High-resolution array CGH clarifies events occurring on 8p in carcinogenesis

Background  

Rearrangement of the short arm of chromosome 8 (8p) is very common in epithelial cancers such as breast cancer. Usually there is an unbalanced translocation breakpoint in 8p12 (29.7 Mb – 38.5 Mb) with loss of distal 8p, sometimes with proximal amplification of 8p11-12. Rearrangements in 8p11-12 have been investigated using high-resolution array CGH, but the first 30 Mb of 8p are less well characterised, although this region contains several proposed tumour suppressor genes.     

Wild-type p53 is required for apoptosis induced by growth factor deprivation in factor-dependent leukaemic cells.

The p53 gene is a growth control gene, abnormalities of which have been implicated in a variety of cancers. Recently wild-type p53 has been shown to exist in two interchangeable conformational variants, which can be distinguished by specific p53 monoclonal antibodies. One conformation acts as a suppressor (PAb240-/PAb1620+) and one acts as a promoter (PAb240+/PAb1620-) of cell proliferation; the latter conformation is also that of mutant p53. We have previously shown that acute myeloblastic leukaemia (AML) blasts which proliferate autonomously in vitro express only p53 in the promoter conformation. In contrast, expression of PAb1620 was found only in blasts with non-autocrine growth in vitro and was diminished following stimulation by exogenous growth factors when there was a switch to p53 in the promoter (PAb240+) conformation. As AML blasts with non-autocrine growth undergo apoptosis when deprived of exogenous growth factors, we studied whether this was mediated by wild-type p53. Antisense oligonucleotides to p53 were used to suppress p53 protein expression in blasts with non-autocrine growth and also the factor-dependent human erythroleukaemia cell line TF-1. Following growth factor deprivation for 48 h, 20.6-53.6% of control blasts were apoptotic and demonstrated a typical ''ladder'' on DNA electrophoresis characteristic of internucleosomal degradation of DNA. In the presence of p53 antisense, apoptosis was suppressed despite the absence of growth factor, however cell proliferation was not stimulated. We conclude that apoptosis occurring in factor-dependent AML blasts following growth factor deprivation is mediated by wild-type p53 (PAb1620+), and that conformational change of p53 to the PAb240+ conformation occurring either by mutation or by the action of autocrine growth factors would permit leukaemic cell survival by suppressing apoptosis.     

The prevalence of thrombophilia in patients with chronic venous leg ulceration

BACKGROUND: Thrombophilia is increasingly recognized as a risk factor for deep venous thrombosis (DVT), which in turn is a major risk factor for chronic venous ulceration (CVU). However, the relationship between thrombophilia and CVU remains unknown. The aim of this study was to define the prevalence of thrombophilia in patients with CVU and to determine whether this is associated with a history or duplex scan evidence of DVT. METHODS: Eighty-eight patients with CVU were prospectively studied. The patients underwent clinical assessment and duplex ultrasound scanning. Blood was drawn for antithrombin, proteins C and S, activated protein C resistance, factor V Leiden, prothrombin 20210A, lupus anticoagulant, and anticardiolipin antibodies. RESULTS: The study included 35 men with a median age of 61 years (interquartile range, 45 to 72 years) and 53 women with a median age of 76 years (interquartile range, 69 to 82 years). Thirty-six percent of the patients had either a history or duplex scan evidence suggestive of previous DVT. The following abnormalities were detected: four, five, and six cases of antithrombin, protein C, and protein S deficiencies, respectively; 14 cases of activated protein C resistance; 11 cases of factor V Leiden mutation; three cases of prothrombin 20210A mutation; eight cases of lupus anticoagulant; and 12 cases of anticardiolipin antibodies. Thrombophilia was not significantly related to previous DVT, deep reflux, or disease severity. CONCLUSION: Patients with CVU have a 41% prevalence rate of thrombophilia. This rate is two to 30 times higher than the rate of the general population but is similar to that reported for patients with previous DVT. However, in patients with CVU, thrombophilia does not appear to be related to a history of DVT, a pattern of reflux, or severity of disease. Many patients with CVU may have unsuspected postthrombotic disease.     

Reading speed test for potential central vision measurement

This study examines the validity and reliability of a reading speed test as a measure of potential central vision. Reading speed was calculated in words per minute (wpm) from the time taken to read 30 words of 1.20 logMAR size text. Scores were obtained from subjects with cataract (n = 48), macular disease(n = 35), peripheral vision loss(n = 14) and normal eyes (n = 10). Subjects with macular disease (27.0 +/- 13.2 wpm) read much slower than subjects with cataract (91.9 +/- 13.6 wpm). Little difference was found between subjects with cataract, peripheral vision loss (91.5 +/- 14.7 wpm)and normal eyes (103.8 +/- 15.5 wpm). Repeat testing gave values within +/- 16% of reading speed. These results suggest that a reading speed test using large text could be useful as a potential central vision test in cataract patients.     

Identification of major loci controlling clinical manifestations of ankylosing spondylitis

OBJECTIVE: To identify genomic regions linked with determinants of age at symptom onset, disease activity, and functional impairment in ankylosing spondylitis (AS). METHODS: A whole genome linkage scan was performed in 188 affected sibling pair families with 454 affected individuals. Traits assessed were age at symptom onset, disease activity assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and functional impairment assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). Parametric and nonparametric quantitative linkage analysis was performed using parameters defined in a previous segregation study. RESULTS: Heritabilities of the traits studied in this data set were as follows: BASDAI 0.49 (P = 0.0001, 95% confidence interval [95% CI] 0.23-0.75), BASFI 0.76 (P = 10(-7), 95% CI 0.49-1.0), and age at symptom onset 0.33 (P = 0.005, 95% CI 0.04-0.62). No linkage was observed between the major histocompatibility complex (MHC) and any of the traits studied (logarithm of odds [LOD] score <1.0). "Significant" linkage (LOD score 4.0) was observed between a region on chromosome 18p and the BASDAI. Age at symptom onset showed "suggestive" linkage to chromosome 11p (LOD score 3.3). Maximum linkage with the BASFI was seen at chromosome 2q (LOD score 2.9). CONCLUSION: In contrast to the genetic determinants of susceptibility to AS, clinical manifestations of the disease measured by the BASDAI, BASFI, and age at symptom onset are largely determined by a small number of genes not encoded within the MHC.