Effective resolution of racemic pirlindole at the preparative scale

Pirlindole, a racemic antidepressant drug, was recently resolved using the derivatization method coupled with preparative HPLC. In order to improve this technique, the use of amino acid derivatives as chiral derivatizing agents (CDA) was investigated. Among different residues, the (L)-phenylalanine methyl ester was found to be very effective to separate pirlindole enantiomers using a medium pressure liquid chromatographic (MPLC) method. This procedure is better adapted to preparative application than HPLC. Thus, several grams of the pirlindole antipodes were isolated and characterized. These two enantiomers permitted the study of the stereochemical influence at the pharmacological level. Chirality 11:261–266, 1999. © 1999 Wiley-Liss, Inc.     

Antibody responses to NY-ESO-1 in primary breast cancer identify a subtype target for immunotherapy

The highly immunogenic human tumor antigen NY-ESO-1 (ESO) is a target of choice for anti-cancer immune therapy. In this study, we assessed spontaneous antibody (Ab) responses to ESO in a large cohort of patients with primary breast cancer (BC) and addressed the correlation between the presence of anti-ESO Ab, the expression of ESO in the tumors and their characteristics. We found detectable Ab responses to ESO in 1% of the patients. Tumors from patients with circulating Ab to ESO exhibited common characteristics, being mainly hormone receptor (HR)⁻ invasive ductal carcinomas of high grade, including both HER2⁻ and HER2⁺ tumors. In line with these results, we detected ESO expression in 20% of primary HR⁻ BC, including both ESO Ab⁺ and Ab⁻ patients, but not in HR⁺ BC. Interestingly, whereas expression levels in ESO⁺ BC were not significantly different between ESO Ab⁺ and Ab⁻ patients, the former had, in average, significantly higher numbers of tumor-infiltrated lymph nodes, indicating that lymph node invasion may be required for the development of spontaneous anti-tumor immune responses. Thus, the presence of ESO Ab identifies a tumor subtype of HR⁻ (HER2⁻ or HER2⁺) primary BC with frequent ESO expression and, together with the assessment of antigen expression in the tumor, may be instrumental for the selection of patients for whom ESO-based immunotherapy may complement standard therapy.     

The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats

The study of the proteins that bind to telomeric DNA in mammals has provided a deep understanding of the mechanisms involved in chromosome-end protection. However, very little is known on the binding of these proteins to nontelomeric DNA sequences. The TTAGGG DNA repeat proteins 1 and 2 (TRF1 and TRF2) bind to mammalian telomeres as part of the shelterin complex and are essential for maintaining chromosome end stability. In this study, we combined chromatin immunoprecipitation with high-throughput sequencing to map at high sensitivity and resolution the human chromosomal sites to which TRF1 and TRF2 bind. While most of the identified sequences correspond to telomeric regions, we showed that these two proteins also bind to extratelomeric sites. The vast majority of these extratelomeric sites contains interstitial telomeric sequences (or ITSs). However, we also identified non-ITS sites, which correspond to centromeric and pericentromeric satellite DNA. Interestingly, the TRF-binding sites are often located in the proximity of genes or within introns. We propose that TRF1 and TRF2 couple the functional state of telomeres to the long-range organization of chromosomes and gene regulation networks by binding to extratelomeric sequences.     

A two-phase heuristic for the energy-efficient scheduling of independent tasks on computational grids

The sensitivity analysis of a Cellular Genetic Algorithm (CGA) with local search is used to design a new and faster heuristic for the problem of mapping independent tasks to a distributed system (such as a computer cluster or grid) in order to minimize makespan (the time when the last task finishes). The proposed heuristic improves the previously known Min-Min heuristic. Moreover, the heuristic finds mappings of similar quality to the original CGA but in a significantly reduced runtime (1,000 faster). The proposed heuristic is evaluated across twelve different classes of scheduling instances. In addition, a proof of the energy-efficiency of the algorithm is provided. This convergence study suggests how additional energy reduction can be achieved by inserting low power computing nodes to the distributed computer system. Simulation results show that this approach reduces both energy consumption and makespan.     

DENS: data center energy-efficient network-aware scheduling

In modern data centers, energy consumption accounts for a considerably large slice of operational expenses. The existing work in data center energy optimization is focusing only on job distribution between computing servers based on workload or thermal profiles. This paper underlines the role of communication fabric in data center energy consumption and presents a scheduling approach that combines energy efficiency and network awareness, named DENS. The DENS methodology balances the energy consumption of a data center, individual job performance, and traffic demands. The proposed approach optimizes the tradeoff between job consolidation (to minimize the amount of computing servers) and distribution of traffic patterns (to avoid hotspots in the data center network).     

Candidate Luminal B Breast Cancer Genes Identified by Genome,Gene Expression and DNA Methylation Profiling

Breast cancers (BCs) of the luminal B subtype are estrogen receptor-positive (ER+), highly proliferative, resistant to standard therapies and have a poor prognosis. To better understand this subtype we compared DNA copy number aberrations (CNAs), DNA promoter methylation, gene expression profiles, and somatic mutations in nine selected genes, in 32 luminal B tumors with those observed in 156 BCs of the other molecular subtypes. Frequent CNAs included 8p11-p12 and 11q13.1-q13.2 amplifications, 7q11.22-q34, 8q21.12-q24.23, 12p12.3-p13.1, 12q13.11-q24.11, 14q21.1-q23.1, 17q11.1-q25.1, 20q11.23-q13.33 gains and 6q14.1-q24.2, 9p21.3-p24,3, 9q21.2, 18p11.31-p11.32 losses. A total of 237 and 101 luminal B-specific candidate oncogenes and tumor suppressor genes (TSGs) presented a deregulated expression in relation with their CNAs, including 11 genes previously reported associated with endocrine resistance. Interestingly, 88% of the potential TSGs are located within chromosome arm 6q, and seven candidate oncogenes are potential therapeutic targets. A total of 100 candidate oncogenes were validated in a public series of 5,765 BCs and the overexpression of 67 of these was associated with poor survival in luminal tumors. Twenty-four genes presented a deregulated expression in relation with a high DNA methylation level. FOXO3, PIK3CA and TP53 were the most frequent mutated genes among the nine tested. In a meta-analysis of next-generation sequencing data in 875 BCs, KCNB2 mutations were associated with luminal B cases while candidate TSGs MDN1 (6q15) and UTRN (6q24), were mutated in this subtype. In conclusion, we have reported luminal B candidate genes that may play a role in the development and/or hormone resistance of this aggressive subtype.     

Hair to document exposure to glibenclamide

Among the drugs that are used to incapacitate victims such as kids or elderly for sedation or for criminal gain such as sexual offences or robberies, glibenclamide, an antidiabetic was never mentioned. To document the interest of hair testing in such forensic situations, we have developed an original method to test for glibenclamide. A 30-year-old man was admitted to the Emergency Unit for coma and seizures after a party with some members of his family. Blood glucose was 0.40 g/l. A hair specimen was collected several weeks after the event and divided into two segments of 2 cm. Twenty milligrams of each segment cut into small pieces were incubated overnight in a phosphate buffer (pH 5.5), in presence of gliclazide used as internal standard (IS). A liquid/liquid extraction was realized with a mixture of diethyl ether/methylene chloride, and hair extract was separated on a XTerra MS C18 column using a gradient of acetonitrile and formate buffer. Detection of glibenclamide was achieved using two transitions: m/z 493.9 to 168.9 and 493.9 to 368.8. Linearity was observed from 5 to 1000 pg/mg (r2 = 0.956) with a limit of quantification at 5 pg/mg and a clean-up recovery of about 61%. Within-batch precision and bias were 9.0 and 9.5%, respectively. Ion suppression tested on drug-free hair was about 50%. Glibenclamide tested positive in the two consecutive segments (root to 2 cm: 23 pg/mg and 2-4 cm: 31 pg/mg). These findings were in accordance with a repetitive exposure to the drug. The concentrations were compared with those obtained after a single and a daily dose administration. In the hair of a subject receiving a single 5mg dose and collected 4 weeks later, glibenclamide was detected in the proximal segment at 5 pg/mg. After a 20 mg/day dose, the hair concentration of a subject under glibenclamide therapy was 650 pg/mg.