Design and use of conditional MHC class I ligands

Major histocompatibility complex (MHC) class I molecules associate with a variety of peptide ligands during biosynthesis and present these ligands on the cell surface for recognition by cytotoxic T cells. We have designed conditional MHC ligands that form stable complexes with MHC molecules but degrade on command, by exposure to a defined photostimulus. 'Empty MHC molecules' generated in this manner can be loaded with arrays of peptide ligands to determine MHC binding properties and to monitor antigen-specific T-cell responses in a high-throughput manner. We document the value of this approach by identifying cytotoxic T-cell epitopes within the H5N1 influenza A/Vietnam/1194/04 genom

The role of radiotherapy in the conservative treatment of ductal carcinoma in situ of the breast.

Breast-conserving surgery (BCS) followed by radiotherapy (RT) has become the standard of care for the treatment of early-stage (St. I-II) invasive breast carcinoma. However, controversy exists regarding the value of RT in the conservative treatment of ductal carcinoma in situ (DCIS). In this article we review the role of RT in the management of DCIS. Retrospective and prospective trials and meta-analyses published between 1975 and 2007 in the MEDLINE database, and recent issues of relevant journals/handbooks relating to DCIS, BCS and RT were searched for. In retrospective series (10,194 patients) the 10-year rate of local recurrence (LR) with and without RT was reported in the range of 9-28% and 22-54%, respectively. In four large randomised controlled trials (NSABP-B-17, EORTC-10853, UKCCCR, SweDCIS; 4,568 patients) 50 Gy whole-breast RT significantly decreased the 5-year LR rate from 16-22% (annual LR rate: 2.6-5.0%) to 7-10% (annual LR rate: 1.3-1.9%). In a recent meta-analysis of randomised trials the addition of RT to BCS resulted in a 60% risk reduction of both invasive and in situ recurrences. In a multicentre retrospective study, an additional dose of 10 Gy to the tumour bed yielded a further 55% risk reduction compared to RT without boost. To date, no subgroups have been reliably identified that do not benefit from RT after BCS. In the NSABP-B-24 trial, the addition of tamoxifen (TAM) to RT reduced ipsilateral (11.1% vs. 7.7%) and contralateral (4.9% vs. 2.3%) breast events significantly. In contrast, in the UKCCCR study, TAM produced no significant reduction in all breast events. Based on available evidence obtained from retrospective and prospective trials, all patients with DCIS have potential benefit from RT after BCS. Further prospective studies are warranted to identify subgroups of low-risk patients with DCIS for whom RT can be safely omitted. Until long-term results of ongoing studies on outcomes of patients treated with BCS alone (with or without TAM or aromatase inhibitors) are available, RT should be routinely recommended after BCS for all patients except those with contraindication

Road towards development of new antimalarial: organelle associated metabolic pathways in Plasmodium as drug targets and discovery of lead drug candidates

Malaria remains a global threat with millions of deaths annually. Emergence of parasite strains resistant to widely used antimalarials, including the artemisinin combination therapy (ACT), and the absence of an effective vaccine makes treatment of malaria difficult than ever before. The need of the hour is to re-evaluate the chemotherapeutic approach and to identify new drug targets and develop new pharmacophores against the parasite. An important approach for antimalarial drug discovery is to understand critical metabolic pathways in the parasite which may help us to identify critical targets in the parasites and design specific inhibitors for these targets. Here, we have discussed proteins and pathways in different parasite organelles, i.e. apicoplast, mitochondrial and food vacuole, which have been suggested as potential drug targets; these unique parasite proteins can be targeted to develop new and novel antimalarials. In addition, we have also discussed several antimalarial projects currently under different stages of drug development pipeline. These promising antimalarial compounds have the potential to overcome multidrug resistance. Ongoing global efforts to develop new antimalarials and to identify drug targets suggest a promising future on malaria elimination and eradication