Alveolar progenitor cells and the origin of lung cancer.

Lung Cancer is the leading cause of cancer-related deaths worldwide. This is mainly due to late diagnosis and therefore advanced stage of the disease. Understanding the cell of origin of cancer and the processes that lead to its transformation will allow for earlier diagnosis and more accurate prediction of tumour type, ultimately leading to better treatments and lower patient morbidity. In this review, we focus on alveolar type 2 (AT2) cells as the cell of origin of lung adenocarcinoma (LUAD), the most common type of lung cancer. We first elaborate on the different oncogenes that are associated with LUAD and other lung cancers. After, we lay out in detail what is known about AT2 biology, to further delve into AT2 cells as cell of origin for adenocarcinoma. Understanding the precursors of LUAD and identifying the molecular changes during its progression will allow for earlier detection and better molecular targeting of the disease in early stages.

H3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression.

Epigenetic regulators are attractive anticancer targets, but the promise of therapeutic strategies inhibiting some of these factors has not been proven in vivo or taken into account tumor cell heterogeneity. Here we show that the histone methyltransferase G9a, reported to be a therapeutic target in many cancers, is a suppressor of aggressive lung tumor-propagating cells (TPCs). Inhibition of G9a drives lung adenocarcinoma cells towards the TPC phenotype by de-repressing genes which regulate the extracellular matrix. Depletion of G9a during tumorigenesis enriches tumors in TPCs and accelerates disease progression metastasis. Depleting histone demethylases represses G9a-regulated genes and TPC phenotypes. Demethylase inhibition impairs lung adenocarcinoma progression in vivo. Therefore, inhibition of G9a is dangerous in certain cancer contexts, and targeting the histone demethylases is a more suitable approach for lung cancer treatment. Understanding cellular context and specific tumor populations is critical when targeting epigenetic regulators in cancer for future therapeutic development.

[Frequency and influencing factors of ketoacidosis at diabetes onset in children and adolescents--a long-term study between 1995 and 2009]. / Häufigkeit und Einflussfaktoren der Ketoazidose bei Diabetesmanifestation im Kindes- und Jugendalter--eine Langzeitstudie von 1995 bis 2009.

BACKGROUND: Diabetic ketoacidosis (DKA) is a frequent acute complication at onset of type 1 diabetes. It is assumed that increased public awareness about diabetes symptoms may reduce DKA rate at diabetes onset. To investigate the time-dependent trend in DKA prevalence we analysed the frequency and determinants of DKA at disease onset over 15 years in pediatric patients. PATIENTS AND METHODS: The prevalence of DKA at disease onset was analysed in individuals aged ≤18 years treated for the first time from 1995-2009 within 7 days after diagnosis in pediatric centers. Simple and multiple logistic regression analysis was performed to investigate influencing factors on DKA prevalence. Change of the probability of ketoacidosis over years were modelled in the logistic regression as linear trend. RESULTS: 16 562 individuals from 170 institutions were studied with a mean age of 9.2 ± 4.2 years. DKA (pH <7.3) was present in 20.8% of patients without a significant trend between 1995 and 2009 (p=0.222). DKA prevalence was higher in children ≤5 years (26.3%) and in the age group 10-15 years (21.7%) than in individuals aged 5-10 years (16.4%) and 15-18 years (16.9%, p<0.001). Girls had DKA more often than boys (21.2% vs. 19.3%, p=0.002). DKA frequency was increased in individuals with migration background (26.5% vs. 19.2%, p<0.001). CONCLUSIONS: DKA prevalence at diabetes onset was constant at about 21% during the last 15 years. Very young children, pubertal adolescents, girls and individuals with migration background are at higher risk for DKA at diagnosis. To prevent DKA earlier diagnosis of type 1 diabetes is warranted especially in these patient groups.

Exposure to inhalable dust and its cyclohexane soluble fraction since the 1970s in the rubber manufacturing industry in the European Union.

OBJECTIVES: As exposures to airborne particulates in the European rubber industry might still be causing genotoxic risks, it is important to assess trends in levels of inhalable dust and its cyclohexane soluble fraction (CSF) between the 1970s and 2003. METHODS: 13 380 inhalable and 816 respirable dust and 5657 CSF measurements, collected within the framework of the European Union Concerted Action EXASRUB, were analysed. Hierarchical mixed effects models were applied to assess exposure trends, taking into account between-factory, between-worker/location and day-to-day variances. RESULTS: Geometric mean levels of inhalable dust and CSF exposure changed by -4% (range -5.8 to +2.9%) and -3% (range -8.6 to 0%) per year, respectively. Significant reductions in inhalable dust concentrations were found in all countries for handling of crude materials and mixing and milling (-7% to -4% per year), as well as for miscellaneous workers (-11% to -5% per year), while significant CSF exposure reductions were found in curing (-8.6% per year) and maintenance and engineering departments (-5.4% per year). CONCLUSION: These analyses suggest that on average exposure levels of inhalable dust and its CSF in the European rubber manufacturing industry have steadily declined. Most likely genotoxic risks have also lessened over time since exposure levels have decreased and the most toxic chemicals have been replaced. In addition to differences in exposure reductions and levels among various stages of the production process, large differences across countries were noted. These patterns should be taken into account in retrospective assessment of exposure for epidemiological studies assessing cancer risk in the rubber industry.

Improvements and new potentials in pharmacological therapy of diabetes mellitus in children and adolescents.

Subcutaneous insulin substitution is not physiological. Despite the many attempts using intensified insulin regimens to render current insulin substitution protocols more physiological, a nondiabetic circulating insulin profile cannot be simulated in patients with type 1 diabetes. Despite many efforts, the pharmacological treatment of type 1 diabetes consists of an unphysiological attempt to substitute only one of the hormones which are lost after beta-cell destruction, namely insulin. It is therefore mandatory to search for additional means to achieve physiological regulation of glucose homeostasis and overall metabolic status. Peptides which are being developed as additional new therapeutic compounds for type 1 diabetes include, for example, IGF-I, leptin, C-peptide and amylin. In addition, the application of insulin analogues has already been introduced into clinical practice. However, so far none of these pharmaceutical compounds has been shown to offer real clinical benefits and substantially improve metabolic control in patients with type 1 diabetes. The results of long-term clinical trials using the peptide compounds listed above for the treatment of type 1 diabetes are still not available.

A novel immunosuppressive factor in bovine colostrum blocks activation of the interleukin 2 gene enhancer at the NFAT site.

A factor in bovine colostrum (colostrum inhibitory factor, CIF) inhibits interleukin 2 (IL2) production in activated T helper cells by blocking the accumulation of IL2 mRNA. To determine whether CIF blocks at the level of IL2 transcription, we introduced reporter plasmids into the human T leukemia cell line Jurkat by transient transfection. These contained the luciferase gene under the control of either the human IL2 upstream enhancer region (segments -326 to +45) or three repeats of the NFAT element contained within it (segments -255 to -285). Expression of luciferase in these cells was induced by phorbol myristate acetate plus a calcium ionophore. CIF inhibited induction of either construct as did cyclosporine, which is known to block activation of the NFAT element. CIF failed to inhibit several other enhancer elements. The NFAT-controlled luciferase gene system distinguishes CIF from other T cell inhibitory activities present in colostrum, in particular, TGF beta 1 and TGF beta 2 and the glucocorticoids. Stably transfected Jurkat cells behaved similarly to the transiently transfected ones with respect to inhibition by CIF and cyclosporine. The NFAT-luc assay is a useful technique for the rapid, sensitive measurement of CIF or other immunosuppressants with a similar mode of action.