The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer

Previous studies have shown that BRCA1-related breast cancers are often high-grade tumors that do not express estrogen receptors, HER2, p27(Kip1), or cyclin D1, but do express p53 and cyclin E. In addition, the expression of cytokeratin 5/6 (CK5/6), indicating a basal epithelial phenotype, is frequent in BRCA1-related breast cancer. Here, in a series of 247 breast cancers, we demonstrate that CK5/6 expression was associated with nearly all of the features of BRCA1-related breast cancer and was also associated with a poor prognosis. In a parsimonious multivariable proportional hazards model, protein levels of cyclin E, p27(Kip1), p53, and the presence of glomeruloid microvascular proliferation all independently predicted outcome after breast cancer. In this model, only cyclin E and p27(Kip1) levels were independent predictors in lymph node-negative cancers, whereas glomeruloid microvascular proliferation and tumor size independently predicted outcome in node-positive disease. The molecular determinants of the basal epithelial phenotype encapsulate many of the key features of breast cancers occurring in germ-line BRCA1 mutation carriers and have independent prognostic value. Basal breast cancer deserves recognition as an important subtype of breast cancer.     

A basal epithelial phenotype is more frequent in interval breast cancers compared with screen detected tumors.

Interval breast cancer reduce the effectiveness of mammography screening programs. We studied 95 interval cancers, diagnosed during 1996 to 2001 as part of the population-based Norwegian Breast Cancer Screening Program. These cases were matched on size (+/-2.0 mm) to 95 screen-detected breast cancers, and the tumors were compared by immunohistochemical methods using tissue microarrays. Patients with interval cancers were more likely to be younger [odds ratio (OR), 4.7; P = 0.0001], to have dense breasts (OR, 3.4; P = 0.004), and to have estrogen receptor-negative tumors (OR, 2.6, P = 0.01), and p53 expression was more frequent (OR, 4.0; P = 0.001). Notably, interval cancers were more likely to have a basal epithelial phenotype, in that expression of cytokeratin 5/6 (OR, 2.3; P = 0.04) and P-cadherin (OR, 2.5; P = 0.04) was more frequent in interval cases than in size-matched, screen-detected tumors. In a logistic regression model, p53 expression, age, and breast density were independent predictors of interval cancers. Our data suggest that breast cancers with a basal epithelial phenotype are more likely than nonbasal breast cancers to present between regular mammograms.     

Psoriasis patients who are homozygous for the HLA-Cw*0602 allele have a 2.5-fold increased risk of developing psoriasis compared with Cw6 heterozygotes

BACKGROUND: Psoriasis is strongly associated with certain human leucocyte-associated antigens, especially HLA-Cw*0602. Patients who are HLA-Cw*0602 positive have been reported to have more active disease and a younger age at disease onset than HLA-Cw6-negative patients. OBJECTIVES: To ascertain whether there are differences in the clinical features and relative risk between HLA-Cw*0602 homozygous and heterozygous psoriasis patients. METHODS: One thousand and six patients with chronic plaque psoriasis were evaluated clinically and HLA-C typed. In addition, 512 unrelated controls were typed for HLA-C. RESULTS: Of the patients 646 (64.2%) were HLA-Cw*0602 positive, and 68 (6.8%) were homozygous for this allele. Heterozygosity was associated with a relative risk of developing psoriasis of 8.9 compared with 23.1 for the Cw6 homozygous patients. The homozygous patients also had an earlier disease onset (mean 15.0 vs. 17.8 years, P = 0.04). However, the Cw6 homozygotes did not differ from the heterozygotes with respect to disease severity, guttate onset, distribution of plaques, nail changes or any other clinical parameter recorded. CONCLUSIONS: Homozygosity for the gene in the major histocompatibility complex region has a major additive impact on the risk of developing psoriasis and predisposes to an earlier disease onset, but does not have any marked influence on the phenotype or the severity of the disease.     

Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin.

Patients with myasthenia gravis (MG) and thymoma have in their sera antibodies which react with non-receptor antigens from striated muscle. The purpose of this investigation was to characterize the antigen(s). Polypeptides in homogenates from rat skeletal muscle were separated by SDS-PAGE and trans-blotted to nitrocellulose. Sera from six patients with MG and thymoma stained a large (molecular weight greater than 500 kD) polypeptide, while no staining was observed with sera from 20 non-thymoma MG patients. Titin is one of the large (greater than 500 kD) polypeptides of striated muscle and the antibody containing MG sera have antibodies that bind to titin in a preparation of myofibrillary proteins from rabbit skeletal muscle. The staining pattern is identical to that obtained with antiserum to titin, showing that the antigen has the same electrophoretic mobility as titin. Antibodies from the sera of the patients with MG and thymoma, affinity-purified on the large polypeptide, reacted with skeletal muscle sections in a cross-striational pattern, near the A/I band junction but within the I band, corresponding to the localization of one of the epitopes of titin. Our findings therefore indicate that the muscle antibodies found in the sera from some MG patients with thymoma are directed against titin.     

A biochemically distinct sub-population of neurons in the human substantia gelatinosa. Study with G-6-PD histochemistry

A method for localization of glucose-6-phosphate dehydrogenase (G-6-PD; D-glucose-6-phosphate: NADP+ oxidoreductase; E.C. 1.1.1.49) activity has been applied to human nervous tissue. Intensely staining cells, not definable by conventional histologic techniques, have been identified in the human spinal cord, with highest numbers present in the substantia gelatinosa of the sacral region. The cells have a neuron-like morphology and express neuronal-specific antigen but are heterogeneous in size and shape. They are not detectable in infant spinal cord, but stain heavily in adults. We propose that these cells are homologous to the G-6-PD-active dorsal medullary cells first noted by Sakharova et al. (1979) and together with the latter group, may comprise a hitherto unrecognized system of neurons in the human central nervous system.     

Long PCR detection of the C4A null allele in B8-C4AQ0-C4B1-DR3

The genes coding for the two components of complement 4 (C4), C4A and C4B, are located within the major histocompatibility complex (MHC) on the short arm of chromosome 6. Several studies have shown that deficiency of C4A is associated with systemic lupus erythematosus (SLE), rheumatoid arthritis and scleroderma. A large deletion covering most of the C4A gene and the 21-hydroxylase-A (21-OHA) pseudogene found on the extended haplotype B8-C4AQ0-C4B1-DR3 is estimated to account for approximately two-thirds of C4A deficiency in Caucasian SLE patients. Detection of this C4A null allele has been technically difficult due to the high degree of homology between C4A and C4B, with protein analysis and restriction fragment length polymorphism (RFLP) analysis using Southern blotting being the only approaches available. In this study, a long PCR strategy was used to rapidly genotype for the C4A deletion through specific primer design. The methodology makes use of the unique sequence of the G11 gene upstream of C4A and the sequence of a 6.4 kb retrotransposon, the human endogenous retrovirus HERV-K(C4), which is present in intron 9 of C4A but absent in the case of the deletion.     

Non-contact specular microscopy of the normal corneal endothelium

The corneal endothelium of 179 healthy persons (327 eyes), 4–89 years of age, was photographed through a non-contact specular microscope. From the histograms of the cell areas of each eye, other parameters were derived and subjected to computerized statistical analysis. In addition, photographs of both eyes of one person were taken on two different days and examined to determine the reproducibility of the method.The known age-dependent increase in the mean cell area as well as the decrease of the cell density with age could be confirmed. Other parameters that increase with age are the variability of the mean cell area and the maximum cell area; the latter correlates so well with age and is so easily measured that this parameter may facilitate further morphometric evaluations. For these age-dependent correlations not only regression lines but also third-rank regression curves, which seem to fit better, were calculated. Finally,age-independent parameters were found that may serve as potential additional criteria for a qualitative evaluation of the individual corneal endothelium.     

Pseudomonas aeruginosa and a Proteomic Approach to Bacterial Pathogenesis

Pseudomonas aeruginosa is a Gram-negative bacterium that is ubiquitous in the environment and can cause a variety of diseases in compromised patients. The genome of P. aeruginosa strain PAO1 has been reported to contain 5570 potential proteins. The value of this genomic database is that new proteins can be recognized to use as diagnostic markers, novel drug targets, and to better understand the physiology of this organism. However, similar to what has been observed in other sequenced bacterial genomes, approximately one third of the potential proteins have no known function. This is somewhat surprising given the long-standing interest in P. aeruginosa as an opportunistic pathogen. Obviously new tools, in addition to sequence similarity analysis, are needed to determine the role of these proteins. Proteomics using two-dimensional gel electrophoresis followed by mass spectrometry to detect and identify P. aeruginosa proteins represents a novel approach to address this gap.