Update on HER-2 as a target for cancer therapy: The ERBB2 promoter and its exploitation for cancer treatment

Overexpression of the ERBB2 proto-oncogene is associated with amplification of the gene in breast cancer but increased activity of the promoter also plays a significant role. Members of two transcription factor families (AP-2 and Ets) show increased binding to the promoter in over-expressing cells. Consequently, strategies have been devised to target promoter activity, either through the DNA binding sites for these factors, or through another promoter sequence, a polypurine-polypyrimidine repeat structure. The promoter has also been exploited for its tumour-specific activity to direct the accumulation of cytotoxic compounds selectively within cancer cells. Our current understanding of the ERBB2 promoter is reviewed and the status of these therapeutic avenues is discussed

Parasite-Dependent Expansion of TNF Receptor II–Positive Regulatory T Cells with Enhanced Suppressive Activity in Adults with Severe Malaria

Severe Plasmodium falciparum malaria is a major cause of global mortality, yet the immunological factors underlying progression to severe disease remain unclear. CD4+CD25+ regulatory T cells (Treg cells) are associated with impaired T cell control of Plasmodium spp infection. We investigated the relationship between Treg cells, parasite biomass, and P. falciparum malaria disease severity in adults living in a malaria-endemic region of Indonesia. CD4+CD25+Foxp3+CD127lo Treg cells were significantly elevated in patients with uncomplicated (UM; n = 17) and severe malaria (SM; n = 16) relative to exposed asymptomatic controls (AC; n = 10). In patients with SM, Treg cell frequency correlated positively with parasitemia (r = 0.79, p = 0.0003) and total parasite biomass (r = 0.87, p<0.001), both major determinants for the development of severe and fatal malaria, and Treg cells were significantly increased in hyperparasitemia. There was a further significant correlation between Treg cell frequency and plasma concentrations of soluble tumor necrosis factor receptor II (TNFRII) in SM. A subset of TNFRII+ Treg cells with high expression of Foxp3 was increased in severe relative to uncomplicated malaria. In vitro, P. falciparum–infected red blood cells dose dependently induced TNFRII+Foxp3hi Treg cells in PBMC from malaria-unexposed donors which showed greater suppressive activity than TNFRII− Treg cells. The selective enrichment of the Treg cell compartment for a maximally suppressive TNFRII+Foxp3hi Treg subset in severe malaria provides a potential link between immune suppression, increased parasite biomass, and malaria disease severity. The findings caution against the induction of TNFRII+Foxp3hi Treg cells when developing effective malaria vaccines

Beyond equilibrium climate sensitivity

ISSN:1752-0908ISSN:1752-089

Pleural mesothelioma of epithelial type and pulmonary adenocarcinoma: an ultrastructural and cytochemical comparison.

Twelve diffuse pleural mesotheliomas of epithelial type have been compared with 20 intrapulmonary adenocarcinomas. All mesotheliomas were negative for epithelial mucin by diastase periodic acid Schiff staining and for carcinoembryonic antigen by immunoperoxidase staining, whereas 17/20 carcinomas stained for epithelial mucin and 15/20 for carcinoembryonic antigen. Hyaluronidase-sensitive alcian blue positive material was present in 6/10 mesotheliomas and 0/20 carcinomas. Previously described electron microscopic differences were validated, including one which has so far received insufficient emphasis: microvilli making direct contact through basement membrane deficiencies with collagen fibres on the abluminal side of tumour cells were identified in 10/12 mesotheliomas and in 0/20 carcinomas

The potassium iodide patch test in the dermatitis herpetiformis in relation to treatment with a gluten-free diet and dapsone.

The potassium iodide patch test was studied in twenty-six patients with dermatitis herpetiformis. Histological assessment was found more sensitive than clinical. All of five patients with active disease and not on treatment had a positive test, whereas only two of six patients taking a gluten-free diet (GFD) and one of eight taking dapsone were positive. In another two patients taking a GFD, but in whom the diet had not been strict, the test was positive. All three patients in remission and both patients with the linear pattern of IgA (but with active disease) were negative. Immunofluorescence studies showed no difference in the presence, quantity, or distribution of immunoglobulin, complement or fibrinogen between the patch test site and uninvolved skin, or in the uninvolved skin between patients with and without active lesions

Comparison of intra-articular simple compression and extra-articular distal radial fractures

Background: The impact of a single well-reduced or stable intra-articular fracture oriented in the sagittal plane on the outcome of internal fixation of a distal radial fracture is uncertain. We tested the hypothesis that wrist motion and function scores would not differ between patients with an extra-articular fracture and those with a single sagittal intra-articular fracture following open fracture reduction and internal fixation with use of a volar locking plate. Methods: Thirty-seven patients with a single sagittal intra-articular fracture of the distal aspect of the radius and seventyfour age and sex-matched patients with an extra-articular distal radial fracture were retrospectively analyzed with use of data gathered in a cohort study of plate and screw fixation of distal radial fractures. A volar locking plate was used in all patients. The two cohorts were analyzed for differences in motion, grip strength, pain, and Gartland and Werley, DASH (Disabilities of the Arm, Shoulder and Hand), and SF-36 (Short Form-36) scores six, twelve, and twenty-four months after surgery. Differences between the cohorts and differences within each cohort over time were determined with use of regression analysis and the likelihood ratio test. Results: Patients with a single sagittal intra-articular fracture and those an extra-articular fracture did not differ significantly with respect to motion, grip strength, Gartland and Werley score, or DASH score at any time point. However, there was a trend toward less pronation (95% compared with 98% of that in the contralateral arm) and less grip strength (76% compared with 81% of that in the contralateral arm) at six months and toward a smaller flexion-extension arc (118°compared with 128°) at one year after surgery in patients with a single sagittal intra-articular fracture. Conclusions: Open reduction and volar locking plate and screw fixation of extra-articular fractures and of simple intra-articular fractures of the distal aspect of the radius are associated with comparable impairment and disability within two years of surgery. Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2011 by The Journal of Bone and Joint Surgery, Incorporated.link_to_subscribed_fulltex

A common variant of HMGA2 is associated with adult and childhood height in the general population

Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P= 4x10(-8)). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P= 3x10(-11), overall P= 4x10(-16), including the genome-wide association data). We also observed the association in children (P=1x 10(-6), N= 6,827) and a tall/short case-control study (P= 4x10(-6), N=3,207). We estimate that rs1042725 explains similar to 0.3% of population variation in height (similar to 0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitative traits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height