PDGFRß promotes oncogenic progression via STAT3/STAT5 hyperactivation in anaplastic large cell lymphoma.

BACKGROUND: Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin T cell lymphoma commonly driven by NPM-ALK. AP-1 transcription factors, cJUN and JUNb, act as downstream effectors of NPM-ALK and transcriptionally regulate PDGFRß. Blocking PDGFRß kinase activity with imatinib effectively reduces tumor burden and prolongs survival, although the downstream molecular mechanisms remain elusive. METHODS AND RESULTS: In a transgenic mouse model that mimics PDGFRß-driven human ALCL in vivo, we identify PDGFRß as a driver of aggressive tumor growth. Mechanistically, PDGFRß induces the pro-survival factor Bcl-xL and the growth-enhancing cytokine IL-10 via STAT5 activation. CRISPR/Cas9 deletion of both STAT5 gene products, STAT5A and STAT5B, results in the significant impairment of cell viability compared to deletion of STAT5A, STAT5B or STAT3 alone. Moreover, combined blockade of STAT3/5 activity with a selective SH2 domain inhibitor, AC-4-130, effectively obstructs tumor development in vivo. CONCLUSIONS: We therefore propose PDGFRß as a novel biomarker and introduce PDGFRß-STAT3/5 signaling as an important axis in aggressive ALCL. Furthermore, we suggest that inhibition of PDGFRß or STAT3/5 improve existing therapies for both previously untreated and relapsed/refractory ALK+ ALCL patients.

Advancing Biomarker Development Through Convergent Engagement: Summary Report of the 2nd International Danube Symposium on Biomarker Development, Molecular Imaging and Applied Diagnostics; March 14-16, 2018; Vienna, Austria.

Here, we report on the outcome of the 2nd International Danube Symposium on advanced biomarker development that was held in Vienna, Austria, in early 2018. During the meeting, cross-speciality participants assessed critical aspects of non-invasive, quantitative biomarker development in view of the need to expand our understanding of disease mechanisms and the definition of appropriate strategies both for molecular diagnostics and personalised therapies. More specifically, panelists addressed the main topics, including the current status of disease characterisation by means of non-invasive imaging, histopathology and liquid biopsies as well as strategies of gaining new understanding of disease formation, modulation and plasticity to large-scale molecular imaging as well as integrative multi-platform approaches. Highlights of the 2018 meeting included dedicated sessions on non-invasive disease characterisation, development of disease and therapeutic tailored biomarkers, standardisation and quality measures in biospecimens, new therapeutic approaches and socio-economic challenges of biomarker developments. The scientific programme was accompanied by a roundtable discussion on identification and implementation of sustainable strategies to address the educational needs in the rapidly evolving field of molecular diagnostics. The central theme that emanated from the 2nd Donau Symposium was the importance of the conceptualisation and implementation of a convergent approach towards a disease characterisation beyond lesion-counting "lumpology" for a cost-effective and patient-centric diagnosis, therapy planning, guidance and monitoring. This involves a judicious choice of diagnostic means, the adoption of clinical decision support systems and, above all, a new way of communication involving all stakeholders across modalities and specialities. Moreover, complex diseases require a comprehensive diagnosis by converging parameters from different disciplines, which will finally yield to a precise therapeutic guidance and outcome prediction. While it is attractive to focus on technical advances alone, it is important to develop a patient-centric approach, thus asking "What can we do with our expertise to help patients?"

Non-nutrient causes of low-grade, systemic inflammation: support for a 'canary in the mineshaft' view of obesity in chronic disease.

A form of low-grade, systemic inflammation ('metaflammation') is linked to many types of chronic disease. Initially, this was thought to be causally related to weight gain and obesity and a possible explanation of the link between obesity and disease. However, several lifestyle-related inducers of such inflammation, some of which are associated with obesity, but some of which are not, have now been identified. The most common of these have been nutritive related, suggesting that there could still be a relationship, either directly or indirectly, with obesity. Here we provide evidence for non-nutritive inflammatory inducers, providing further support for an earlier suggestion that while obesity, beyond a point, may have a direct link with disease, this may be neither necessary nor sufficient to explain the current epidemic of chronic disease. A more ubiquitous cause encompassing all inflammatory inducers is the modern, post-industrial environment and lifestyles emanating from this. Obesity may thus be more of 'a canary in the mineshaft', warning of bigger global problems, than just a single pathway to modern environmentally driven disease.

Should obesity be the main game? Or do we need an environmental makeover to combat the inflammatory and chronic disease epidemics?

There is a link between obesity and chronic disease. However, the causal relationship is complicated. Some forms of obesity are associated with low-level systemic inflammation, which is linked to disease. But lifestyle behaviours that may not necessarily cause obesity (poor diet, inadequate sleep, smoking, etc.) can independently cause inflammation and consequent disease. It is proposed here that it is the environment driving modern lifestyles, which is the true cause of much chronic disease, rather than obesity per se, and that obesity may be a marker of environmental derangement, rather than the primary cause of the problem. Attempts to clinically manage obesity alone on a large scale are therefore unlikely to be successful at the population level without significant lifestyle or environmental change. Environmental factors influencing obesity and health have now also been implicated in ecological perturbations such as climate change, through the shift to positive energy balance in humans caused by the exponential use of fossil fuels in such areas as transport, and consequent rises in carbon emissions into the atmosphere. It is proposed therefore that a more policy-based approach to dealing with obesity, which attacks the common causes of both biological and ecological 'dis-ease', could have positive effects on both chronic disease and environmental problems. A plea is thus made for a greater health input into discussions on environmental regulation for chronic disease control, as well as climate change.

Dousing our inflammatory environment(s): is personal carbon trading an option for reducing obesity--and climate change?

Obesity and climate change are two problems currently challenging humanity. Although apparently unrelated, an epidemiological approach to both shows a similar environmental aetiology, based in modern human lifestyles and their driving economic forces. One way of analysing this is through inflammation (defined as '. . . a disturbance of function following insult or injury') of both the internal (biological) and external (ecological) environments. Chronic, low-grade, systemic inflammation has recently been shown to accompany obesity, as well as a range of biological pathologies associated with obesity (diabetes, heart disease, some cancers, etc.). This is influenced by the body's inability to soak up excess glucose as a result of insulin resistance. In a broader sense, inflammation is a metaphor for ecological 'pathologies', manifest particularly in unnatural disturbances like climate change, ocean acidity, rising temperatures and species extinction, associated with the inability of the world's environmental 'sinks' to soak up carbon dioxide ('carbon resistance'?). The use of such a metaphorical analysis opens the possibilities for dealing with two interdisciplinary problems simultaneously. Strategies for managing climate change, including personal carbon trading, could provide a 'stealth intervention' for reducing population levels of obesity by increasing personal energy expenditure and decreasing energy-dense food intake, as well as reducing the carbon emissions causing climate change.

Dissecting obesogenic behaviours: the development and application of a test battery for targeting prescription for weight loss.

There are limited practical tools to help clinicians or public health workers manage obesity in their patients. We have previously developed a scanning technique for diagnosing environments leading to obesity (Analysis Grid for Environments/Elements Leading to Obesity). Here we describe the development of a tool for identifying behaviours in an individual most likely to lead to obesity. A questionnaire battery of five tests called the DAB-Q (Diet, Activity and Behaviour Questionnaire) was developed, piloted and internally validated with overweight women from a commercial weight loss programme. Outcome from the tests, which are available free on the Internet, provides clinicians with a simple, effective and time-saving tool for ranking foods, drinks and activities likely to be most effectively targeted for weight loss in an individual. This is based on total scores derived from measures of frequency, potential for change and potency of each item as a potential contributor to overweight.

Dealing with obesity: an Australian perspective.

Over half of all Australians are classified as overweight or obese and this is increasing by 1% of the population per year. Obesity is linked with a range of health ailments including type 2 diabetes, heart diseases and some cancers. At a population level it is well accepted that obesity is a result of the increasing use of modern technology, resulting in decreased energy expenditure, in combination with easily available high energy density foods, the "obesogenic environment". In the modern environment, there are two major areas of management to assist the overweight and obese. Both include a change in lifestyle. Future strategies in weight management should include reduction in energy density and increase in daily physical activity.

High plasma levels of alpha- and beta-carotene are associated with a lower risk of atherosclerosis: results from the Bruneck study.

BACKGROUND AND PURPOSE: A large number of studies have contributed to the hypothesis that carotenoids, vitamins A and E are protective against atherosclerosis by acting as antioxidants. The aim of this study was to assess the relationship between plasma levels of carotenoids (alpha- and beta- carotene, lutein, lycopene, zeaxanthin, beta-cryptoxanthin), vitamins A and E, and atherosclerosis in the carotid and femoral arteries. METHODS: This prospective and cross sectional study involved a randomly selected population sample of 392 men and women aged 45-65 years. Carotid and femoral artery atherosclerosis was assessed by high-resolution duplex ultrasound. RESULTS: alpha- and beta- carotene plasma levels were inversely associated with the prevalence of atherosclerosis in the carotid and femoral arteries (P=0.004) and with the 5-year incidence of atherosclerotic lesions in the carotid arteries (P=0.04). These findings were obtained after adjustment for other cardiovascular risk factors (sex, age, LDL (low density lipoproteins), ferritin, systolic blood pressure, smoking, categories of alcohol consumption, social status, C-reactive protein). Atherosclerosis risk gradually decreased with increasing plasma alpha- and beta-carotene concentrations (P=0.004). No associations were found between vitamin A and E plasma levels and atherosclerosis. CONCLUSIONS: This study provides further epidemiological evidence of a protective role of high alpha- and beta- carotene in early atherogenesis.

The affinity of MCF7 breast cancer cells to hyaluronan substrates of different molecular weight and concentrations in an in vitro model.

The affinity of MCF7 breast cancer cells to hyaluronan (HA) was investigated in an in vitro model. The cells form a tightly adhering monolayer on native HA with a concentration of 5 mg/ml. On native HA at higher concentrations the cells reduce their adhesion to the substrate in favor of increased intercellular bonds, resulting in a cluster-like aggregate that tends to detach from the substrate. Aggregate formation is accomplished after 12 h incubation. The phenomenon is independent of the CD44 receptor. Degradation of native HA by hyaluronidase abolishes aggregate formation even at high HA concentrations in favor of formation of a firmly adhering monolayer. This model may help to understand tumor spread on HA tissue structures and may explain therapy successes with hyaluronidase in tumor patients.

Polymorphonuclear leukocyte functions as predictive markers for infections after organ transplantation.

Infectious complications are still a major cause of morbidity and mortality after organ transplantation, and early therapy would certainly reduce the risk associated with severe infections. We therefore investigated the significance of polymorphonuclear leukocyte (PMN) functional tests as predictive markers for infection in transplant patients under immunosuppressive therapy in a longitudinal study. In 41 patients, blood PMN migration and reactive oxygen species release, the blood levels of PMN elastase, malondialdehyde, neopterin, sICAM-1 and sVCAM-1, and urine neopterine were measured in 3- and 4-day intervals after liver-, kidney-, kidney-pancreas-, and heart and lung transplantation. PMN migration was determined in whole blood and estimated by the amount of PMNs to penetrate into a membrane filter upon FMLP stimulation. Three groups of patients were formed according to their postoperative course. Group I patients (n = 23) had no or only minor local infection, group II patients (n = 11) had infections with distinct systemic involvement, and group III patients (n = 7) developed sepsis. A first elastase-level of over 100 mg/L after surgery, followed by a drop in the amount of blood PMNs ready to migrate, on FMLP stimulation, to below 12 %, turned out to be a marker for impending infection, whereas all other parameters tested were not predictive. In six of seven group III patients, this marker became positive (sensitivity 85.7 %) up to 15 days before clinical manifestation of sepsis. In group I (largely uneventful recovery) only one of 23 patients was positive (specificity 95.6 % ), whereas group II patients were in between (4 of 11 positive). By this method it seems possible to diagnose severe infections in the pre-clinical phase, which may help prevent them if treatment is begun promptly.

Distinct risk profiles of early and advanced atherosclerosis: prospective results from the Bruneck Study.

Most epidemiological surveys on risk factors of atherosclerosis were cross-sectional in design and did not consider the existence of pathologically distinct processes. The Bruneck Study is a prospective survey in the general community (age range, 40 to 79 years). The baseline examination and first reevaluation were performed in the summers of 1990 and 1995 (participation, 92%; follow-up, 96%). Carotid atherosclerosis was monitored with high-resolution duplex ultrasound. Early (incidence and/or extension of nonstenotic lesions) and advanced (incidence and/or progression of stenosis >40%) stages of atherogenesis were differentiated. The risk profile of early atherogenesis consists of traditional risk factors, such as hypertension, hyperlipidemia, and cigarette smoking (pack-years), supplemented by a variety of less well-established risk conditions, including high body iron stores, hypothyroidism, microalbuminuria, and high alcohol consumption. In contrast, the risk profile of advanced atherogenesis includes markers of enhanced prothrombotic capacity, attenuated fibrinolysis, and clinical conditions known to interfere with coagulation: high fibrinogen, low antithrombin, factor V Leiden mutation, lipoprotein(a) >0.32 g/L, high platelet count, cigarette smoking, and diabetes. Hyperlipidemia and hypertension were of only minor relevance. These findings, along with the epidemiological features of advanced atherogenesis and emergence of an elevated fibrin turnover, suggest atherothrombosis to be a key mechanism in the development of advanced stenotic atherosclerosis. Supplementary 6-category logistic regression models illustrate the changing association between major risk predictors and atherosclerosis of increasing severity and substantiate appropriateness of the 40% threshold applied for the definition of advanced stenotic atherosclerosis. Atherosclerosis is a heterogeneous process that subsumes etiologically and epidemiologically distinct disease entities. The multifactorial etiology of atherosclerosis, which goes far beyond the traditional risk factors, has not yet achieved adequate attention in clinical practice and disease prevention.

Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study.

OBJECTIVES: Focus of the current study was on the significance of bacterial endotoxin, which shows a variety of pro-atherogenic properties and may occur at high concentration in the circulation of infected subjects. BACKGROUND: The possibility of an infectious risk factor in atherogenesis and cardiovascular disease has stimulated research interest, but the nature of such process remains obscure. METHODS: We measured plasma endotoxin levels (LAL assay) in a random population of 516 men and women 50 to 79 years old at the 1990 baseline evaluation (Bruneck Study). End points of this prospective survey were incident (early) atherosclerosis in the carotid arteries as assessed with high-resolution Duplex ultrasound (five-year follow-up rate, 98%) and incident cardiovascular disease (follow-up rate, 100%). RESULTS: Median endotoxin concentration amounted to 14.3 pg/ml (range, 6.0 to 209.2 pg/ml). Subjects with levels beyond 50 pg/ml (90th percentile) faced a threefold risk of incident atherosclerosis (odds ratio [95% confidence interval] 2.9 [1.4-6.3]; p < 0.01). The risk associated with high endotoxin was most pronounced in subjects with chronic infections and in current and ex-smokers. Notably, smokers with low endotoxin levels and nonsmokers did not differ in their atherosclerosis risk, whereas smokers with high levels almost invariably developed new lesions. All findings emerged as independent of vascular risk factors. Similar results were obtained for incident cardiovascular disease. CONCLUSIONS: The current study yields first epidemiologic evidence that endotoxemia constitutes a strong risk factor of early atherogenesis in subjects with chronic or recurrent bacterial infections and a link in the association between cigarette smoking and atherosclerotic disease.

Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis : clinical significance determined in a follow-up study.

BACKGROUND: Previous work has proved that increased titers of antibodies against heat-shock protein (hsp) 65 are associated with atherosclerotic lesions independently of other established risk factors. The present follow-up study was designed to further scrutinize the association of hsp antibodies and atherosclerosis and evaluate the possible predictive value of these antibodies for the development and/or progression of lesions in the same population. METHODS AND RESULTS: A total of 750 subjects 45 to 74 years old were recruited, and the rate of participation was 93.6%; 58 subjects died between 1990 and 1995. All participants were subjected to determination of serum antibodies against hsp65 and sonography to assess carotid atherosclerotic lesions and evaluate other risk factors, ie, age, sex, body mass index, blood cholesterol, apolipoprotein B, apolipoprotein A, triglycerides, lipoprotein(a), fibrinogen, leukocyte number, antithrombin III, ESR, ferritin, hypertension, smoking, and diabetes mellitus. Our data show that hsp65 antibody titers in the population emerged as highly consistent over a 5-year observation period (r=0.78, P<0.0001). Titers were significantly elevated in subjects with progressive carotid atherosclerosis and correlated with intima/media thickness. Multiple linear regression analysis documented these associations to be independent of age, sex, and other risk factors. Subanalyses revealed a preferential association of hsp65 antibody titers with advanced lesions (odds ratio, 1.42; 95% CI, 1.02 to 1.98; P=0.039). Other risk factors neither confounded nor modified this association. Finally, hsp65 antibody titers significantly predicted the 5-year mortality (hazard ratio, 1.52; 95% CI, 1.14 to 2.03; P<0.001). CONCLUSIONS: These findings indicate a sustained existence of anti-hsp65 antibodies in subjects with severe atherosclerosis, which is predictive for mortality.

Plasma glucose within the normal range is not associated with carotid atherosclerosis: prospective results in subjects with normal glucose tolerance from the Bruneck Study.

OBJECTIVE: There is substantial evidence that glucose intolerance is associated with an increased risk of cardiovascular disease. However, it is not well established whether plasma glucose is independently related to atherosclerosis when glucose tolerance is normal and, if so, to which stage of the complex atherosclerotic process. RESEARCH DESIGN AND METHODS: We prospectively examined the status of carotid arteries in 625 subjects aged 40-79 years who were randomly selected from the general population and had normal glucose tolerance (according to World Health Organization criteria) both at baseline and at 5 years of follow-up. All subjects had high-resolution echo-duplex evaluation of the common and internal carotid arteries (eight regions of interest on both sides) in 1990 and 1995 to detect the change in carotid status over time. The occurrence of new plaques in previously normal segments was termed "incident nonstenotic" or "early atherosclerosis," and the occurrence of stenosis in >40% of previously normal segments was termed "incident stenotic" or "advanced atherosclerosis." In addition, we evaluated the changes in the atherosclerosis score (the sum of all plaques) during the follow-up, and we measured intimal-medial thickening (IMT) in the common carotid artery in 1995. In all subjects, several candidate risk factors were assessed: sex, age, BMI, waist-to-hip ratio, glucose, HbA1c, insulin, urate, lipids, apolipoproteins A1 and B, blood pressure, lipoprotein(a), fibrinogen, antithrombin III, factor V Leiden mutation, ferritin, leukocyte count, smoking, alcohol intake, physical activity, and socioeconomic status. Fasting plasma glucose (FPG), plasma glucose 2 hr after the glucose load (2-h PG), and HbA1c concentrations in 1990 and 1995 were averaged in each subject to obtain an estimate of long-term glucose exposure of the arterial wall. RESULTS: Linear or logistical regression analyses indicated that neither baseline glucose and HbA1c levels nor mean FPG, mean 2-h PG, or mean HbA1c in 1990 and 1995 were independently related to IMT, a 5-year change in the atherosclerotic score, incident nonstenotic (early) atherosclerosis, or incident stenotic (advanced) atherosclerosis. Likewise, subjects with FPG levels above the median and subjects in the new category of "impaired fasting glucose" did not have an increased occurrence or progression of atherosclerosis. All results were consistent before and after adjustment for other vascular risk factors and possible confounders. CONCLUSIONS: These results suggest that plasma glucose levels within the normal range (<7.8 mg/dl both at FPG and 2-h PG) are not independently related to any stage of atherosclerosis.

TARPARE: a method for selecting target audiences for public health interventions.

OBJECTIVE: This paper presents a model to assist the health promotion practitioner systematically compare and select what might be appropriate target groups when there are a number of segments competing for attention and resources. METHOD: TARPARE assesses previously identified segments on the following criteria: T: The Total number of persons in the segment; AR: The proportion of At Risk persons in the segment; P: The Persuability of the target audience; A: The Accessibility of the target audience; R: Resources required to meet the needs of the target audience; and E: Equity, social justice considerations. The assessment can be applied qualitatively or can be applied such that scores can be assigned to each segment. Two examples are presented. CONCLUSIONS: TARPARE is a useful and flexible model for understanding the various segments in a population of interest and for assessing the potential viability of interventions directed at each segment. The model is particularly useful when there is a need to prioritise segments in terms of available budgets. IMPLICATIONS: The model provides a disciplined approach to target selection and forces consideration of what weights should be applied to the different criteria, and how these might vary for different issues or for different objectives. TARPARE also assesses segments in terms of an overall likelihood of optimal impact for each segment. Targeting high scoring segments is likely to lead to greater program success than targeting low scoring segments.

Alcohol consumption and atherosclerosis: what is the relation? Prospective results from the Bruneck Study.

BACKGROUND AND PURPOSE: Potential effects of regular alcohol consumption on atherogenesis are still controversial mainly due to the lack of prospective population-based studies. METHODS: The Bruneck Study is a prospective population-based survey of atherosclerosis and its risk factors. The study population comprises a sex- and age-stratified random sample of men and women aged 40 to 79 years. Participation and follow-up were more than 90% complete. Changes in carotid atherosclerosis between the 1990 baseline and the first follow-up in 1995 were monitored by high-resolution duplex ultrasonography. Alcohol intake was quantified with a standardized questionnaire and prospective diet records. RESULTS: Alcohol consumption less than once a week (occasional drinking) had no effect on atherogenesis. The association between regular alcohol intake and incident carotid atherosclerosis (early atherogenesis) was J-shaped, with light drinkers facing a lower risk than either heavy drinkers or abstainers. Protection offered by alcohol consumption of <50 g/d appeared to act through inhibition of the injurious action of high levels of low-density lipoprotein (LDL) cholesterol. Excess risk of incident atherosclerosis observed among heavy alcohol consumers (> or =100 g/d) clearly surpassed the risk burden afforded by heavy smoking. The association between regular alcohol intake and incident carotid stenosis (advanced atherogenesis) was U-shaped. Odds ratios were generally shifted toward protection and did not rely on LDL cholesterol levels. We failed to find any differential effects of alcohol from various sources. All associations remained independently significant when we adjusted for lifestyle, coincidental smoking, and the metabolic complex associated with drinking. CONCLUSIONS: Our findings support the view that adverse and beneficial effects of alcohol on arterial disease are mediated in part by a dose-dependent promotion or deceleration of atherogenesis. The protection afforded by light drinking may possibly be attributed to antithrombotic effects and inhibition of the atherogenic action of high levels of LDL cholesterol.

U-shaped and J-shaped relationships between serum insulin and coronary heart disease in the general population. The Bruneck Study.

OBJECTIVE: To evaluate the relationship existing between serum insulin and coronary heart disease (CHD) in the general population. RESEARCH DESIGN AND METHODS: In a cross-sectional survey on atherosclerosis and its risk factors, 500 men and 500 women aged 40-79 years were randomly selected from the population of Bruneck, Italy. Clinical, biochemical, and behavioral risk factors of atherosclerosis were assessed in the 936 subjects who participated in the study. Serum insulin was measured at fasting (n = 888) and 2 h (n = 811, known diabetic subjects were excluded) after an oral glucose load. CHD was ascertained by an abnormal electrocardiogram and/or a history of angina or myocardial infarction. RESULTS: Subjects were stratified according to serum insulin quintiles at fasting or 2 h after glucose loading. After adjustment for sex, age, BMI, smoking, physical activity, alcohol intake, and socioeconomic status (analysis of covariance), cardiovascular risk factors clustered in subjects of the top insulin quintile. Multiple logistic regression analysis, including sex and age in model 1, sex, age, BMI, glucose tolerance, socioeconomic status, and behavioral variables in model 2, or this set of variables together with triglycerides and apoproteins A1 and B, fibrinogen, and blood pressure status in model 3, revealed a significant association between high serum insulin and CHD when median insulin quintile was used as the reference class. Moreover, low serum insulin levels, such as those found in subjects of the lowest quintile, were independently related to CHD. These results were found either before (model 1) or after (models 2 and 3) adjusting for several covariates. Consistent results were found in men and women, as well as in younger and older subjects. CONCLUSIONS: Results of the present study suggest that both hyperinsulinemia and "hypoinsulinemia" are independent indicators of CHD. Furthermore, it is proposed that the relationship between CHD and fasting insulin is U-shaped, whereas that between CHD and postglucose insulin may be J-shaped.