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.     

Different chromosomal breakpoints impact the level of LMO2 expression in T-ALL

The t(11;14)(p13;q11) is presumed to arise from an erroneous T-cell receptor delta TCRD V(D)J recombination and to result in LMO2 activation. However, the mechanisms underlying this translocation and the resulting LMO2 activation are poorly defined. We performed combined in vivo, ex vivo, and in silico analyses on 9 new t(11;14)(p13;q11)-positive T-cell acute lymphoblastic leukemia (T-ALL) as well as normal thymocytes. Our data support the involvement of 2 distinct t(11;14)(p13;q11) V(D)J-related translocation mechanisms. We provide compelling evidence that removal of a negative regulatory element from the LMO2 locus, rather than juxtaposition to the TCRD enhancer, is the main determinant for LMO2 activation in the majority of t(11;14)(p13;q11) translocations. Furthermore, the position of the LMO2 breakpoints in T-ALL in the light of the occurrence of TCRD-LMO2 translocations in normal thymocytes points to a critical role for the exact breakpoint location in determining LMO2 activation levels and the consequent pressure for T-ALL development.     

Intradermal Vaccinations With RNA Coding for TAA Generate CD8+ and CD4+ Immune Responses and Induce Clinical Benefit in Vaccinated Patients

The aim of this phase I/II nonrandomized trial was to assess feasibility, safety as well as immunological and clinical responses of a mRNA-based vaccination in patients with stage IV renal cell cancer using granulocyte-macrophage colony stimulating factor (GM-CSF) as adjuvant. Intradermal injections of in vitro transcribed naked mRNA, which was generated using plasmids coding for the tumor-associated antigens mucin 1(MUC1), carcinoembryonic (CEA), human epidermal growth factor receptor 2 (Her-2/neu), telomerase, survivin, and melanoma-associated antigen 1 (MAGE-A1) were performed in 30 enrolled patients. In the first 14 patients (cohort A) vaccinations were administered on days 0, 14, 28, and 42 (20 µg/antigen) while in the consecutive 16 patients (cohort B) an intensified protocol consisting of injections at days 0–3, 7–10, 28, and 42 (50 µg/antigen) was used. In both cohorts, after this induction period, vaccinations were repeated monthly until tumor progression analyzed by Response Evaluation Criteria In Solid Tumors criteria (RECIST). Vaccinations were well tolerated with no severe side effects and induced clinical responses [six stable diseases (SD) and one partial response in cohort A and nine SD in cohort B]. In cohort A, 35.7% survived 4 years (median survival 24 months) compared to 31.25% in cohort B (median survival 29 months). Induction of CD4⁺ and CD8⁺ T cell responses was shown for several tumor-associated antigens (TAA) using interferon-γ (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and Cr-release assays.     

Radiotherapy planning: direct tumor location on simulation and port films using CT. Part I. Principles

Although there have been great advances in cancer diagnosis in recent years, it remains difficult to transfer tumor location information from cross-sectional computed tomographic (CT) scans or magnetic resonance images to the simulation and verification films used in planning radiotherapy. A newly developed system uses radioopaque markers attached to the patient as reference points. These markers are identified on both CT scans and simulation films and their locations entered into the treatment planning computer. The tumor and any desired normal structures are then outlined manually on each CT section. Transparent overlays produced by the computer show the position of the reference markers and tumor outlines for any combination of gantry angles and source-film distance. Because the overlays are scaled to the simulation films, the reference points enable precise alignment of overlay and film. The tumor outline thus appears on the simulation or verification films exactly as it is "seen" by the therapy beam, making field verification straightforward and accurate, even on oblique films.     

Dummies and the sudden infant death syndrome

The association between dummy use and sudden infant death syndrome (SIDS) was investigated in 485 deaths due to SIDS in the postneonatal age group and compared with 1800 control infants. Parental interviews were completed in 87% of subjects. The prevalence of dummy use in New Zealand is low and varies within New Zealand. Dummy use in the two week period before death was less in cases of SIDS than in the last two weeks for controls (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.57 to 1.02). Use of a dummy in the last sleep for cases of SIDS or in the nominated sleep for controls was significantly less in cases than controls (OR 0.44, 95% CI 0.26 to 0.73). The OR changed very little after controlling for a wide range of potential confounders. It is concluded that dummy use may protect against SIDS, but this observation needs to be repeated before dummies can be recommended for this purpose. If dummy sucking is protective then it is one of several factors that may explain the higher mortality from SIDS in New Zealand than in other countries, and may also explain in part the regional variation within New Zealand.     

Comparison of Timed Automata with Discrete Event Simulation for Modeling of Biomarker-Based Treatment Decisions: An Illustration for Metastatic Castration-Resistant Prostate Cancer

Background

With the advent of personalized medicine, the field of health economic modeling is being challenged and the use of patient-level dynamic modeling techniques might be required.

Structurally diverse molecular deletions in the beta-globin gene cluster exhibit an identical phenotype on interaction with the beta S- gene

We have characterized a new deletion that increases hemoglobin F synthesis in an American black woman who is doubly heterozygous for this mutation and the beta S-gene. The 5' endpoint is 2.4 +/- 0.1 kilobases (kb) upstream from the delta-globin gene, and the 3' endpoint is 0.2 +/- 0.1 kb downstream from the beta-globin gene; the deletion is 12 kb long. Both members of the Alu moderately repetitive DNA sequence family, normally present upstream from the delta-globin gene, are preserved. The patient is asymptomatic with a mild anemia and 24.8% HbF. The patient's husband and daughter have a similar clinical syndrome, with HbF levels of 22.4% and 25.4%, respectively. Both husband and daughter are doubly heterozygous for the beta S-gene and the Ghana type of hereditary persistence of fetal hemoglobin (HPFH) deletion (HPFH-2). The 5' end of this deletion is in the psi beta-gene, and its total length is more than 70 kb. All three members of the family have normocytic red cells, of which 95% or more are F cells as detected by immunofluorescence. Previous studies have shown that culture of the erythroid progenitors (BFU-E) from both types of these compound heterozygotes in the presence of fetal sheep serum, rich in "switching factor," resulted in complete suppression of HbF synthesis. Although the newly described deletion resembles the Sicilian type of delta beta-thalassemia by its size and preservation of the Alu sequences, the clinical and biological phenotype produced by its interaction with the beta S-gene is very similar to that of the HPFH- type deletion.     

Gender and the sudden infant death syndrome

Abstract A nationwide case-control study compared the prevalence and magnitude of risk factors for sudden infant death syndrome (SIDS) in male and female infants. The risk factors of SIDS and their magnitude for males and females are very similar. After adjustment for potential confounders male infants had a 1.42-fold (95% CI = 1.04, 1.94) increased risk of SIDS compared with females. Risk factors identified in most epidemiological studies are not the reason for the increased SIDS mortality seen in male infants.     

Novel insights into the development of T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) results from malignant transformation of immature cells of the T-cell lineage. T-ALL is a heterogeneous disease both clinically and genetically. It is generally accepted that T-ALL cells are the malignant counterpart of normally developing T cells in the thymus (thymocytes). Recent data using genome-wide gene expression profiling and assessment of the rearrangement status of the T-cell receptor loci confirm this notion. T-ALL cells differ from normal thymocytes in the overexpression of oncogenes that arise either from chromosomal translocations or via other mechanisms. In addition, signaling pathways that control the very first stages of thymocyte development (of note, the Notch and Wnt pathways) are involved in development of T-ALL in mice and humans when constitutively expressed. In particular, the activating mutations in the Notch pathways are believed to occur in a large proportion of human T-ALL. These findings on genetic events open up new therapeutic possibilities.     

Platelet-associated IgG in patients with lymphoma

Levels of platelet-associated IgG (PA-IgG) were studied in 72 patients with Hodgkin's (HD) and non-Hodgkin's lymphoma (NHL). Thirty-nine percent of patients with HD and 20% of patients with NHL had elevated PA-IgG levels. There was a positive correlation between disease activity and the presence of PA-IgG in HD and NHL. In patients with HD, PA-IgG strongly correlated with extent of disease and may serve as a marker of disease activity. PA-IgG may have facilitated platelet destruction in 5 of 11 thrombocytopenic patients with HD and increased PA-IgG and in 2 patients with HD and increased PA-IgG who developed severe thrombocytopenia when treated with chemotherapy.