Metabolic Syndrome in Childhood Cancer Survivors

Over 200,000 children under the age of fifteen are diagnosed with cancer worldwide every year. Cancer is the second most common cause of death among children between the ages of 1 and 14 years in developed countries, surpassed only by accidents.Nearly one third of the cancers diagnosed in children are leukemias (particularly acute lymphoblastic leukemia (ALL)), followed by cancer of the brain or central nervous system (21%), soft tissue sarcomas (including neuroblastoma (7%) and rhabdomyosarcoma (3%)), renal (nephroblastoma) tumors (5%), and non-Hodgkin lymphoma (4%). Childhood cancer survival has increased significantly over the past few decades (Figure 1). Especially the advent of combination chemotherapy in the late 1960s and 1970s brought about large increases in survival for many childhood cancers. Furthermore, improved surgery, radiotherapy, stem cell transplantation, supportive care and better stratification of therapy regimens played an important role. Population-based statistics show the probability of fiveyear survival of cancer in those under the age of 20 in the United States to be 80%. This success in therapy translates into a growing and aging population of long-term survivors. To date, 1 out of 640 young adults in the United States is a childhood cancer survivor. In the Netherlands, currently 7000 adults are long-term childhood cancer survivors

Adrenal function in adult long-term survivors of nephroblastoma and neuroblastoma

AbstractBackgroundAdrenal insufficiency, or relative insufficiency, might partly explain increased mortality rates in nephroblastoma and neuroblastoma survivors after unilateral adrenalectomy.ObjectiveTo assess adrenal function and its metabolic effects in survivors after adrenalectomy.MethodsIn this cross-sectional study, 67 adult long-term survivors of nephroblastoma, 36 survivors of neuroblastoma and 49 control subjects participated. Adrenal function was assessed by a 1μg short Synacthen-test. Levels of cortisol, adrenocorticotrophic hormone (ACTH), low (LDL-C) and high-density lipoprotein-cholesterol (HDL-C), triglycerides, apolipoprotein-B, glucose and insulin were assessed in blood samples taken at baseline. In addition, cortisol levels were assessed after 30 (t=30) and 60min. Homoeostatic Model Assessment (HOMA) was calculated.ResultsAdrenal insufficiency was not present in survivors. Interestingly, baseline serum cortisol levels were higher in survivors after unilateral adrenalectomy (mean 503nmol/l) (N=46) than in survivors with both adrenals intact (mean 393nmol/l, P=0.002) (N=52), and than in controls (mean 399nmol/l, P=0.013) (N=49). After correcting for age, sex and use of oral oestrogens, unilateral adrenalectomy was independently associated with elevated baseline cortisol and ACTH levels. Baseline cortisol levels were positively associated with triglycerides (P<0.001), LDL-C (P=0.004), apolipoprotein-B (P<0.001) and HOMA (P=0.008).ConclusionsNo adrenal insufficiency was observed in survivors of nephroblastoma and neuroblastoma. Survivors treated with unilateral adrenalectomy had relatively high basal cortisol and ACTH levels, indicating a higher central setpoint of the hypothalamic-pituitary-adrenal axis. This higher setpoint was associated with lipid concentrations and insulin resistance and can therefore influence the cardiovascular risk profile in long-term survivors of nephroblastoma and neuroblastoma

Nuclear equation of state at high density and the properties of neutron stars

We discuss the relativistic nuclear equation of state (EOS) using a relativistic transport model in heavy-ion collisions. From the baryon flow for $Au + Au$ systems at SIS to AGS energies and above we find that the strength of the vector potential has to be reduced moderately at high density or at high relative momenta to describe the flow data at 1-10 A GeV. We use the same dynamical model to calculate the nuclear EOS and then employ this to calculate the gross structure of the neutron star considering the core to be composed of neutrons with an admixture of protons, electrons, muons, sigmas and lambdas at zero temperature. We then discuss these gross properties of neutron stars such as maximum mass and radius in contrast to the observational values.Comment: 17 pages, 5 figures, to be published in Phy. Rev.

Beyond aggression: Androgen-receptor blockade modulates social interaction in wild meerkats

In male vertebrates, androgens are inextricably linked to reproduction, social dominance, and aggression, often at the cost of paternal investment or prosociality. Testosterone is invoked to explain rank-related reproductive differences, but its role within a status class, particularly among subordinates, is underappreciated. Recent evidence, especially for monogamous and cooperatively breeding species, suggests broader androgenic mediation of adult social interaction. We explored the actions of androgens in subordinate, male members of a cooperatively breeding species, the meerkat (Suricata suricatta). Although male meerkats show no rank-related testosterone differences, subordinate helpers rarely reproduce. We blocked androgen receptors, in the field, by treating subordinate males with the antiandrogen, flutamide. We monitored androgen concentrations (via baseline serum and time-sequential fecal sampling) and recorded behavior within their groups (via focal observation). Relative to controls, flutamide-treated animals initiated less and received more high-intensity aggression (biting, threatening, feeding competition), engaged in more prosocial behavior (social sniffing, grooming, huddling), and less frequently initiated play or assumed a ‘dominant’ role during play, revealing significant androgenic effects across a broad range of social behavior. By contrast, guarding or vigilance and measures of olfactory and vocal communication in subordinate males appeared unaffected by flutamide treatment. Thus, androgens in male meerkat helpers are aligned with the traditional trade-off between promoting reproductive and aggressive behavior at a cost to affiliation. Our findings, based on rare endocrine manipulation in wild mammals, show a more pervasive role for androgens in adult social behavior than is often recognized, with possible relevance for understanding tradeoffs in cooperative systems

Matrix metalloproteinases in human melanoma cell lines and xenografts: increased expression of activated matrix metalloproteinase-2 (MMP-2) correlates with melanoma progression

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in tumour progression and metastasis. In this study, we investigated the in vitro and in vivo expression patterns of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1 and TIMP-2 mRNA and protein in a previously described human melanoma xenograft model. This model consists of eight human melanoma cell lines with different metastatic behaviour after subcutaneous (s.c.) injection into nude mice. MMP-1 mRNA was detectable in all cell lines by reverse transcription polymerase chain reaction (RT-PCR), but the expression was too low to be detected by Northern blot analysis. No MMP-1 protein could be found using Western blotting. MMP-2 mRNA and protein were present in all cell lines, with the highest expression of both latent and active MMP-2 in the highest metastatic cell lines MV3 and BLM. MMP-3 mRNA was expressed in MV3 and BLM, and in the non-metastatic cell line 530, whereas MMP-3 protein was detectable only in MV3 and BLM. None of the melanoma cell lines expressed MMP-9. TIMP-1 and TIMP-2 mRNA and protein, finally, were present in all cell lines. A correlation between TIMP expression level and metastatic capacity of cell lines, however, was lacking. MMP and TIMP mRNA and protein expression levels were also studied in s.c. xenograft lesions derived from a selection of these cell lines. RT-PCR analysis revealed that MMP-1 mRNA was present in MV3 and BLM xenografts, and to a lesser extent in 530. Positive staining for MMP-1 protein was found in xenograft lesions derived from both low and high metastatic cell lines, indicating an in vivo up-regulation of MMP-1. MMP-2 mRNA was detectable only in xenografts derived from the highly metastatic cell lines 1F6m, MV3 and BLM. In agreement with the in vitro results, the highest levels of both latent and activated MMP-2 protein were observed in MV3 and BLM xenografts. With the exception of MMP-9 mRNA expression in 530 xenografts, MMP-3, MMP-9, and TIMP-1 mRNA and protein were not detectable in any xenograft, indicating a down-regulated expression of MMP-3 and TIMP-1 in vivo. TIMP-2 mRNA and protein were present in all xenografts; interestingly, the strongest immunoreactivity of tumour cells was found at the border of necrotic areas. Our study demonstrates that of all tested components of the matrix metalloproteinase system, only expression of activated MMP-2 correlates with increased malignancy in our melanoma xenograft model, corroborating an important role of MMP-2 in human melanoma invasion and metastasis. © 1999 Cancer Research Campaig

Metabolic syndrome detection with biomarkers in childhood cancer survivors

Purpose: Augmented survival of childhood nephroblastoma and neuroblastoma has increased long-term side effects such as metabolic syndrome (MetS). Risk stratification is difficult after abdominal radiation because waist circumference underestimates adiposity. We aimed to develop a strategy for determining MetS in irradiated survivors using an integrated biomarker profile and vascular ultrasonography. Methods: The NCEP-ATPIII MetS-components, 14 additional serum biomarkers and 9 vascular measurements were assessed in a single-centre cohort of childhood nephroblastoma (n = 67) and neuroblastoma (n = 36) survivors and controls (n = 61). Multivariable regression models were used to study treatment effects. Principal component analysis (PCA) was used to study all biomarkers in a combined analysis, to identify patterns and correlations. Results: After 27.5 years of follow-up, MetS occurred more often in survivors (14%) than controls (3%). Abdominal radiotherapy and nephrectomy, to a lesser extent, were associated with MetS and separate components and with several biomarker abnormalities. PCA of biomarkers revealed a pattern on PC1 from favourable lipid markers (HDL-cholesterol, adiponectin) towards unfavourable markers (triglycerides, LDL-cholesterol, apoB, uric acid). Abdominal radiotherapy was associated with the unfavourable biomarker profile (β = 1.45, P = 0.001). Vascular measurements were not of added diagnostic value. Conclusions: Long-term childhood nephro-and neuroblastoma survivors frequently develop MetS. Additional assessment of biomarkers identified in PCA – adiponectin, LDL, apoB, and uric acid – may be used especially in abdominally irradiated survivors, to classify MetS as alternative for waist circumference. Vascular ultrasonography was not of added value

Close-to-threshold Meson Production in Hadronic Interactions

Studies of meson production at threshold in the hadron--hadron interaction began in the fifties when sufficient energies of accelerated protons were available. A strong interdependence between developments in accelerator physics, detector performance and theoretical understanding led to a unique vivid field of physics. Early experiments performed with bubble chambers revealed already typical ingredients of threshold studies, which were superseded by more complete meson production investigations at the nucleon beam facilities TRIUMF, LAMPF, PSI, LEAR and SATURNE. Currently, with the advent of the new cooler rings as IUCF, CELSIUS and COSY the field is entering a new domain of precision and the next step of further progress. The analysis of this new data in the short range limit permits a more fundamental consideration and a quantitative comparison of the production processes for different mesons in the few--body final states. The interpretation of the data take advantage of the fact that production reactions close-to-threshold are characterized by only a few degrees of freedom between a well defined combination of initial and exit channels. Deviations from predictions of phase-space controlled one-meson-exchange models are indications of new and exciting physics. Precision data on differential cross sections, isospin and spin observables -- partly but by no means adequately available -- are presently turning up on the horizon. There is work for the next years and excitement of the physics expected. Here we try to give a brief and at the same time comprehensive overview of this field of hadronic threshold production studies.Comment: 100 pages, Review article to be published in Prog. Part. Nucl. Phys. Vol. 49, issue 1 (2002