Tumour stem cells--the evidence and the ambiguity

Progressive growth of malignant tumours, metastatic spread and local recurrence after treatment can only be explained by the presence of cells with unlimited proliferative ability. While this is generally accepted, the proportion of such cells and their organization in a hierarchical system of stem cells and non-stem cell progeny is still a matter of controversy. Results of quantitative transplantation and dose requirement of curative radiotherapy have indicated low stem cell fractions in human and early passage rodent tumours, but uncertainty is introduced by uncontrollable experimental or biological factors and the probabilistic nature of stem cell performance itself. Studies using a particular mouse carcinoma (AT17) have given direct insight into the number and clonal expansion of stem cells in situ, strongly supporting the hierarchical concept. The implications are important and concern the relevance of predictive assays, possible mechanisms of accelerated repopulation, or the role of adjuvant treatment strategies.     

Dependencies of the radiation sensitivity of human tooth enamel in EPR dosimetry.

The EPR dose response of tooth enamel was determined for human molars collected in Egypt. The influence of age, gender and residence of the tooth donors as well as tooth position and sample preparation on EPR sensitivity and its variability over the enamel samples was investigated. The EPR sensitivity and its variability were found to depend only on the sample preparation procedure. The variability in EPR sensitivity of enamel from Egyptian teeth was maximally 10% and the mean sensitivity was in good agreement with that of German teeth.     

Identification of novel Angiogenin (ANG) gene missense variants in German patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by the selective death of motor neurons in the motor cortex, brain stem and spinal cord. Recently, missense variants in the angiogenin gene (ANG), an angiogenic factor expressed in ventral horn motor neurons that is up-regulated by hypoxia, have been found in ALS patients of Irish/Scottish, North American, Italian, French and Dutch descent. To investigate the role of ANG in the German population, we screened for mutations by sequencing the entire coding region of the ANG gene in a large sample of 581 German ALS cases and 616 sex- and age-matched healthy controls. We identified two heterozygous missense variants, F(−13)L and K54E, in two German sporadic ALS cases but not in controls. Both missense variants are novel and have not been previously found in ALS cases. Our results suggest that missense variants in the ANG gene play a role in ALS in the German population and provide further evidence to support the hypothesis that angiogenic factors up-regulated by hypoxia are involved in the pathophysiology of ALS. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Meeting report: Vienna 2008 Workshop of the German–Austrian Working Group for Studying Prognostic Factors in Myelodysplastic Syndromes

Criteria, scoring systems, and treatment algorithms for myelodysplastic syndromes (MDS) have been updated repeatedly in recent years. This apparently results from increased awareness and early recognition of the disease, an increasing number of new diagnostic and prognostic markers and tools, and new therapeutic options that may change the course and thus prognosis in MDS. To address these challenges and to create useful new diagnostic and prognostic parameters and scores, the German–Austrian Working Group for Studying Prognostic Factors in MDS was established in 2003 and later was extended to centers in Switzerland (D-A-CH group). In addition, the group cooperates with the European LeukemiaNet, the MDS Foundation, and other national and international working groups in order to improve diagnosis and prognostication. The current article represents a meeting report from the latest workshop organized by the group in Vienna in October 2008.     

GeneChip analyses point to novel pathogenetic mechanisms in mantle cell lymphoma

The translocation t(11;14)(q13;q32) is the genetic hallmark of mantle cell lymphoma (MCL) but is not sufficient for inducing lymphomagenesis. Here we performed genome-wide 100K GeneChip Mapping in 26 t(11;14)-positive MCL and six MCL cell lines. Partial uniparental disomy (pUPD) was shown to be a recurrent chromosomal event not only in MCL cell lines but also in primary MCL. Remarkably, pUPD affected recurrent targets of deletion like 11q, 13q and 17p. Moreover, we identified 12 novel regions of recurrent gain and loss as well as 12 high-level amplifications and eight homozygously deleted regions hitherto undescribed in MCL. Interestingly, GeneChip analyses identified different genes , encoding proteins involved in microtubule dynamics, such as MAP2 , MAP6 and TP53, as targets for chromosomal aberration in MCL. Further investigation, including mutation analyses, fluorescence in situ hybridisation as well as epigenetic and expression studies, revealed additional aberrations frequently affecting these genes. In total, 19 of 20 MCL cases, which were subjected to genetic and epigenetic analyses, and five of six MCL cell lines harboured at least one aberration in MAP2, MAP6 or TP53 . These findings provide evidence that alterations of microtubule dynamics might be one of the critical events in MCL lymphomagenesis contributing to chromosomal instability.     

Longitudinal study on cat allergen exposure and the development of allergy in young children

BACKGROUND: The influence of cat allergen exposure in early childhood on the development of sensitization and allergic diseases is complex. Little is known about the natural course of the sensitization development within individuals. OBJECTIVE: We investigated the association between cat allergen exposure in infancy and cat ownership and cat contact during childhood and the development of cat sensitization and allergic diseases up to age 6 years using a longitudinal analysis approach. METHODS: Overall, 2166 children from an ongoing birth cohort study were included in the analysis. House dust samples were collected 3 months after birth. Cat allergen levels were extracted. Blood samples were collected when the children were 2 and 6 years old. Information on the allergic symptoms of children and doctor-diagnosed allergic disease were collected at each follow-up using questionnaires. RESULTS: Cat allergen exposure in infancy was positively associated with sensitization at age 2 years but not at age 6 years. No associations existed between cat allergen exposure in infancy and allergic symptoms and diseases up to age 6 years. Cumulative allergen exposure from cat ownership and regular cat contact increased the risk of cat sensitization up to age 6 years. CONCLUSION: Cat allergen exposure in infancy increases the risk of sensitization development in early childhood but not in school-age children. Cumulative allergen exposure from cat ownership and regular cat contact during childhood contribute to sensitization development up to school age. CLINICAL IMPLICATIONS: Cat allergen avoidance at home alone might be not effective to prevent the development of allergic sensitization in young children.     

Sodium intake and bronchial hyperresponsiveness in adults

BACKGROUND: Several investigations suggested a relationship between sodium intake and asthma and bronchial hyperresponsiveness (BHR), respectively. However, clinical and epidemiological studies did not show consistent finding. OBJECTIVE: We analysed the association between dietary sodium intake and BHR to methacholine among 613 adults aged 20-65 years as one of the two German centres of the European Community Respiratory Health Survey (ECRHS). METHODS: Dietary sodium intake was estimated from a 3-day weighed record of food intake. We applied multiple logistic regression models contrasting the three higher quartiles of sodium intake versus the lowest to assess the risk of BHR and mild BHR estimated by PD20 and PD10, respectively, controlling for potential confounders and stratified for sex. In addition, we analysed PD20 (dose of methacholine causing a fall of 20% in forced expiratory volume in 1s) as continuous variable expressed as transformed dose-response slope (tDRS) in the linear model. RESULTS: Women were as expected more likely to be bronchial hyperresponsive (PD20: 26.1%; PD10: 52.2%) than men (PD20:15.8%; PD10: 34.8%) and had a lower mean daily sodium intake (2.36 g) compared with men (3.15 g). Logistic regression did not show any significant relationship between sodium intake and BHR in terms of PD20 after adjustment for age group, education, smoking status, body mass index and height in men or women. However, mild BHR assessed as PD10 was statistically significant positively related to the third (OR: 2.35; CI: 1.11-5.00) and highest quartile of sodium intake (OR: 2.28; CI: 1.06-4.88) in women, but not in men for third quartile (OR: 1.29; CI: 0.68-2.44) and for fourth quartile (OR: 1.07; CI: 0.56-2.07), respectively. CONCLUSION: Sodium intake by several food items does not alter BHR assessed as PD20 to methacholine but may increase mild BHR assessed as PD10. We conclude that, in addition, PD10 has to be considered when the effect of sodium intake on BHR is studied.     

Glycoprotein gp110 of Epstein-Barr virus determines viral tropism and efficiency of infection

The Epstein-Barr virus (EBV) genome has been detected in lymphomas and in tumors of epithelial or mesenchymal origin such as nasopharyngeal carcinoma or leiomyosarcoma. Thus, there is little doubt that EBV can infect cells of numerous lineages in vivo, in contrast to its in vitro infectious spectrum, which appears restricted predominantly to B lymphocytes. We show here that the EBV BALF4 gene product, the glycoprotein gp110, dramatically enhances the ability of EBV to infect human cells. gp110(high) viruses were up to 100 times more efficient than their gp110(low) counterparts in infecting lymphoid or epithelial cells. In addition, gp110(high) viruses infected the carcinoma cell line HeLa and the T cell lymphoma cell line Molt-4, both previously thought to be refractory to EBV infection. Analysis of several virus isolates showed that the amount of BALF4 present within mature virions markedly differed among these strains. In some strains, gp110 was found expressed during lytic replication not only at the nuclear but also at the cellular membrane. Heterologous expression of gp110 during the virus lytic phase neither altered virus concentration nor affected virus binding to cells. It appears that gp110 plays a crucial role after the virus has adhered to its cellular target. gp110 constitutes an important virulence factor that determines infection of non-B cells by EBV. Therefore, the use of gp110(high) viruses will help to determine the range of the target cells of EBV beyond B lymphocytes and provide a useful in vitro model to assess the oncogenic potential of EBV in these cells.     

Evidence for differences in the mechanisms by which antibodies against CD44 promote adhesion of erythroid and granulopoietic progenitors to marrow stromal cells

Adhesive interactions between haemopoietic progenitor cells and stromal elements involve a number of different molecules, some of which may be progenitor-lineage- and stage-specific. CD44 is one such molecule, although little is known about the mechanism(s) by which it is involved. In this study, several anti-CD44 monoclonal antibodies (mAb) increased the adherence of clonogenic cells, without affecting the total number of types of progenitors recoverable from the adhesion cultures. All of these mAb recognized epitopes on the globular head of CD44. In contrast, two mAb that recognized other regions of CD44 reduced progenitor adhesion to stroma. The mechanism by which one of the anti-CD44 mAb (L178) enhanced progenitor adhesion did not involve CD44-crosslinking, and was independent of VLA-4-, VLA-5- or LFA-1-mediated interactions, Ca or Mg cations, or accessory cells. In addition, CD44 expression on both progenitors and stromal cells contributed to L178-enhanced progenitor adhesion. Baseline adherence of erythroid progenitors to stroma required tyrosine kinase activity, whereas that of granulopoietic progenitors did not. However, the increase in adhesion did require tyrosine kinase activation. Additional experiments suggested that enhanced adhesion of CFU-GM to stroma may also be adenylate cyclase-dependent. Taken together, the present studies indicate both similarities and differences in the mechanisms of CD44-mediated adhesion of erythroid and granulopoietic progenitors to stromal cells.