Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia.

Little is known about the impact of DNA methylation on the evolution/progression of Ph+ chronic myeloid leukemia (CML). We investigated the methylome of CML patients in chronic phase (CP-CML), accelerated phase (AP-CML) and blast crisis (BC-CML) as well as in controls by reduced representation bisulfite sequencing. Although only ~600 differentially methylated CpG sites were identified in samples obtained from CP-CML patients compared with controls, ~6500 differentially methylated CpG sites were found in samples from BC-CML patients. In the majority of affected CpG sites, methylation was increased. In CP-CML patients who progressed to AP-CML/BC-CML, we identified up to 897 genes that were methylated at the time of progression but not at the time of diagnosis. Using RNA-sequencing, we observed downregulated expression of many of these genes in BC-CML compared with CP-CML samples. Several of them are well-known tumor-suppressor genes or regulators of cell proliferation, and gene re-expression was observed by the use of epigenetic active drugs. Together, our results demonstrate that CpG site methylation clearly increases during CML progression and that it may provide a useful basis for revealing new targets of therapy in advanced CML.

[Is Work in Older Age Healthy? Findings from Family Run Businesses Using the Example of Bavarian Rural Economics]. / Ist Arbeit im Alter gesund? Erkenntnisse aus Familienunternehmen am Beispiel der bayerischen Agrarwirtschaft.

AIM OF STUDY: Working in second half of life is individually and socially important. The aim of this study is to multidimensionally evaluate the subjective health situation of older people, in particular those beyond the legal age of retirement who are working or assisting in family run businesses, using the example of Bavarian rural economics. METHODS: A 3 stage random sample stratified proportionally to regional population numbers was selected for a cross-sectional questionnaire survey (personal delivery, postal return n=3 176, 39.1%). Sample results can be generalised (men 59.8%, at least 65 years old 60.8%, smallest/small enterprises 61.8%). RESULTS: Life satisfaction is similar to that of the German age cohort population. In comparison to commercial and technical fields, physic and psychological complaints are lower and work pleasure is much higher. Health indicators are not dependent on enterprise structures, but on age and gender - on age partly non-linearly. CONCLUSION: Our results indicate that working in older age can be a source of subjective health. Process of family business succession may effect health. RESULTS might be applicable to other structurally similar agriculture regions and to craft sector. They promote individual confrontation with and social debate on a positive image of old age and aging.

The Hsp32 inhibitors SMA-ZnPP and PEG-ZnPP exert major growth-inhibitory effects on D34+/CD38+ and CD34+/CD38- AML progenitor cells.

Heat shock protein 32 (Hsp32), also known as heme oxygenase 1 (HO-1), has recently been identified as a potential target in various hematologic malignancies. We provide evidence that Hsp32 is constitutively expressed in primary leukemic cells in patients with acute myeloid leukemia (AML) and in various AML cell lines (HL60, U937, KG1). Expression of Hsp32 mRNA was demonstrable by qPCR, and expression of the Hsp32 protein by immunocytochemistry and Western blotting. The stem cell-enriched CD34+/CD38+ and CD34+/CD38- fractions of AML cells were found to express Hsp32 mRNA in excess over normal CD34+ progenitor cells. Two Hsp32-targeting drugs, pegylated zinc-protoporphyrin (PEG-ZnPP) and styrene-maleic-acid-copolymer-micelle-encapsulated ZnPP (SMAZnPP), were found to inhibit cytokine-dependent and spontaneous proliferation in all 3 AML cell lines as well as in primary AML cells. Growth inhibitory effects of SMA-ZnPP and PEG-ZnPP were dose-dependent with IC50 values ranging between 1 and 20 µM, and were accompanied by apoptosis as evidenced by light- and electron microscopy, Tunel assay, and caspase-3 activation. Finally, we were able to demonstrate that SMA-ZnPP inhibits cytokine-dependent proliferation of CD34+/CD38+ and CD34+/CD38- AML progenitor cells in vitro in all patients as well as leukemiainitiation of AML stem cells in NOD-SCID IL-2Rγ(-/-) (NSG) mice in vivo. Together, our data suggest that Hsp32 plays an important role as a survival factor in leukemic stem cells and as a potential new target in AML.

[Migration and health--from deficiency analysis to diversity vision?]. / Migration und Gesundheit--von Defizitanalysen zum Diversity-Ansatz?

In times of globalization the subjects migration and health are gaining more and more in importance. At the same time, one can observe a discrepancy between published opinions, politically intended messages and scientifically proved evidence. With approximately 15.4 million people with a migration background (this is equivalent to approximately 19% of the German population), migrants perform as an important "customer group" for health care and social security. In 2005, the category migrant background was introduced for the first time by the Federal Statistical Office. This category suggests homogeneity, which in fact is not given. Persons with migration background (including active immigrants, their children and grandchildren, repatriates, foreigners), have to be examined in a differentiated way concerning the consequences that the migration process has on health. Apart from potentially pathogenic influences associated with migration (e. g., ethnicity, national origin, cultural/religious characteristics, migration-related stressors), for example, education, social status, life-style and participation in work and society have to be taken into consideration as important "confounders". In this, a recent sociological approach (sinus migrant milieu) could be useful for socio-medical research and practice. Health-relevant information on migrants results on the one hand from scientific studies primarily designed for this purpose and, on the other hand, from routine data from official health reports. In the interpretation of secondary data, the problem arises that the definition of the target group (migrants) is different in the diverse data sources (for example, Germans, non-Germans, foreigners, migration background) and that important confounders (for example, from socio-cultural milieu) are not included. This may result in, among other things, an under- or overestimation of health risks or even incorrect conclusions. In consideration of these limitations, by means of data sets from official statistics (among others, Federal Statistical Office, social insurance agencies) and recent scientific research the present article analyses chosen aspects of migrant health (for example, health behaviour, morbidity, sickness absence, early retirement, health-care system, rehabilitation and mortality). Finally, possible implications for a more intensive discussion and further development of health care practice are pointed out.

Targeting of Hsp32 in solid tumors and leukemias: a novel approach to optimize anticancer therapy.

Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related anti-apoptotic molecule, that has been implicated in enhanced survival of neoplastic cells and in drug-resistance. We here show that Hsp32 is expressed in most solid tumors and hematopoietic neoplasms and may be employed as a new therapeutic target as evidenced by experiments using specific siRNA and a Hsp32-targeting pharmacologic inhibitor. This Hsp-32 targeting drug, SMA-ZnPP, was found to inhibit the proliferation of neoplastic cells with IC(50) values ranging between 1 and 50 microM. In addition, SMA-ZnPP induced apoptosis in all neoplastic cells examined. Furthermore, SMA-ZnPP was found to synergize with other targeted and conventional drugs in producing growth-inhibition. Resulting synergistic effects were observed in all tumor and leukemia cells examined. Interestingly, several of the drug partners, when applied as single agents, induced the expression of Hsp32 in neoplastic cells, suggesting that synergistic effects resulted from SMA-ZnPP-induced ablation of a Hsp32-mediated survival-pathway that is otherwise used by tumor cells to escape drug-induced apoptosis. Together, Hsp32 is an important survival factor and target in solid tumors and hematopoietic neoplasms, and may be used to optimize anticancer therapy by combining conventional or targeted drugs with Hsp32-inhibitors. Based on these data, it seems desirable to explore the value of Hsp32-targeting drugs as anti-cancer agents in clinical trials.

[Occupational mental well-being--utopia or necessity?]. / Psychosoziale Gesundheit im Beruf - Utopie oder Notwendigkeit?

The remarkable social-medical and economical importance of psychic and psychosomatic diseases is empasised by broad public discussions. According to recent epidemiological findings, these kinds of health disorders are not only more frequent than assumed formerly, but they also have severe social consequences. Contrary to the trend of a lowering level of the ill population, during the last decade psychic diseases were leading with all legal health insurance companies to a rising trend in days of inability to work, which now seems to consolidate at a high level. In addition to this, nearly e very third premature loss of occupation induced by illnesses - far before having reached the regular age limit - with legally pension-insured persons is based on psychic diseases. With civil servants, each second premature service inability has its roots in such a kind of suffering. At present, the reasons for this development are being discussed controversially. Psychosocial loads of the globalised, market-focused working sphere are regarded in this context as (sole) causing or at least as manifestation-promoting factors. The present article illuminates selected aspects of psychosomatic diseases concerning public health and the importance of work-associated psychosocial loads under consideration of the background of changes in society and working sphere. According to broad consent the setting "job" implies an enormous potential of prevention of psychic diseases, therefore, we will finally point out action options for an operational, psychosocial health promotion, which do not only focus on aspects of competition.

[Mobbing--a work related risk factor of service-based society?]. / Mobbing--eine arbeitsbedingte Gesundheitsgefahr der Dienst-Leistungs-Gesellschaft?

About a decade the background of the both public and scientific increasing interest in the topic "mobbing". But unfortunately the term "mobbing" is often applied in dubious and inflationary way as synonym for each professional disagreement. The reason for this may among others be that until today no internationally acknowledged standard definition on mobbing exists. According to the in German operational and judicial practice contemporarily most frequent and favourite paraphrases mobbing includes: intended chicanery/hostility (systematics) towards a person (purpose, asymmetry of power) in certain frequency/continuity (at least once a week for six months) with the intention to ostracize a person from his/her employment. In the European states prevalence varies between 2% and 15%, in Germany a national report supports with representative data about 3%, here women are more affected than man. The highest prevalence rates are found in services sector and in public health, social services and education. Aetiology places mobbing mainly as a multi-factor process with complex reciprocity between individual and professional/social factors conditioned in many cases by unresolved conflicts or occupational changes. In first place mobbing is no medical diagnosis, but health injuries resulting from mobbing makes this phenomenon more and more important for social and professional medicine. In view of diagnostic safeguarding with respect to differential diagnostic clarification of a mobbing case good interdisciplinary cooperation of both internal and external protagonists is recommended. Mobbing interventions include individual (for instance social support) as well as operational measures (for instance role of top executives, calling in of a mediation committee). Prevention against occupational mobbing must given high attention. An essential part is regarded the introduction of occupational conventions against mobbing. Within the scope of juridical examination of mobbing results (for example regarding potential impairments of health) in individual case aspects of criminal, civil, social, industrial or occupational law have checked. Mobbing and by means of mobbing caused or conditioned impairments of health are due to present valid juridical regulations neither regarded as occupational disease according to section sign 9 paragraph 1 or 2 SGB II nor as industrial accident. From aspect of prevention ( section sign 14 SGB VII/ section sign 20 SGB V) mobbing has to be considered as a serious psychosocial health hazard conditioned by work.