Screening of male breast cancer and of breast-ovarian cancer families for BRCA2 mutations using large bifluorescent amplicons

41 breast cancer or breast-ovarian cancer families, including 12 families with at least one affected first-degree male relative, were screened for mutations in the BRCA2 gene. Mutations had not been found in the BRCA1 gene of these families. Chemical cleavage of Mismatch was used to identify nucleotide changes within large PCR products (average size 1.2 kb) that carried strand-specific fluorescent end-labels. 15 amplicons were sufficient to scan 18 exons, including the large exon 11. The remaining 9 small exons were examined by Denaturing Gradient Gel Electrophoresis. The high sensitivity of this approach was documented by the detection, in these 41 patients, of all 9 exonic single nucleotide polymorphisms reported with heterozygosity >0.1. Truncating BRCA2 mutations were found in 7 of the 41 families. 3 of them were in the group of 12 families comprising cases of male breast cancer. Since the methods used here have no bias for particular types of mutations, these data confirm the high proportion of frameshifts among mutations in BRCA2. However, relevant single nucleotide substitutions were also found: one resulting in a stop codon and another one, present in a male patient, was the previously reported change Asp2723His, that affects a highly conserved region of the BRCA2 protein. This study indicates a BRCA2 contribution of 10% (95% CI 2.5–17.5) to our original cohort of 59 breast-ovarian cancer families, whereas the contribution of BRCA1 had been estimated at 46% (95% CI 33–59). © 2001 Cancer Research Campaign http://www.bjcancer.co

Lipid Biomarker and Isotopic Study of Community Distribution and Biomarker Preservation in a Laminated Microbial Mat from Shark Bay, Western Australia

Modern microbial mats from Shark Bay present some structural similarities with ancient stromatolites; thus, the functionality of microbial communities and processes of diagenetic preservation of modern mats may provide an insight into ancient microbial assemblages and preservation. In this study, the vertical distribution of microbial communities was investigated in a well-laminated smooth mat from Shark Bay. Biolipid and compound-specific isotopic analyses were performed to investigate the distribution of microbial communities in four distinct layers of the mat. Biomarkers indicative of cyanobacteria were more abundant in the uppermost oxic layer. Diatom markers (e.g. C25 HBI alkene, C20:4ω6 and C20:5ω3 polar lipid fatty acids (PLFAs)) were also detected in high abundance in the uppermost layer, but also in the deepest layer under conditions of permanent darkness and anoxia, where they probably used NO3 − for respiration. CycC19:0, an abundant PLFA of purple sulfur bacteria (PSB), was detected in all layers and presented the most 13C-depleted values of all PLFAs, consistent with photoautotrophic PSB. Sulfur-bound aliphatic and aromatic biomarkers were detected in all layers, highlighting the occurrence of early sulfurisation which may be an important mechanism in the sedimentary preservation of functional biolipids in living and, thus, also ancient mats

Tumour invasiveness, the local and systemic environment and the basis of staging systems in colorectal cancer

background: The present study aimed to examine the relationship between tumour invasiveness (T stage), the local and systemic environment and cancer-specific survival (CSS) of patients with primary operable colorectal cancer. methods: The tumour microenvironment was examined using measures of the inflammatory infiltrate (Klintrup-Makinen (KM) grade and Immunoscore), tumour stroma percentage (TSP) and tumour budding. The systemic inflammatory environment was examined using modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR). A 5-year CSS was examined. results: A total of 331 patients were included. Increasing T stage was associated with colonic primary, N stage, poor differentiation, margin involvement and venous invasion (P<0.05). T stage was significantly associated with KM grade (P=0.001), Immunoscore (P=0.016), TSP (P=0.006), tumour budding (P<0.001), and elevated mGPS and NLR (both P<0.05). In patients with T3 cancer, N stage stratified survival from 88 to 64%, whereas Immunoscore and budding stratified survival from 100 to 70% and from 91 to 56%, respectively. The Glasgow Microenvironment Score, a score based on KM grade and TSP, stratified survival from 93 to 58%. conclusions: Although associated with increasing T stage, local and systemic tumour environment characteristics, and in particular Immunoscore, budding, TSP and mGPS, are stage-independent determinants of survival and may be utilised in the staging of patients with primary operable colorectal cancer

Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

Platinum complexes of the type [Pt(PL)(AL)]2+ where PL is a derivative of 1,10-phenanthroline and AL is cis-1,4-diaminocyclohexane (1,4-dach), have been synthesised and characterised by ultraviolet spectroscopy, elemental microanalysis, nuclear magnetic resonance and X-ray crystallography. The calf-thymus DNA binding affinity of these complexes was determined by isothermal titration calorimetry, revealing higher DNA affinity than their 1S,2S-diaminocyclohexane analogues. In vitro cytotoxicity was assessed in eleven human cell lines, revealing unexpectedly low activity for the 1,4-dach complexes

Matrix Models and D-branes in Twistor String Theory

We construct two matrix models from twistor string theory: one by dimensional reduction onto a rational curve and another one by introducing noncommutative coordinates on the fibres of the supertwistor space P^(3|4)->CP^1. We comment on the interpretation of our matrix models in terms of topological D-branes and relate them to a recently proposed string field theory. By extending one of the models, we can carry over all the ingredients of the super ADHM construction to a D-brane configuration in the supertwistor space P^(3|4). Eventually, we present the analogue picture for the (super) Nahm construction.Comment: 1+37 pages, reference added, JHEP style, published versio