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?"

'Obesity paradox' misunderstands the biology of optimal weight throughout the life cycle.

The 'obesity paradox' refers to observations that run counter to the thesis that normal weight (BMI 18.5-24.9 g/m(2)) provides the lowest mortality and higher weight is associated with greater mortality. We argue that the weight of lowest mortality is influenced by aging and chronic disease, with mortality advantage extending into the overweight and even class I obese ranges under some circumstances. A focus on quality nutrition, physical activity, fitness, and maintaining function in these weight ranges may be preferable to a focus on intentional weight loss, which has uncertain effects. The 'obesity paradox' is no 'paradox' if one defines and interprets 'ideal' weight appropriately.

The art and science of chronic disease management come together in a lifestyle-focused approach to primary care.

Changes in patterns of living result in changes in the nature and causes of disease. The industrial revolution of the late 18th century, and the technological revolution of the late 20th century are cases in point. The former was associated with a decline in infectious diseases; the latter with an increase in lifestyle and environmentally induced chronic diseases . Health practices are typically modified to deal with such changes, hence the recent rise in interest in lifestyle-oriented forms of clinical practice.

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.

Long-term follow-up of patients with phenylketonuria receiving tetrahydrobiopterin treatment.

Treatment with tetrahydrobiopterin (BH4), the natural cofactor of phenylalanine hydroxylase (PAH), can reduce blood phenylalanine (Phe) levels in patients with BH4-responsive phenylketonuria (PKU). A number of studies has reported on the short-term BH4 treatment of patients with PKU, but long-term data are lacking. Here, we describe the effects of long-term treatment with BH4 on 16 patients, who showed a >28% reduction in blood Phe following testing for BH4 overload. The mean dose of BH4 was 16 mg/kg body weight (range 5-36 mg/kg body weight). The mean treatment duration was 56 months (range 24-110 months). Of 16 patients, 14 achieved long-term Phe control with BH4 treatment, with a mean blood Phe concentration of 321 ± 236 µmol/l. The mean decrease from baseline in blood Phe levels in these 14 patients was 54.6%. Of the seven patients who required continued dietary restriction, Phe intake increased from 200-300 mg/day to 800-1000 mg/day. Factors that may cause fluctuation of Phe levels in BH4-treated patients include patients' PAH genotype, Phe intake, changes in protein catabolism or anabolism, and periods of illness or infection.

Inflammatory effects of nutritional stimuli: further support for the need for a big picture approach to tackling obesity and chronic disease.

The discovery of a form of low-grade systemic inflammation (called 'metaflammation'), and the close evolutionary link between the immune and metabolic systems, poses questions about the supposed antigens (inducers) of such an immune reaction. Initially, this was thought to be mediated through obesity. However, we have identified a number of lifestyle or environmentally related inducers that may cause metaflammation, even in the absence of obesity. In this paper, the third of a series linking obesity with broad environmental and evolutionary factors, we identify nutritional stimuli with evidence of an involvement in metaflammation. From this we propose that components of certain foods and beverages with which humans have not evolved, are more often the inducers of an inflammatory effect in the body than those with which humans have become more familiar, and to which a neutral, or anti-inflammatory response may be expected to have developed. The implications of such a finding are considered in relation to broader aspects of the environment, economic growth, policy change and current global financial issues.

Significance of genotype in tetrahydrobiopterin-responsive phenylketonuria.

BACKGROUND: The value of genotyping to identify tetrahydrobiopterin-responsive (BH(4)-responsive) patients with phenylalanine hydroxylase (PAH) deficiency is a matter of debate. METHODS: We reviewed 250 cases of patients with PAH deficiency, using published data from 198 cases and unpublished data from 52 cases of patients attending our own clinic. Patients underwent analyses for BH(4) load and genetic mutations. Partial and full BH(4) responses were defined as a 10-29% decrease and a >or=30% decrease from baseline in blood phenylalanine levels, respectively. BH(4)-responsive alleles were identified from BH(4)-responsive patients as either homozygous for a specific allele or compound heterozygous for that allele with a null mutation. RESULTS: Most inconsistencies between observed genotype and BH(4) response were associated with mutations in the regulatory domain of PAH (p.R68S, p.I65T, p.L48S and p.F39C), where 20/62 alleles (32.2%) were non-responsive. In the catalytic domain (mutations p.Y414C, p.R261Q, p.E390G, p.A300S, p.R241C, p.A403V and p.V388M), only 8/125 alleles (6.4%) were non-responsive. Seven patients had a genotype with two BH(4)-responsive alleles resulting in no response or only a partial response to BH(4). Ten patients had identical genotypes but inconsistent responses in BH(4) load. CONCLUSIONS: These results show that BH(4) non-responsiveness is associated with genotype. However, patients with mutations in the regulatory domain show inconsistent results. In patients with two responsive alleles, non-responsiveness may be related to negative inter-allelic complementation. In patients with the same genotype and inconsistent results for BH(4) load, external factors such as intestinal absorption of BH(4), catabolic conditions or other genetic factors may be responsible. Further in vitro studies are necessary to clarify the genotype-phenotype correlation in patients with BH(4)-responsive PKU.

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.

The structure of the cushions in the feet of African elephants (Loxodonta africana).

The uniquely designed limbs of the African elephant, Loxodonta africana, support the weight of the largest terrestrial animal. Besides other morphological peculiarities, the feet are equipped with large subcutaneous cushions which play an important role in distributing forces during weight bearing and in storing or absorbing mechanical forces. Although the cushions have been discussed in the literature and captive elephants, in particular, are frequently affected by foot disorders, precise morphological data are sparse. The cushions in the feet of African elephants were examined by means of standard anatomical and histological techniques, computed tomography (CT) and magnetic resonance imaging (MRI). In both the forelimb and the hindlimb a 6th ray, the prepollex or prehallux, is present. These cartilaginous rods support the metacarpal or metatarsal compartment of the cushions. None of the rays touches the ground directly. The cushions consist of sheets or strands of fibrous connective tissue forming larger metacarpal/metatarsal and digital compartments and smaller chambers which were filled with adipose tissue. The compartments are situated between tarsal, metatarsal, metacarpal bones, proximal phalanges or other structures of the locomotor apparatus covering the bones palmarly/plantarly and the thick sole skin. Within the cushions, collagen, reticulin and elastic fibres are found. In the main parts, vascular supply is good and numerous nerves course within the entire cushion. Vater-Pacinian corpuscles are embedded within the collagenous tissue of the cushions and within the dermis. Meissner corpuscles are found in the dermal papillae of the foot skin. The micromorphology of elephant feet cushions resembles that of digital cushions in cattle or of the foot pads in humans but not that of digital cushions in horses. Besides their important mechanical properties, foot cushions in elephants seem to be very sensitive structures.

The elephant knee joint: morphological and biomechanical considerations.

Elephant limbs display unique morphological features which are related mainly to supporting the enormous body weight of the animal. In elephants, the knee joint plays important roles in weight bearing and locomotion, but anatomical data are sparse and lacking in functional analyses. In addition, the knee joint is affected frequently by arthrosis. Here we examined structures of the knee joint by means of standard anatomical techniques in eight African (Loxodonta africana) and three Asian elephants (Elephas maximus). Furthermore, we performed radiography in five African and two Asian elephants and magnetic resonance imaging (MRI) in one African elephant. Macerated bones of 11 individuals (four African, seven Asian elephants) were measured with a pair of callipers to give standardized measurements of the articular parts. In one Asian and three African elephants, kinematic and functional analyses were carried out using a digitizer and according to the helical axis concept. Some peculiarities of healthy and arthrotic knee joints of elephants were compared with human knees. In contrast to those of other quadruped mammals, the knee joint of elephants displays an extended resting position. The femorotibial joint of elephants shows a high grade of congruency and the menisci are extremely narrow and thin. The four-bar mechanism of the cruciate ligaments exists also in the elephant. The main motion of the knee joint is extension-flexion with a range of motion of 142 degrees . In elephants, arthrotic alterations of the knee joint can lead to injury or loss of the cranial (anterior) cruciate ligament.

Estimating changes in daily physical activity levels over time: implication for health interventions from a novel approach.

The aim of this study was to use a novel method to examine and compare physical activity levels in four different groups of men to investigate the impact of modernity on activity levels. Physical activity levels of four different groups of men were measured and compared, using a tri-axial accelerometer (Tracmor). The first group (HA = historically active) were actors in a historical theme park who play the part of Australian settlers 150 years ago, the second were sedentary modern-day office workers (MS = modern sedentary), the third men who had successfully lost weight (SWL) in a modern men's weight loss program and the last, men who were unsuccessful (UWL) in the same program. Men who had successfully lost weight in a weight loss program were active at a level similar to that of men performing activity at a level carried out historically. Both of these groups were in turn significantly more active than modern-day sedentary workers (p < 0.05) and men who had not been successful at losing weight (p < 0.01). A linear regression between weekly average activity levels and the degree of waist size loss showed a significant positive association (r = 0.52, p < 0.01). The data suggest that a higher activity level facilitates the maintenance of long-term weight loss and this level is likely to approximate activity levels in the past. For the prevention and treatment of obesity an increase in physical activity is necessary, because (long-term) weight loss or weight maintenance is unlikely to occur when people are as sedentary as most people are today.

Metabolic syndrome: epidemiology and more extensive phenotypic description. Cross-sectional data from the Bruneck Study.

OBJECTIVES: The present study aimed at evaluating the prevalence of the Metabolic Syndrome and at identifying its additional clinical features. RESEARCH DESIGN AND METHODS: Within a prospective population-based survey examining 888 subjects aged 40-79 y, subjects were identified fulfilling the WHO and the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria for diagnosing the Metabolic Syndrome. In these subjects and in the rest of the sample (controls), several metabolic and nonmetabolic biochemical parameters were compared. RESULTS: The prevalence of the Metabolic Syndrome by WHO criteria was 34.1% (95% CI 31.0-37.2) and by NCEP-ATPIII criteria 17.8% (15.5-20.3). The prevalence was significantly higher in older subjects and in those less physically active. Subjects with the Metabolic Syndrome either by WHO or by NCEP-ATPIII criteria showed higher levels of oxidized low-density lipoprotein, apolipoprotein B, urate, leptin, fibrinogen, leukocytes, erythrocyte sedimentation rate, GOT, gamma-GT and soluble endothelial adhesion molecules (E-selectin, vascular adhesion molecule-1 and intercellular adhesion molecule-1) and lower apolipoprotein A concentrations. Insulin resistance, as assessed by the Homeostasis Model Assessment, increased with the increase in the number of traits composing the syndrome found within the single individual. Subjects with insulin resistance had more pronounced abnormalities in several parameters, including the additional features of the syndrome (eg fibrinogen and soluble adhesion molecules). CONCLUSIONS: The Metabolic Syndrome occurs very frequently in the general population aged 40-79 y, and is associated with several additional metabolic and nonmetabolic abnormalities that likely contribute to an increased cardiovascular risk. Insulin resistance seems to play a major role in classic and additional abnormalities featuring the Metabolic Syndrome.

Impaired blood polymorphonuclear leukocyte migration and infection risk in severe trauma.

OBJECTIVES: We investigated the association of impaired blood polymorphonuclear leukocyte (PMN) migration with the incidence of bacterial infections in patients with severe trauma. METHOD: Twenty-six intensive-care patients with different injury severity scores were enrolled in a prospective study. PMN migration was measured daily using 300 microl fresh whole blood in a membrane filter assay. Migration was evaluated in an automated image analyzer that recorded numbers and distribution of the immigrant PMNs within a filter. The relevant parameter was the percentage of PMNs that migrated from the blood samples into the filters upon f-Met-Leu-Phe stimulation. RESULTS: Nine patients developed posttraumatic infections verified microbiologically. These patients showed a reduced PMN migratory capacity in comparison with the 17 patients without infections. A migrating portion of six per cent or less at least three days in succession preceded infections by one to 19 days and indicated infection in eight true positive versus three false positive cases, and 14 true negative versus one false negative case, i.e. specificity was 82.3% and sensitivity 88.8%, p=0.0008. Trauma severity had no influence on PMN migration. CONCLUSIONS: Trauma patients with impaired PMN migration are at risk for bacterial infections. Whole-blood migration tests can define the infection risk and thus may be useful predictive markers for infections.