enhancer. Lymphomas developed not only in the lymph nodes and the spleen but also in the thymus between the ages of 7 and 21 weeks. Analyses of cell surface phenotypes and Ig gene rearrangement revealed that these tumors were surface IgM−B220+ pre‐B lymphomas. The rearrangement pattern of the Ig heavy chain locus indicated that the tumor cells were mono‐ or oligoclonal. Northern blot analysis showed that the ret transgene was expressed at a high level not only in the tumors but also in the prelymphomatous lymphoid tissues. We found that the expression of N‐myc was dramatically down‐regulated in the tumor cells, while the expression of c‐myc was rather stable. Further experiments demonstrated that ret gene product did not directly down‐regulate the expression of N‐myc in transformed pre‐B cell lines by in vitro transfection assay. From these results, we conclude that under the control of Ig enhancer, the ret transgene affected B lymphocytes at the early maturation stage as a prerequisite for transformation, preferentially generating a unique maturation stage of pre‐B lymphomas whose N‐myc expression was developmentally down‐regulated.
Prognostic value of CHA2DS2-VASc score in patients with 'non-valvular atrial fibrillation' and valvular heart disease: the Loire Valley Atrial Fibrillation Project.

AIMS The CHA2DS2VASc score is a clinical risk stratification tool which estimates the risk of stroke and thromboembolism in non-valvular atrial fibrillation (AF). We aimed to establish the value of this score for risk evaluation in patients with non-valvular AF and valvular heart disease. METHODS AND RESULTS Among 8053 patients with non-valvular AF (ESC guidelines definition), patients were categorized into Group 1 (no valve disease, n = 6851; 85%) and Group 2 (valve disease with neither rheumatic mitral stenosis nor valve prothesis, n = 1202; 15%). After follow-up of 868 ± 1043 days, 627 stroke/ thromboembolic (TE) events were recorded. Group 2 was significantly older, had a higher CHA2DS2VASc score and had a higher risk of thromboembolic events [hazard ratio (HR) 1.39; 95% CI 1.14-1.69, P = 0.001] compared with Group 1. Severe valve disease was not associated with worse prognosis for stroke/TE events. In the two groups, stroke/TE risk increased with a higher CHA2DS2VASc score. Factors independently associated with increased risk of stroke/TE events were older age (HR 1.25, 95% CI 1.14-1.36 per 10-year increase, P < 0.0001) and higher CHA2DS2VASc score (HR 1.33, 95% CI 1.23-1.45, P < 0.0001). The predictive value (c-statistic) of the CHA2DS2VASc score was similar in the two groups. CONCLUSION In patients with non-valvular AF, left-sided valvular heart disease (excluding mitral stenosis and protheses) was associated with an increased risk of stroke/TE events. A higher CHA2DS2VASc score in these patients is likely to explain these results.
Ultrastructural Changes in an Obligately Barophilic Marine Bacterium after Decompression

The bacterial isolate MT-41 from 10,476 m, nearly the greatest ocean depth, is obligately barophilic. The purpose of this study was to describe the morphological changes in MT-41 due to nearly isothermal decompression followed by incubation at atmospheric pressure. Two cultures were grown at 103.5 MPa and 2°C and then decompressed to atmospheric pressure (0.101 MPa). One of the cultures was fixed just before decompression. The other culture, kept at 0°C, was sampled immediately and four more times over 168 h. The number of CFU (assayed at 103.5 MPa and 2°C) declined with incubation time at atmospheric pressure. Decompression itself did not lead to immediate morphological changes. The ultrastructure, however, was altered with increasing time at atmospheric pressure. The first aberrations were intracellular vesicles and membrane fragments in the medium. After these changes were plasmolysis, cell lysis, the formation of extracellular vesicles, and the formation of ghost cells. Intact cells in the longest incubation at atmospheric pressure had the normal cytoplasmic granularity suggestive of ribosomes but had few and poorly stained fibrils in the bacterial nucleoids. From the practical standpoint, samples of hadal deep-sea regions need to be fixed either in situ or shortly after arrival at the sea surface even when recovered in insulated sampling gear. This should prevent drastic structural degradation of sampled cells, thus allowing both accurate estimates of deep-sea benthic standing stock and realistic morphological descriptions.
Functionally and Spatially Distinct Modes of munc18-Syntaxin 1 Interaction*

Eukaryotic membrane trafficking is a conserved process under tight temporal and spatial regulation in which the fusion of membranes is driven by the formation of the ternary SNARE complex. Syntaxin 1a, a core component of the exocytic SNARE complex in neurons and neuroendocrine cells, is regulated directly by munc18-1, its cognate Sec1p/munc18 (SM) protein. SM proteins show remarkable structural conservation throughout evolution, indicating a common binding mechanism and function. However, SM proteins possess disparate binding mechanisms and regulatory effects with munc18-1, the major brain isoform, classed as atypical in both its binding specificity and its mode. We now show that munc18-1 interacts with syntaxin 1a through two mechanistically distinct modes of binding, both in vitro and in living cells, in contrast to current models. Furthermore, these functionally divergent interactions occur at distinct cellular locations. These findings provide a molecular explanation for the multiple, spatially distinct roles of munc18-1.
Dietary habits and lung cancer risk among non-smoking women

A case–control study was conducted to investigate the relationship between diet and the risk of lung cancer among women non-smokers and to compare with women smokers in the same population. Data collected by personal interviews from 435 microscopically confirmed cases and 1710 controls were analysed using unconditional logistic regression. In addition to results for all study subjects, associations between diet and lung cancer risk were compared between two highly contrasting groups: smokers (odds ratio (OR) 7.03) and non-smokers (OR 1.00). A protective effect of frequent (daily or several times per week) black tea drinking appeared among non-smoking women (OR 0.65, 95% confidence interval (CI) 0.43–0.99). Among smoking women, protective effects were observed for frequent intake of milk/dairy products (OR 0.56, 95% CI 0.32–0.96), coffee (OR 0.47, 95% CI 0.25–0.88), and wine consumption (daily or weekly OR 0.60, 95% CI 0.37–0.98; monthly OR 0.60, 95% CI 0.39–0.94). Inverse associations with the risk appeared for physical exercise for smokers only, and for the body mass index both among non-smoking and smoking women. Some items of diet may contribute to variation in risk among women in the Czech Republic; their importance seems to vary in relation to their status in smoking, the dominant factor in the aetiology of lung cancer.
HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: A large‐scale study

Twin and family studies suggest there is a significant genetic component to primary biliary cirrhosis (PBC). However, the inability to replicate reported associations has been a recurring problem, with the only consistently reported genetic association that between PBC and HLA‐DRB1*0801. However, recently even this has been questioned, and a number of novel associations have also been reported. We reinvestigated HLA class II DRB1, DQA1, and DQB1 alleles and haplotypes in a total of 492 well‐characterized PBC patients, 412 from the United Kingdom and an additional 80 patients from northern Italy. There was a clear and significant association with HLA‐DRB1*0801 in both groups of patients compared to population‐specific healthy controls (12% versus 4% in the UK patients, P = .00087, OR = 3.05; and 18% versus 6% in the Italian patients, P = .021, OR = 3.15). There were also significant protective associations with DRB1*11 in the Italian patients (28% versus 47%, P = .0071, OR = 0.42), but not in the UK patients (8% versus 8%) and a protective association with DRB1*13 in both series (14% versus 20%, P = .042, OR = 0.65 in the UK patients; and 10% versus 31%, P = .00092, OR = 0.25 in the Italian patients). In conclusion, a complex relationship exists between HLA and PBC, and some genetic associations may be population specific. (HEPATOLOGY 2006;44:667–674.)
Genotypic interaction between DRD4 and DAT1 loci is a high risk factor for attention‐deficit/hyperactivity disorder in Chilean families

Attention‐deficit/hyperactivity disorder, ADHD [MIM 126452], is a common, highly heritable neurobiological disorder of childhood onset, characterized by hyperactivity, impulsiveness, and/or inattentiveness. As part of an ongoing study of ADHD, we carried out a family‐based discordant sib‐pair analysis to detect possible associations between dopamine receptor D4 (DRD4) and dopamine transporter 1 (DAT1) polymorphisms and ADHD in Chilean families. Both loci individually classified as homozygotes or heterozygotes for the DRD4 7‐repeat and DAT1 10‐repeat alleles, did not exhibit genotype frequency differences between affected children and their healthy siblings (Fisher's exact test P > 0.25 in both cases). However, the simultaneous presence of both DRD4 7‐repeat heterozygosity and DAT1 10 allele homozygosity were significantly higher (34.6%) in cases (26), compared with their unaffected siblings (25) (4%; Fisher's exact test P = 0.0096; odds‐ratio, OR = 12.71). Increased density of dopamine transporter in ADHD brains, along with abundance of 7‐repeat D4 receptors in prefrontal cortex, which is impaired in ADHD patients, make the observed gene–gene interaction worthy of further incisive studies. © 2005 Wiley‐Liss, Inc.
Safety, tolerability, and pharmacokinetics of a single dose of pasireotide long-acting release in healthy volunteers: a single-center Phase I study.

OBJECTIVE This study was conducted to evaluate the safety, tolerability, and pharmacokinetics (PKs) of different doses of a long-acting release (LAR) formulation of pasireotide in healthy subjects. DESIGN Single-center, open-label, randomized Phase I study. METHODS Twelve healthy male subjects received a single s.c. dose of pasireotide 300 μg followed by a washout period of 7 days (or at least 5 days), before receiving an i.m. injection of pasireotide -LAR 40 mg (n=5) or 60 mg (n=7). Assessments included adverse events (AEs), PKs, and glucose, insulin, glucagon, and HbA1c levels. RESULTS Pasireotide LAR showed an extended-release profile over 1 month with two concentration peaks observed 1 and around 20 days after injection. The area under curve exposure of pasireotide LAR was dose proportional when the dose levels were compared, and the bioavailability of the LAR relative to the s.c. formulation was complete. Administration of pasireotide LAR resulted in an increase in fasting and postprandial glucose levels; however, an attenuation of the hyperglycemic effect was observed after 15 days. The most frequently reported AEs were mild-to-moderate diarrhea, abdominal pain, and flatulence. Only gastrointestinal AEs and injection site reactions were suspected to be drug related. CONCLUSIONS Pasireotide LAR was generally well tolerated with mostly mild AEs at doses up to 60 mg and showed a dose-proportional, extended-release profile in healthy subjects. Based on the favorable results of this study, further clinical development of pasireotide LAR is under way, which will give insight into the PKs, efficacy, and safety of pasireotide LAR in patient populations.
Sexual identity, partner gender, and sexual health among adolescent girls in the United States.

OBJECTIVES We examined associations between adolescent girls' sexual identity and the gender of their sexual partners, on one hand, and their reports of sexual health behaviors and reproductive health outcomes, on the other. METHODS We analyzed weighted data from pooled Youth Risk Behavior Surveys (2005 and 2007) representative of 13 US jurisdictions, focusing on sexually experienced girls in 8th through 12th grade (weighted n=6879.56). We used logistic regression with hierarchical linear modeling to examine the strength of associations between reports about sexual orientation and sexual and reproductive health. RESULTS Sexual minority girls consistently reported riskier behaviors than did other girls. Lesbian girls' reports of risky sexual behaviors (e.g., sex under the influence of drugs or alcohol) and negative reproductive health outcomes (e.g., pregnancy) were similar to those of bisexual girls. Partner gender and sexual identity were similarly strong predictors of all of the sexual behaviors and reproductive health outcomes we examined. CONCLUSIONS Many sexual minority girls, whether categorized according to sexual identity or partner gender, are vulnerable to sexual and reproductive health risks. Attention to these risks is needed to help sexual minority girls receive necessary services.