Miracle-dz/UniFAR-FTUs huggingface dataset:
Design and Synthesis of a Focused Library of Novel Aryl‐ and Heteroaryl‐Ketopiperazides

1‐Phenyl‐4‐piperazinyl‐carbonyl‐substituted nitrogen‐containing heterocycles were discovered at Zentaris as a new class of potent, synthetic, small molecule tubulin inhibitors with strong antiproliferative activity. The lead structure of this class, D‐24203, proved to be a potent inhibitor of in vivo tumor growth in different xenograft models including mammary and renal cancers. As part of our efforts in the lead optimization process to expand structural diversity as well as to optimize bioavailability parameters such as solubility and metabolic stability for these compounds, we produced and evaluated a focused library containing 320 compounds. Five new heterocyclic compound classes with comparable activity properties in the cytotoxicity and tubulin polymerization assay could be identi fied. In silico calculated bioavailability parameters for selected library members provides new compound classes with improved solubility properties.
Inherent high peritoneal transport and ultrafiltration deficiency: their mid-term clinical relevance.

BACKGROUND High peritoneal transport has been associated with poorer outcome in peritoneal dialysis (PD) patients, but not necessarily because of PD-dependent conditions. Our primary objective was to analyse the influences of baseline peritoneal small solute transport and ultrafiltration (UF) capacity on patient and technique survival, after adjusting for comorbid conditions. A secondary objective was to determine whether high transport was associated with basal comorbidity. METHODS In this prospective observational patient/technique survival study, we followed 410 patients who started PD. At the baseline, we collected data to define comorbidities, tally the Charlson index, determine the baseline mass transfer area coefficients (MTAC) of urea and creatinine, net UF, plasma albumin and residual renal function (RRF). No data other than the information on patient and technique survival were recorded after baseline. RESULTS The mean follow-up was 33 +/- 28 months. Dropouts during the study were due to renal transplantation in 140 cases, death in 142 cases and transfer to haemodialysis (HD) in 77 cases. Patients with inherent UF deficiency, high transport rate or both were not significantly different in the survival analysis from the rest. In the Cox hazards analysis, only age, Charlson index and a lower RRF were the significant mortality risk factors. None of the baseline parameters studied was a predictor of technique failure. High transporter patients had lower plasma albumin and UF capacity, comorbidity and more frequent liver diseases than the rest. Moderate to severe liver disease (n = 14) was significantly associated with the inherent high transport status, but was never accompanied by UF failure (UFF). UFF patients showed higher RRF, creatinine-MTAC and age. CONCLUSIONS Neither the high transport nor the inherent UFF status has any influence on patient and technique survival. The inherent high small solute transport status is associated with hypoalbuminaemia and a greater comorbidity index. The Charlson index, age and lower RRF are the only independent predictors of mortality. Technique dropout is not predicted by any of the variables studied at the baseline.
Cefotaxime prophylaxis in major non-contaminated head and neck surgery: one-day vs. seven-day therapy

Abstract Patients who undergo major surgery of head and neck benefit from perioperative antibiotic prophylaxis. This study was developed to determine if seven days of antibiotic administration would be more effective than one day. A prospective randomized double blind study was designed. Patients were randomly assigned to receive cefotaxime sodium for either 24 hours or seven days. In each case, the drug was administered intramuscularly, beginning one to two hours pre-operatively and continued for the prescribed period. Sixty patients were included in the trial. Of 30 patients assigned to one day of perioperative prophylaxis, wound infection developed in four (13 per cent). Of 30 patients assigned to seven days of perioperative antibiotic prophylaxis, wound infection developed in three (10 per cent) (P>0.05). These data suggest that no beneficial effect from administration of antibiotics for longer than 24 hours post-operatively can be achieved in patients who undergo major head and neck surgery.
Mutation specificity of 8-methoxypsoralen plus two doses of UVA irradiation in the hprt gene in diploid human fibroblasts.

To investigate which specific kinds of base changes are induced by psoralen adducts in the genomic DNA of diploid human fibroblasts, cells were exposed to 8-methoxypsoralen (8-MOP) at 2-12 microM followed by one dose of UVA (365 nm) irradiation (PUVA-I treatment) or two doses of UVA (PUVA-II treatment). While PUVA-I treatment produced little effect on the induction of cytotoxicity, PUVA-II treatment significantly reduced the fibroblasts' colony-forming ability and resulted in about 10-fold increases in mutation frequency at the D0 dose. Mutations in the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene of 36 independent PUVA-II mutants were characterized by direct sequencing of cDNA amplified by the polymerase chain reaction (PCR). Seventeen mutants contained single base substitutions and the other 19 mutants either lacked one or more exons, or had deleted or gained nucleotides in the exon boundaries in their cDNA. The intron--exon boundaries of 10 of these 19 putative splicing mutants were further characterized by direct sequencing of the PCR-amplified hprt gene. The results showed that nine contained single base substitutions at the consensus splicing donor and acceptor sites. One splicing mutant possessed two base substitutions located at exon 8, whereas its splicing sites were intact. Most of the base substitutions occurred at T-A base pairs (24/29). The majority of T.A changes occurred at thymine of 5'TA and 5'ATA on the non-transcribed strand. Four of the five G.C base substitutions were located at guanines of 5'TG sites adjacent 3' to AT or TA sequences. In addition, the occurrence of a specific type of mutation was highly correlated to the 5' flanking bases of TA sites. The mutagenesis of 13 of the 16 mutational events at 5'TA sites on the non-transcribed strand can be explained by the preferential incisions of the photoadducts on the transcribed strand followed by misalignment--realignment during translesion repair synthesis of the bulky lesions on the non-transcribed strand.
Polygeneration Energy Container: Designing and Testing Energy Services for Remote Developing Communities

Nearly one and a half billion people in the world do not have access to electricity, and even when energy resources are available, millions of people are unable to pay for them. As so, the access to modern affordable and renewable-based energy services in developing countries is essential to achieve a sustainable development by reducing poverty and improving the living conditions (health, security, etc.). In this paper, we analyze how rural electrification efforts can benefit from the implementation of microgrid systems. Following a systematic methodology, we estimate a demand that can evolve through time and design a system that copes with the demand increase. Then, we test the operation of such a facility using a pilot installation, the polygeneration energy container (PEC), an experimental setup that mimics the deployment of a hybrid microgrid system. The development of the experiment has allowed us to test design issues and solve operation and maintenance challenges associated with autonomous electricity production systems. The results demonstrated that it is possible to design systems that are robust and flexible to operate under different conditions.
Prognosis value of residual disease monitoring by polymerase chain reaction in patients with CBF beta/MYH11-positive acute myeloblastic leukemia.

To the Editor: Pericentric inversion of chromosome 16, translocation (16; 16), and del(16q), resulting in a chimeric fusion of the CBFβ and MYH11 genes, are typically seen in the M4Eo French-American-British (FAB) subset of acute myelogenous leukemias (AML). Karyotypic detection of these
ClgR regulation of chaperone and protease systems is essential for Mycobacterium tuberculosis parasitism of the macrophage.

Chaperone and protease systems play essential roles in cellular homeostasis and have vital functions in controlling the abundance of specific cellular proteins involved in processes such as transcription, replication, metabolism and virulence. Bacteria have evolved accurate regulatory systems to control the expression and function of chaperones and potentially destructive proteases. Here, we have used a combination of transcriptomics, proteomics and targeted mutagenesis to reveal that the clp gene regulator (ClgR) of Mycobacterium tuberculosis activates the transcription of at least ten genes, including four that encode protease systems (ClpP1/C, ClpP2/C, PtrB and HtrA-like protease Rv1043c) and three that encode chaperones (Acr2, ClpB and the chaperonin Rv3269). Thus, M. tuberculosis ClgR controls a larger network of protein homeostatic and regulatory systems than ClgR in any other bacterium studied to date. We demonstrate that ClgR-regulated transcriptional activation of these systems is essential for M. tuberculosis to replicate in macrophages. Furthermore, we observe that this defect is manifest early in infection, as M. tuberculosis lacking ClgR is deficient in the ability to control phagosome pH 1 h post-phagocytosis.
EGFR and KRAS mutation status of lung adenocarcinomas in African Americans.

11065 Background: The 2004 discovery of the tyrosine kinase inhibitor-sensitizing mutations in the epidermal growth factor receptor (EGFR) represents a major advance in the study and management of non-small cell lung cancer. Conversely, KRAS mutations in these cancers confer resistance to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. EGFR mutations occur almost exclusively in adenocarcinoma, and are more common in never smokers, women, and people born in East Asian (compared to Whites). No comprehensive studies exist of EGFR and KRAS mutations in lung cancers from African-American patients. METHODS We collected formalin-fixed paraffin-embedded material from 121 resected lung adenocarcinomas from African-American patients for DNA extraction. EGFR exon 19 deletions and exon 21 L858R point mutations were detected by sensitive mutation-specific PCR-based methods. KRAS codon 12 and 13 mutation testing was performed by mass-spectrometry (Sequenom)-based genotyping and direct sequencing. These data were compared to Memorial Sloan-Kettering data for EGFR and KRAS mutations in all resected adenocarcinomas in white patients. RESULTS EGFR mutations were detected in 23 of 121 cases (19%), while KRAS mutations were found in 21 (17%). Exon 19 deletions accounted for 18 of 23 of the EGFR mutations compared to 5 EGFR L858R mutations. KRAS mutations were primarily the transversion type mutations (17 of 21). When compared to data from Memorial Sloan-Kettering for White patients (81/273, 30%), the 17% rate of KRAS mutations in lung adenocarcinomas from African-Americans was significantly lower (p=0.01). EGFR mutation status was similar between African-Americans and Whites (19% vs 18%, p=0.9) and the proportion of exon 19 deletions and L858R mutations was comparable as well. CONCLUSIONS This is the first large series reporting results of mutation testing in lung adenocarcinoma specimens from African-Americans. African-American patients are less likely than Whites to harbor KRAS mutations in their lung adenocarcinomas. There was no significant difference in the prevalence of EGFR mutations. Since biological characteristics underlie clinical factors, these differences may help explain differences in outcomes comparing African-Americans to other groups. No significant financial relationships to disclose.
Analysis of the factors affecting auxological response to GnRH agonist treatment and final height outcome in girls with idiopathic central precocious puberty.

The aim of this retrospective study was to analyze the factors which affected the auxological response to GnRH agonist treatment and the final height (FH) outcome in 71 girls with idiopathic and truly precocious (onset before 8 years) central puberty (CTPP) who had been treated with the same therapy protocol (Decapeptyl Depot, 60 microg/kg i.m. every 28 days) for at least 2 years (since 7.0+/-1. 3 (S.D.) years of age) and followed until puberty was completed and FH was reached. During the entire treatment period we observed: (a) a decrease of height standard deviation scores (SDS) (from 1.5+/-1.7 to 0.9+/-1.3 SDS, P<0.01); (b) a striking deceleration of bone age (BA), revealed by the subnormal DeltaBA:Deltachronological age (CA) ratio (0.2+/-0.1); (c) an increase of predicted adult height (from 155.6+/-7.0 to 160.7+/-6.7 cm, P<0.0005). Treatment interruption was followed by an important catch-down growth, with an FH (158.4+/-5.8 cm) lower (P<0.025) than that predicted at the end of therapy. However, FH fell within the population norm and the target range in respectively 87.3 and 90% of the patients. The tallest FH was recorded in the patients who started therapy at less than 6 years of age and in those who discontinued treatment at a BA of 12.0--12.5 years. At stepwise regression analysis, FH in the whole study population was positively affected by the following independent factors: (a) height at the end of therapy (F=45.45, P<0.0001); (b) pretreatment height (F=13.91, P<0.0005); (c) treatment duration (F=8. 51, P<0.005); (d) target height (TH) (F=7.70, P<0.01). We conclude that: (i) most girls with idiopathic CTPP treated by GnRH agonists may achieve an adult height within the population norm and/or their target range; (ii) the height gain from therapy onset until FH attainment, however, is generally rather limited (on average 2.9 cm) and only few patients are able to reach their target percentile; (iii) the most favorable height prognosis with respect to TH is generally observed in the subjects with the tallest height at the end of treatment and the lowest BA2:CA2 ratio, due to the important deterioration of height prognosis which frequently follows therapy interruption; (iv) FH is also significantly conditioned by both TH and treatment duration; (v) in order to strengthen the weak therapeutic effect of GnRH agonists in CTPP this treatment should be started as early as possible and discontinued at a BA of 12.0--12.5 years.
Evaluation of glutathione S-transferase P1 polymorphisms (Ile105Val and Ala114Val) in patients with small cell lung cancer.

AIMS Glutathione S-transferase P1 (GSTP1) plays an important role in cellular protection against oxidative stress and toxic chemicals. Polymorphisms within GSTP1 are associated with alterations in enzyme activity, which may lead to development of lung disease and cancer. In this study, we aimed to investigate the GSTP1 Ile105Val and Ala114Val polymorphisms in patients with small cell lung cancer (SCLC). PATIENTS/METHODS GSTP1 Ile105Val polymorphism in exon 5 and GSTP1 Ala114Val polymorphism in exon 6 were determined by using polymerase chain reaction-restriction fragment length polymorphism techniques in 89 patients with SCLC and 108 control patients with chronic obstructive pulmonary disease (COPD). Genotype frequencies and cigarette smoking intensities were compared among SCLC and COPD patients. RESULTS There were significantly less SCLC patients with variant exon 6 genotypes than COPD patients (7.9% vs. 20.4%, p=0.007), while the number of patients with variant exon 5 genotypes were comparable among groups. SCLC and COPD patients with variant exon 6 genotype showed trends toward exhibiting reduced cigarette consumption. CONCLUSIONS The variant GSTP1 exon 6 genotype might be conferring protection against SCLC development. Whether this effect is associated with exposure to cigarette smoking needs to be clarified.
Cytokines Induce Nitric Oxide-mediated mtDNA Damage and Apoptosis in Oligodendrocytes

Nitric oxide (NO) that is produced by inducible NO synthase (iNOS) in glial cells is thought to contribute significantly to the pathogenesis of multiple sclerosis. Oligodendrocytes can be stimulated to express iNOS by inflammatory cytokines, which are known to accumulate in the multiple sclerotic brain. The potentially pathological levels of NO produced under these circumstances can target a wide spectrum of intracellular components. We hypothesized that one of the critical targets for damage that leads to disease is mtDNA. In this study, we found that cytokines, in particular a combination of tumor necrosis factor-α (50 ng/ml) and IFNγ (25 ng/ml), cause elevated NO production in primary cultures of rat oligodendrocytes. Western blot analysis revealed a strong enhancement of iNOS expression 48 h after cytokine treatment. Within the same time period, NO-mediated mtDNA damage was shown by Southern blot analysis and by ligation-mediated PCR. Targeting the DNA repair enzyme human 8-oxoguanine DNA glycosylase (hOGG1) to the mitochondria of oligodendrocytes had a protective effect against this cytokine-mediated mtDNA damage. Moreover, it was shown that mitochondrial transport sequence hOGG1-transfected oligodendrocytes had fewer apoptotic cells compared with cells containing vector only following treatment with the cytokines. Subsequent experiments revealed that targeting hOGG1 to mitochondria reduces the activation of caspase-9, showing that this recombinant protein works to reduce apoptosis that is occurring through a mitochondria-based pathway.
Computer-Taught Coping Techniques for Venepuncture: Preliminary Findings from Usability Testing with Children, Parents and Staff

Teaching cognitive and behavioural coping techniques can reduce children’s pain and distress during medical procedures. However, these simple techniques are often not taught to children due to lack of staff time, training and teaching aids. We developed a computer-based self-administered programme (CTCT) to teach coping skills to school-aged children in the waiting room prior to venepuncture. All children had topical local anaesthetic and parents were present. Children reported only mild pain anddistress from venepuncture and seven children used techniques learned from the CTCT programme. Previous pain coping influenced behavioural distress during venepuncture. Ten children reported that they would use CTCT again. Nine parents stated they would recommend their child use CTCT in future. All staff responded favourably to the use of CTCT for children prior to venepuncture. Our preliminary findings demonstrate that the coping techniques can be taught using a computer game format and that children, parents and staff found the method acceptable.
Divergent Reactions to Globalization: Labor Unions and the NAFTA and the EU Enlargement Process

The 1990s witnessed the launching of two ambitious trade regionalization plans, the NAFTA and EU enlargement to Central and Eastern Europe. In contrast to previous projects for the creation or expansion of regional trade blocs, these two projects concerned states at dramatically different levels of economic development: The NAFTA involved the very wealthy economies of Canada and the USA and the significantly poorer economy of Mexico, whereas EU enlargement involved the very wealthy economy of the 15 member-state European Union and the significantly poorer economies of former Communist states in Central and Eastern Europe. Ultimately, the NAFTA and EU enlargement are responses to the challenges of globalization. Paradoxically, however, they have been met with radically different societal reactions in the wealthy partners that participated in the launching of these processes. This paper focuses on the reaction by labor unions on both sides of the Atlantic. I conclude that while labor relations and welfare institutions constrained the trade policy choices made by labor unions in the United States and Europe, they do not tell the whole story. It would seem that United States labor unions were more sensitive to the potential risks for workers associated to the liberalization of trade than were their European counterparts.
Ordered single chain tree a new coding scheme for standard cell placement

VLSI standard cell placement is a NP hard problem, which divides into global placement and detail placement phases. In this paper, we proposed a novel coding scheme named ordered single chain tree (OSCT) for detail placement in standard cell placement. Its solution space is n! 2n-1 and code length is lgn+(n-1) (where n is the number of cells), which are smaller and shorter than normalized polish expression[3] for standard cell placement. Because of its string structure, OSCT coding scheme can be employed combining with any artificial intelligent algorithms such as simulated annealing (SA) and genetic algorithm (GA) to search for optimal solution in detail placement stage conveniently. This characteristic will enhance the management scale in detail placement, release the workload and uncertainty in global placement, and thus improve whole quality of standard cell placement. Experiments on modified MCNC benchmarks show the effectiveness and efficiency of OSCT coding scheme.
Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease.

BACKGROUND The Food and Drug Administration (FDA) has recommended that cereal-grain products be fortified with folic acid to prevent congenital neural-tube defects. Since folic acid supplementation reduces levels of plasma homocyst(e)ine, or plasma total homocysteine, which are frequently elevated in arterial occlusive disease, we hypothesized that folic acid fortification might reduce plasma homocyst(e)ine levels. METHODS To test this hypothesis, we assessed the effects of breakfast cereals fortified with three levels of folic acid, and also containing the recommended dietary allowances of vitamins B6 and B12, in a randomized, double-blind, placebo-controlled, crossover trial in 75 men and women with coronary artery disease. RESULTS Plasma folic acid increased and plasma homocyst(e)ine decreased proportionately with the folic acid content of the breakfast cereal. Cereal providing 127 microg of folic acid daily, approximating the increased daily intake that may result from the FDA's enrichment policy, increased plasma folic acid by 31 percent (P=0.045) but decreased plasma homocyst(e)ine by only 3.7 percent (P= 0.24). However, cereals providing 499 and 665 microg of folic acid daily increased plasma folic acid by 64.8 percent (P<0.001) and 105.7 percent (P=0.001), respectively, and decreased plasma homocyst(e)ine by 11.0 percent (P<0.001) and 14.0 percent (P=0.001), respectively. CONCLUSIONS Cereal fortified with folic acid has the potential to increase plasma folic acid levels and reduce plasma homocyst(e)ine levels. Further clinical trials are required to determine whether folic acid fortification may prevent vascular disease. Until then, our results suggest that folic acid fortification at levels higher than that recommended by the FDA may be warranted.
Refinements in telemetry procedures: Seventh report of BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement, Part A

Preface 262 1 Aims of this report 263 2 Telemetry and data logging 263 3 How to use this report 264 4 Harms and bene ts associated with telemetry 264 4.1 Potential harms associated with telemetry 265 4.2 Opportunities for re nement using telemetry 266 4.2. 1 Re ning procedures using telemetry 266 4.2. 2 Using telemetry to re ne housing and care 267 4.2. 3 The potential for reduction 267 4.2. 4 Data quality 267 5 Legal issues 268 6 Experimental design 268 6.1 Data and sampling 268 6.2 Physical arrangement of hardware 269 7 Selecting or designing a device 270 7.1 Mass of the device 270 WORKING PARTY REPORT