Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling

Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.     

Comparative analysis of the genome sequences of Bordetella pertussis,Bordetella parapertussis and Bordetella bronchiseptica

Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica are closely related Gram-negative beta-proteobacteria that colonize the respiratory tracts of mammals. B. pertussis is a strict human pathogen of recent evolutionary origin and is the primary etiologic agent of whooping cough. B. parapertussis can also cause whooping cough, and B. bronchiseptica causes chronic respiratory infections in a wide range of animals. We sequenced the genomes of B. bronchiseptica RB50 (5,338,400 bp; 5,007 predicted genes), B. parapertussis 12822 (4,773,551 bp; 4,404 genes) and B. pertussis Tohama I (4,086,186 bp; 3,816 genes). Our analysis indicates that B. parapertussis and B. pertussis are independent derivatives of B. bronchiseptica-like ancestors. During the evolution of these two host-restricted species there was large-scale gene loss and inactivation; host adaptation seems to be a consequence of loss, not gain, of function, and differences in virulence may be related to loss of regulatory or control functions.     

Gap analysis of the vegetation of the Intermountain Semi-Desert ecoregion

A conservation gap analysis was conducted for the Intermountain Semi-Desert ecoregion to assess the representation of land-cover types within areas managed primarily for biodiversity objectives. Mapped distributions of plant communities were summarized by land-management status categories. The total amount of land permanently protected in the ecoregion is < 4%, and most types that are characteristic of the region have < 10%. Of 48 land-cover types, 20 were found to be particularly vulnerable to potential loss or degradation because of low level of representation in biodiversity management areas and the impact of expected land-use activities. Gap analysis data and findings will be useful in providing a regional perspective in project impact assessment and future conservation planning within this ecoregion.     

Deletion of a DNA sequence at the chromosomal region 3p21 in all major types of lung cancer

In childhood malignancies such as retinoblastoma and Wilms tumour, of which both familial and sporadic forms exist, recessive mutations of presumed differentiation genes have been implicated in tumorigenesis. A proportion of cases appear with microscopically visible chromosome deletions which indicate the regions where the genes concerned are located. Mutation or loss of one allele causes a cancer predisposition. For tumour development functional loss of the remaining normal allele is also required. In cancers with both familial and sporadic forms, molecular-genetic studies have shown that deletion is often one of the mutational events. Although familial and sporadic forms have never been distinguished in lung cancer, deletions of the short arm of chromosome 3 have been described for small cell lung cancer (SCLC), but their general occurrence in SCLC has been disputed. Using a molecular-genetic approach, we here present evidence for a consistent deletion at the chromosomal region 3p21, not only in SCLC, but in all major types of lung cancer.     

Cadmium — A complex environmental problem Part II

Summary In intensively populated countries efficient sewage treatment is essential to protect river quality. An inevitable by-product is sewage sludge which has to be disposed of safely and economically. Utilisation of sludge as a fertilizer of agricultural land is the most economic disposal route for inland sewage-treatment works and also benefits farmers by providing a cheap manure. Much of the cadmium in wastewater is concentrated into sludge which consequently contains higher concentrations of cadmium than soil does. It is impracticable to reduce cadmium concentrations in sludge below certain levels. When sludge is used on farmland rates of application must be controlled so that cadmium concentrations in soil never reach levels that could significantly contaminate food crops. Cadmium is a principal factor limiting the use of sludge on land. Nevertheless, it is a local problem since agricultural land in general receives more cadmium from aerial deposition and phosphatic fertilizers. The significance of accumulations of cadmium in soil depends mainly on its availability for crop uptake. Investigations are described which have attempted to identify and to determine the availability of forms of cadmium in soil. There is considerable research interest in cadmium in soil solution which is likely to be directly available for crop uptake. Another area of interest is the apparent disappearance of cadmium from sludge-treated soil. Soil analysis often cannot fully account for the cadmium added in sludge. Apart from the effect of soil conditions, especially pH value, crop uptake varies according to the particular crop examined. Highest concentrations of cadmium occur in tobacco, lettuce, spinach and other leafy vegetables. Using crop uptake data from field trials it is possible to relate potential human dietary intake of cadmium, on which hazard depends, to soil concentrations of cadmium, which can be controlled by regulating applications of sludge. This provides an objective basis for limits for cadmium concentrations in soils receiving sludge. Transfer of cadmium via farm animals to meat and dairy products for human consumption is thought to be minimal, even allowing for some direct ingestion of sludge-treated soil by the animals. Evidence from these and other investigations suggests that a loading rate limit of 5 kg Cd/ha (equivalent to a soil concentration of about 3.5 mg Cd/kg) affords adequate protection to the foodchain where sludge is used on agricultural land. More research work is needed to provide a basis for predicting the long-term availability of cadmium introduced to the soil in sludge.     

Selective blockade of components of potassium activation in Myxicola axons

The K+ conductance in Myxicola giant axons activates in two phases which are pharmacologically separable. The fast phase of K+ activation is specifically inhibited by 4-aminopyridine and by the substitution of D2O for H2O. We suggest Myxicola giant axons, like the amphibian node of Ranvier, may possess more than one variety of K+ channel.     

Translocation of lipid-linked oligosaccharides across the ER membrane requires Rft1 protein.

N-linked glycosylation of proteins in eukaryotic cells follows a highly conserved pathway. The tetradecasaccharide substrate (Glc3Man9GlcNAc2) is first assembled at the membrane of the endoplasmic reticulum (ER) as a dolichylpyrophosphate (Dol-PP)-linked intermediate, and then transferred to nascent polypeptide chains in the lumen of the ER. The assembly of the oligosaccharide starts on the cytoplasmic side of the ER membrane with the synthesis of a Man5GlcNAc2-PP-Dol intermediate. This lipid-linked intermediate is then translocated across the membrane so that the oligosaccharides face the lumen of the ER, where the biosynthesis of Glc3Man9GlcNAc2-PP-Dol continues to completion. The fully assembled oligosaccharide is transferred to selected asparagine residues of target proteins. The transmembrane movement of lipid-linked Man5GlcNAc2 oligosaccharide is of fundamental importance in this biosynthetic pathway, and similar processes involving phospholipids and glycolipids are essential in all types of cells. The process is predicted to be catalysed by proteins, termed flippases, which to date have remained elusive. Here we provide evidence that yeast RFT1 encodes an evolutionarily conserved protein required for the translocation of Man5GlcNAc2-PP-Dol from the cytoplasmic to the lumenal leaflet of the ER membrane.     

Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites

A 12 amino-acid synthetic peptide (NANP)3 comprising the immunodominant epitope of Plasmodium falciparum circumsporozoite protein was conjugated to tetanus toxoid (TT), adjuvanted with aluminium hydroxide, and administered intramuscularly in three doses at monthly intervals to 35 healthy males as a malaria vaccine. No significant adverse reactions were noted, with mild soreness at the injection site the only common symptom. Seroconversions against NANP occurred in 53% and 71% of recipients of 100 or 160 micrograms, respectively, measured by enzyme-linked immunosorbent assay (ELISA). Most ELISA-positive sera reacted with sporozoites by indirect immunofluorescence (IFA). Three vaccinees with the highest ELISA and IFA titres and four unimmunized controls were challenged with P. falciparum sporozoites introduced via the bites of infective Anopheles mosquitoes. Blood stage parasites were detected in all controls by 10 days (mean 8.5 days, range 7-10). In contrast, the two vaccinees who became infected did not manifest parasitaemia until day 11 and the third vacinee showed neither parasites nor symptoms during the 29 day observation period. This first synthetic peptide parenteral vaccine against a communicable disease tested in man is safe and stimulates biologically active antibodies. These observations encourage the development of improved vaccine formulations which, by enhancing immunogenicity, may lead to practical vaccines to assist in the control of falciparum malaria.     

Type VI collagen in experimental atherosclerosis

Summary Diffuse intercellular immunofluorescence staining of type VI collagen was found in the experimentally thickened vascular wall and in control blood vessel tissues as well, superimposed by more intense staining around basement membranes. While the basement membrane staining disappeared in advanced mural thickenings, the diffusely distributed network of type VI collagen remained.