Gender Equality under the Charter of Fundamental Rights - a new lease for positive action?

This paper, which was published as a chapter of a Festskrift for Professor Ruth Nielsen, analyses Article 23 CFREU, the new provision on gender equality. It argues that Article 23 adds to the notion of gender equality in EU law, and not only allows, but also demands positive action measures if necessary to ensure equality between women and men. The provision also demands that positive action measures are suitable to achieve their aim. This implies that the EU legislator has to adapt positive action measure to the specific needs of the sector. The paper offers a critique of the proposal to introduce women quotas in board rooms, as proposed by the EU Commission in late 2012. It argues that the Commission unimaginatively copied rules developed for the German public service into a different sector, although these rules have not proven particularly efficient even in the public service. Consequently, a proposal that is demanding, but adapted to the sector should be developed.

L’action positive est-elle efficace? Une évaluation empirique du programme pour l’équité dans l’emploi en Irlande du Nord

A description, and analysis, of an empirical investigation of the effectiveness of affirmative action in the Northern Ireland employment

STI-571 (imatinib mesylate) enhances the apoptotic efficacy of pyrrolo-1,5-benzoxazepine-6, a novel microtubule-targeting agent, in both STI-571-sensitive and -resistant Bcr-Abl-positive human chronic myeloid leukemia cells

Interactions between the Bcr-Abl kinase inhibitor STI-571 (imatinib mesylate) and a novel microtubule-targeting agent (MTA), pyrrolo-1,5-benzoxazepine (PBOX)-6, were investigated in STI-571-sensitive and -resistant human chronic myeloid leukemia (CML) cells. Cotreatment of PBOX-6 with STI-571 induced significantly more apoptosis in Bcr-Abl-positive CML cell lines (K562 and LAMA-84) than either drug alone (P < 0.01). Cell cycle analysis of propidium iodide-stained cells showed that STI-571 significantly reduced PBOX-6-induced G2M arrest and polyploid formation with a concomitant increase in apoptosis. Similar results were obtained in K562 CML cells using lead MTAs (paclitaxel and nocodazole) in combination with STI-571. Potentiation of PBOX-6-induced apoptosis by STI-571 was specific to Bcr-Abl-positive leukemia cells with no cytoxic effects observed on normal peripheral blood cells. The combined treatment of STI-571 and PBOX-6 was associated with the down-regulation of Bcr-Abl and repression of proteins involved in Bcr-Abl transformation, namely the antiapoptotic proteins Bcl-x(L) and Mcl-1. Importantly, PBOX-6/STI-571 combinations were also effective in STI-571-resistant cells. Together, these findings highlight the potential clinical benefits in simultaneously targeting the microtubules and the Bcr-Abl oncoprotein in STI-571-sensitive and -resistant CML cells.

FLAG-idarubicin and allogeneic stem cell transplantation for Ph-positive ALL beyond first remission

We describe a single centre experience of eight consecutive patients with relapsed or refractory Ph+ ALL treated with the FLAG/idarubicin regimen followed by BMT or PBSCT. Following FLAG/idarubicin, one achieved a partial response and seven CR. All patients subsequently received allogeneic transplants: one sibling BMT, three matched unrelated (MUD) BMT and four sibling PBSCT. Two patients received second transplants with PBSC from their original BM donors following FLA/Ida with no further conditioning. Three patients are alive in CR 9, 24 and 32 months after transplant. Seven of eight patients had a cytogenetic response following FLAG/Ida induction and one of seven became bcr-abl negative. All eight patients had a complete cytogenetic response following transplant. Four of five assessable patients became p190 bcr-abl negative after transplant; three of these subsequently relapsed. Both patients with the p210 bcr-abl transcript remained bcr-abl positive in CR after transplant. FLAG/Ida was well tolerated and appears to be effective in inducing remission in relapsed Ph+ ALL. The use of FDR-containing chemotherapy without further conditioning prior to PBSCT deserves further study in heavily pre-treated patients and, in patients with relapsed ALL following BMT, may be a safer option than DLI (donor lymphocyte infusion) by avoiding the associated risk of aplasia.

Infection of donor lymphocytes with human T lymphotrophic virus type 1 (HTLV-I) following allogeneic bone marrow transplantation for HTLV-I positive adult T-cell leukaemia

Human T lymphotrophic virus type 1 (HTLV-I) associated leukaemia has a poor prognosis even with chemotherapy. We describe a patient with adult T-cell leukaemia treated with allogeneic bone marrow transplantation from an HTLV-I negative identical sibling donor. During follow-up after bone marrow transplantation, HTLV-I could be repeatedly isolated inspite of anti-viral prophylaxis. The patient died of an acute encephalitis and HTLV-I could be detected in autopsy material from the brain. By a PCR-based technique using short tandem repeats (STRs) it was shown that the patient's haemopoiesis was of donor origin. This shows the infection of donor cells in vivo by an aetiological agent which has been implicated in the leukaemogenic process for adult T-cell leukaemia.

Recurrence of Philadelphia chromosome-positive leukemia in donor cells after bone marrow transplantation for chronic granulocytic leukemia

Allogeneic bone marrow transplantation has been shown to be a very effective therapy for Chronic Granulocytic Leukemia with long term disease free survivals in excess of 60%. Relapse rates remain low at 15% following histocompatible sibling transplants and lower rates following matched unrelated donor grafts. Relapse rates however, are higher if BMT is carried out in transformation or blast crisis. Leukemic relapse in donor cells following transplantation for CGL is a rare event. The occurrence of donor leukemia however, may be under reported as accurate and sensitive investigation of the origin of relapsed leukemia following BMT requires DNA based technologies. A possible mechanism of donor leukemia in CGL is transfection of donor cells with the chimeric gene which is unique to this disease. It is possible that the malignant cells found in transformed or blast crisis of CGL may have a greater potential to transfect donor haematopoietic material. Careful evaluation of the incidence of donor leukemia using molecular biology methods may elucidate the frequency of this event following BMT for CGL.

Split Converter-Fed SRM Drive for Flexible Charging in EV/HEV Applications

Electric vehicles (EVs) and hybrid EVs are the way forward for green transportation and for establishing low-carbon economy. This paper presents a split converter-fed four-phase switched reluctance motor (SRM) drive to realize flexible integrated charging functions (dc and ac sources). The machine is featured with a central-tapped winding node, eight stator slots, and six rotor poles (8/6). In the driving mode, the developed topology has the same characteristics as the traditional asymmetric bridge topology but better fault tolerance. The proposed system supports battery energy balance and on-board dc and ac charging. When connecting with an ac power grid, the proposed topology has a merit of the multilevel converter; the charging current control can be achieved by the improved hysteresis control. The energy flow between the two batteries is balanced by the hysteresis control based on their state-of-charge conditions. Simulation results in MATLAB/Simulink and experiments on a 150-W prototype SRM validate the effectiveness of the proposed technologies, which may provide a solution to EV charging issues associated with significant infrastructure requirements.

Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer

In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer

BACKGROUND: Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination.

PATIENTS AND METHODS: DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate.

RESULTS: There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92).

CONCLUSION: Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

Meta-analysis of Positive and Negative Symptoms Reveals Schizophrenia Modifier Genes

BACKGROUND: Evidence suggests that genetic factors may influence both schizophrenia (Scz) and its clinical presentation. In recent years, genome-wide association studies (GWAS) have demonstrated considerable success in identifying risk loci. Detection of "modifier loci" has the potential to further elucidate underlying disease processes.

METHODS: We performed GWAS of empirically derived positive and negative symptom scales in Irish cases from multiply affected pedigrees and a larger, independent case-control sample, subsequently combining these into a large Irish meta-analysis. In addition to single-SNP associations, we considered gene-based and pathway analyses to better capture convergent genetic effects, and to facilitate biological interpretation of these findings. Replication and testing of aggregate genetic effects was conducted using an independent European-American sample.

RESULTS: Though no single marker met the genome-wide significance threshold, genes and ontologies/pathways were significantly associated with negative and positive symptoms; notably, NKAIN2 and NRG1, respectively. We observed limited overlap in ontologies/pathways associated with different symptom profiles, with immune-related categories over-represented for negative symptoms, and addiction-related categories for positive symptoms. Replication analyses suggested that genes associated with clinical presentation are generalizable to non-Irish samples.

CONCLUSIONS: These findings strongly support the hypothesis that modifier loci contribute to the etiology of distinct Scz symptom profiles. The finding that previously implicated "risk loci" actually influence particular symptom dimensions has the potential to better delineate the roles of these genes in Scz etiology. Furthermore, the over-representation of distinct gene ontologies/pathways across symptom profiles suggests that the clinical heterogeneity of Scz is due in part to complex and diverse genetic factors.

Extreme Loads on an Oscillating Wave Surge Converter

A major difficulty in the design of full scale Wave Energy Converters is the need to design for two conflicting design criteria. In one instance devices must be designed to couple heavily to the incident wave force resulting in the efficient extraction of energy in small sea states, however devices must also be capable of withstanding the harsh conditions encountered during extreme seas. This paper presents an initial investigation of the extreme wave loading of a generic, surface-piercing, pitching flap-type device deployed in near shore wave conditions. Slamming of the flap is selected as the extreme load event for further investigation and the experimental methodologies employed are described. Preliminary results showing both local and global loading under such events are presented for the case of a flap tested in a 3-dimensional environment. Results are presented which show flap slamming effects on the pressures experienced on the front face of the flap.