Deficiency of RITA results in multiple mitotic defects by affecting microtubule dynamics.

Deregulation of mitotic microtubule (MT) dynamics results in defective spindle assembly and chromosome missegregation, leading further to chromosome instability, a hallmark of tumor cells. RBP-J interacting and tubulin-associated protein (RITA) has been identified as a negative regulator of the Notch signaling pathway. Intriguingly, deregulated RITA is involved in primary hepatocellular carcinoma and other malignant entities. We were interested in the potential molecular mechanisms behind its involvement. We show here that RITA binds to tubulin and localizes to various mitotic MT structures. RITA coats MTs and affects their structures in vitro as well as in vivo. Tumor cell lines deficient of RITA display increased acetylated α-tubulin, enhanced MT stability and reduced MT dynamics, accompanied by multiple mitotic defects, including chromosome misalignment and segregation errors. Re-expression of wild-type RITA, but not RITA Δtub ineffectively binding to tubulin, restores the phenotypes, suggesting that the role of RITA in MT modulation is mediated via its interaction with tubulin. Mechanistically, RITA interacts with tubulin/histone deacetylase 6 (HDAC6) and its suppression decreases the binding of the deacetylase HDAC6 to tubulin/MTs. Furthermore, the mitotic defects and increased MT stability are also observed in RITA-/- mouse embryonic fibroblasts. RITA has thus a novel role in modulating MT dynamics and its deregulation results in erroneous chromosome segregation, one of the major reasons for chromosome instability in tumor cells.

Quantitative structural information from single-molecule FRET.

Single-molecule studies can be used to study biological processes directly and in real-time. In particular, the fluorescence energy transfer between reporter dye molecules attached to specific sites on macromolecular complexes can be used to infer distance information. When several measurements are combined, the information can be used to determine the position and conformation of certain domains with respect to the complex. However, data analysis schemes that include all experimental uncertainties are highly complex, and the outcome depends on assumptions about the state of the dye molecules. Here, we present a new analysis algorithm using Bayesian parameter estimation based on Markov Chain Monte Carlo sampling and parallel tempering termed Fast-NPS that can analyse large smFRET networks in a relatively short time and yields the position of the dye molecules together with their respective uncertainties. Moreover, we show what effects different assumptions about the dye molecules have on the outcome. We discuss the possibilities and pitfalls in structure determination based on smFRET using experimental data for an archaeal transcription pre-initiation complex, whose architecture has recently been unravelled by smFRET measurements.

Attention deficit/hyperactivity disorder's effects on individuals' scan paths during a simulated drive.

Individuals who have Attention Deficit/Hyperactivity Disorder (ADHD) experience adverse effects relating to driving; additionally, they experience deficits in scanning ability. The present study examined the effects of ADHD on eye tracking while driving. This study consisted of ten participants, of which, five have ADHD. It was hypothesized that individuals who have ADHD will make more saccadic eye movements and thus shorter fixations than individuals without ADHD (Control). Furthermore, it was hypothesized that despite the fact that individuals who have ADHD will make more saccadic eye movements than individuals without ADHD, those individuals with ADHD will commit more traffic violations including collisions compared to the control group. Findings indicated that hypothesis one was not supported by the data, whereas hypothesis two was supported in that ADHD individuals' had more collisions and committed more traffic violations than the control group. Additionally, a significant difference was found in the spatial distributions of the fixations between the ADHD and Control groups. The findings of this study could help better understand the factors involved in ADHD driving and could be used to train individuals with ADHD to become more aware of their surroundings and driving habits and thus become safer drivers.

The cohort of long-term survivors at the German childhood cancer registry.

BACKGROUND: With the increasing number of long-term survivors among patients diagnosed with cancer during childhood, questions concerning late effects have become a major research topic. To ascertain late effects, it is necessary to contact former patients. An essential requirement for such studies is a long-term surveillance (LTS) of former childhood cancer patients in their adolescence and their adulthood. The paper describes the role of the German Childhood Cancer Registry (GCCR) in LTS. A cohort of long-term survivors has been built up over the years. The characteristics of this LTS cohort and strategies for further improvement of LTS will be presented. PATIENTS AND METHODS: Since 1980 the GCCR systematically ascertains all malignant neoplasms and benign brain tumours in children under the age of 15 years at diagnosis. Participants are followed up actively by the treating hospitals and the clinical study groups in the first years after diagnosis, and by the GCCR thereafter. Late effects are accessed within the Scientific Society for Paediatric Oncology and Haematology (GPOH) of different groups with different focal points. Those groups are the GCCR (secondary malignant neoplasms), LESS (late effects after chemotherapy), RiSK (late effects after radiotherapy), and the working group on quality of life (quality of life and data on life circumstances). Additionally, the GCCR provides logistics for contacting patients during LTS. The LTS is supported by a recent basic publication ("position paper") by the GPOH. Newly diseased cancer cases are reported to the GCCR very completely. The GCCR contains mainly epidemiological data. Accessorily, the GCCR ascertains a minimum of data for each patient which enables population-based studies involving long-term survivors of childhood cancer. RESULTS: Out of 37 291 children diagnosed with cancer between 1980 and 2004, 8 896 died (until spring 2007). From those not deceased, 21 987 (77.4%) can be followed up further (i.e. current address is known). For about 70% of the patients in the LTS cohort, follow-up data are available and not older than 5 years. Our experience shows that about 80% of former childhood cancer patients agree to continued data storage at the GCCR, 4% explicitly refuse their consent, the remaining do not answer. LTS for patients with leukemia and lymphomas is particularly complete, whereas for patients with brain tumours it is less complete. CONCLUSIONS: The LTS is considered highly relevant concerning aspects of clinical quality assurance and epidemiological research. The GCCR can guarantee a continuing development and improvement of existing procedures for LTS. The GCCR expects to achieve contacting a high percentage of former childhood cancer patients also in future LTS, even after long periods of time.

Chromophore localization in conjugated polymers: molecular dynamics simulation.

Quantum chemical calculations of undistorted poly(phenylene vinylene) chains at zero temperature exhibit chromophores which are delocalized over the whole polymer. We demonstrate with molecular dynamics simulations that chromophore localization in agreement with experiment can be obtained if the system is simulated at finite temperature. The dependence of the chromophore localization on the temperature is investigated.

Screening for renal cell carcinoma using ultrasonography: a feasibility study.

OBJECTIVE: To assess the practicability and efficacy of systematic screening for renal cell carcinoma (RCC) by ultrasonography (US), as more small RCCs are being detected incidentally by US. SUBJECTS AND METHODS: A 2-year screening programme for RCC was established for the general population (aged >or= 40 years) in two German cities, Mainz and Wuppertal. In cooperation with different health insurers, the organisers recruited general practitioners, internists and urologists in private practice who were experienced in and equipped to conduct renal US. The screening was offered in the form of cost-free renal US in the first year and a re-examination in the second. For any equivocal or positive renal mass, a reference ultrasonogram was provided by the urology departments at the two university hospitals. RESULTS: In all, 9959 volunteers participated in the screening programme (49% men, 51% women, mean age 61 years, range 40-94) in the first year. Of these participants, 79% returned for re-examination in the second year. Thirteen (0.1%) subjects were found to have a renal mass, of which nine were RCC. The sensitivity of the programme was 82% (at the 1-year follow-up), and the predictive value 2% for equivocal findings on initial examination and 50% for positive findings. The incidence of other abnormal findings was 12%. CONCLUSION: The screening programme was well accepted by physicians in private practice and by the eligible population. The method was effective, especially if equivocal findings were re-assessed by reference US before using further imaging studies, e.g. computed tomography or magnetic resonance imaging.

Second malignant neoplasms after treatment of childhood cancer.

The aim of this study was to determine therapy-related risk factors for the development of second malignant neoplasm (SMN) after childhood cancer. The German Childhood Cancer Registry (GCCR) registers all childhood malignancies since 1980 including SMN. A nested case-control study with 238 SMN cases and 450 controls was conducted. A confirmatory, as well as an explorative, analysis was performed. Radiotherapy showed a small effect on the risk of SMN for doses >or=65 Gy. Regarding the chemotherapeutical agents, we saw increased Odds Ratios (OR) for high doses of cyclophosphamide (CP >8000 mg/m(2) OR=6.3 (95% Confidence Interval (CI): 1.3-30.2)), cisplatinum (DDP >435 mg/m(2) OR=2.8 (95% CI: 1.1-6.7)) and mercaptopurine (MP >5000 mg/m(2) OR=4.5 (95% CI: 1.1-18.9)). Patients jointly receiving high doses of MP (>5000 mg/m(2)) and dexamethasone (DEXA >or=1200 mg/m(2)) had an OR=6.9 (95% CI: 1.2-40.3). Our results could be added to those of other investigations to give indications for modifying future therapeutic strategies for childhood cancer.

[Ultrasound screening of renal cell carcinomas]. / Sonographisches Screening von Nierenzellkarzinomen.

The increasing number of incidentally by ultrasound detected small renal cell carcinomas raises the question of the practicability and efficacy of a systematic screening for renal cell carcinoma by ultrasound. A two year screening program for renal cell carcinoma (RCC) was established for the general population (age > 40 years) in two cities, Mainz and Wuppertal. In cooperation with different health insurers, the organizers recruited general practitioners, internists and urologists in private practice who were experienced in and equipped for performing renal ultrasound. The screening was offered in the form of a cost free renal ultrasound in the first year and a re-examination in the second year. For any equivocal/positive renal mass, a reference ultrasound was provided the urology departments at the two university hospitals. 9959 volunteers participated in the screening program (49% male, 51% female) in the first year. The mean age was 61 (40-94) years. 79% of these participants returned for re-examination in the second year. Thirteen (0.1%) subjects were found to have a renal mass, of which nine were RCC. The sensitivity of the program was 82% (one year of follow-up). The predictive value was 2% for equivocal findings on initial exam and 50% for positive findings. The incidence of other abnormal findings was 12%. The screening program was well accepted by physicians in private practice and by the eligible population. The method proved effective, especially if equivocal findings were re-studied by reference sonography before further imaging studies such as CT and MRI were performed.

Vitamin K and childhood cancer: analysis of individual patient data from six case-control studies.

To investigate the hypothesis that neonates who receive intramuscular vitamin K are at an increased risk of developing cancer, particularly leukaemia, a pooled analysis of individual patient data from six case-control studies conducted in Great Britain and Germany has been undertaken. Subjects comprised 2431 case children diagnosed with cancer before 15 years of age and 6338 control children. The retrospective assessment of whether or not an individual baby received vitamin K is not straightforward. In many cases no record was found in stored medical notes and two types of analysis were therefore conducted; in the first it was assumed that where no written record of vitamin K was found it had not been given, and in the second, where no written record of administration was found, information on hospital policy and perinatal morbidity was used to 'impute' whether or not vitamin K had been given. In the first analysis, no association was found between neonatal administration of intramuscular. vitamin K and childhood cancer: odds ratios adjusted for mode of delivery, admission to special care baby unit and low birth weight were 1.09 (95% confidence interval 0.92-1.28) for leukaemia and 1.05 (0.92-1.20) for other cancers. In the second analysis, the adjusted odds ratios increased to 1.21 (1.02-1.44) for leukaemia and 1.10 (0.95-1.26) for other cancers. This shift did not occur in all studies, and when data from the hypothesis generating Bristol study were excluded, the adjusted odds ratios for leukaemia became 1.06 (0.89-1.25) in the first analysis and 1.16 (0.97-1.39) when data on prophylaxis imputed from hospital policy and perinatal morbidity were used. We conclude that whilst the broad nature of the diagnostic groups and the poor quality of some of the vitamin K data mean that small effects cannot be entirely ruled out, our analysis provides no convincing evidence that intramuscular vitamin K is associated with childhood leukaemia.

Population-based epidemiologic data on brain tumors in German children.

BACKGROUND: Brain tumors are the most common disease group of solid tumors in childhood, and children with brain tumors have a relatively poor survival rate. Epidemiologic data from a population-based cancer registry provide the necessary information to obtain a full picture of the frequency of this disease, which is a great challenge in pediatric oncology. METHODS: The German Childhood Cancer Registry (GCCR) is a population-based registry. The level of completeness of patient registration is 95%, but it is somewhat lower for patients with brain tumors. More than 300 children with newly diagnosed brain tumors are reported every year. Analyses of GCCR data are performed according to the International Classification of Childhood Cancer and the recently published World Health Organization classification of tumors of the nervous system. In addition, incidence rates of childhood brain tumors in Germany are compared with those of other countries, as published by the International Agency for Research on Cancer. RESULTS: In the years 1990-1999, a total of 3268 brain tumors were observed (excluding intracranial and intraspinal germ cell tumors). The respective incidence rate for children age < 15 years was 2.6 per 100,000 children and lies between the rates from other countries, which range between 1.7 and 4.1 per 100,000 children. The most common brain tumors were astrocytomas (41.7%), medulloblastomas (18.1%), ependymomas (10.4%), supratentorial primative neuroectodermal tumors (PNETs; 6.7%), and craniopharyngiomas (4.4%). They were located mainly in the cerebellum (27.9%) and the cerebrum (21.2%). The 5-year survival rate for all brain tumors was 64%, with the poorest prognosis for children with PNET. CONCLUSIONS: The large data base of the GCCR made it possible to present representative data on patients with childhood tumors of the central nervous system in Germany. The data quality was high, not least because of the strong cooperation with corresponding clinical trials. However, for children with central nervous system tumors, the ascertainment of newly diagnosed patients needs further improvement.

Long-term survival of children with leukemia achieved by the end of the second millennium.

BACKGROUND: The prognosis for patients with childhood leukemia has improved steadily over the last decades due to major progress in therapy. Much of this progress remains unaccounted for in traditional estimates of long-term survival rates, which essentially reflect the survival experience of patients who were diagnosed many years ago. METHODS: The authors applied a new method of survival analysis, called period analysis, to provide up-to-date estimates of long-term survival rates. The analysis is based on data from the nationwide German Childhood Cancer Registry and includes 8059 children who were diagnosed with leukemia between 1981 and 1998. The most up-to-date 5-year, 10-year, and 15-year survival estimates were obtained by period analysis and were compared with to the most up-to-date survival estimates from traditional methods of survival analysis. RESULTS: Period estimates (95% confidence intervals) of 5-year, 10-year, and 15-year survival rates achieved by 1998 were 81% (79-83%), 77% (74-79%), and 73% (70-76%), respectively, for all patients with leukemia combined; 86% (84-88%), 81% (79-84%), and 77% (74-81%), respectively, for patients with acute lymphocytic leukemia; and 59% (53-65%), 59% (53-65%), and 57% (49-64%), respectively, for patients with acute nonlymphocytic leukemia. Substantially lower estimates would have been obtained with traditional methods of survival analysis. CONCLUSIONS: These results from one of the world's largest childhood cancer registries reveal that cure rates of childhood leukemia achieved by the end of the second millennium are higher than suggested by previous estimates based on traditional methods of survival analysis.

Risk factors for neuroblastoma at different stages of disease. Results from a population-based case-control study in Germany.

Neuroblastoma is one of the childhood cancers included in two recent population-based case-control studies in West Germany. Altogether, 183 children under the age of 8 with neuroblastoma diagnosed in 1988-1994 and 1785 control children sampled from population registration files participated. Information on potential risk factors was obtained from the children's parents by a self-administered questionnaire and subsequent telephone interview. We observed positive associations with the use of oral contraceptives or other sex hormones during pregnancy (particularly with male offspring), a shorter gestational duration, lower birth weight, and maternal alcohol consumption during pregnancy. While the association with maternal use of oral contraceptives or sex hormones was strong for stages I/II (odds ratio 4.5, 95% confidence interval 1.2-16.5), the associations with shorter gestation duration (odds ratio 3.4, 95% confidence interval 1.7-6.7) as well as maternal alcohol consumption during pregnancy (>7 glasses/week odds ratio 5.2, 95% confidence interval 1.3-20.6) were observed only for the unfavourable advanced stages. It is notable that the associations in our study were either observed only for the advanced stages of disease or only for the less advanced stages, but not for both subgroups. This adds to evidence for the hypothesis that neuroblastoma consists of at least two distinct disease entities, which differ in clinical stage at the time of diagnosis.

Risk factors for pediatric tumors of the central nervous system: results from a German population-based case-control study.

BACKGROUND: From 1993 to 1997 we conducted two population-based case-control studies on childhood cancer and a variety of potential risk factors in Germany. One case group involved children under the age of 15 years having a tumor of the central nervous system (CNS). PROCEDURE: For both studies, one conducted in the northwestern area of Germany, the other covering the whole of West Germany, incident cases were identified from the nationwide German Childhood Cancer Registry, and controls were randomly selected from complete population registration files. RESULTS: In total 466 pediatric CNS tumor cases and 2,458 controls were available for analyses. We observed only few positive associations, namely, between CNS tumors and low birth weight [<2,500 g; odds ratio (OR), 1.73; 95% confidence interval (CI), 1.06-2.84], between ependymoma and maternal smoking during pregnancy (>10 cigarettes per day: OR, 4.71; 95% CI, 1.69-13.1), and between astrocytoma and exposure to wood preservatives (OR, 1.91; 95% CI, 1.22-3.01). CNS tumors were not associated with high birth weight, duration of breast feeding, maternal age at time of delivery, duration of gestation, previous fetal losses, paternal smoking during pregnancy, maternal alcohol consumption, the child's exposure to pesticides, maternal diagnostic X-ray examinations during pregnancy, X-ray examinations of the child, or exposure to residential magnetic fields. CONCLUSIONS: Despite the large study population, we found only few factors that were associated with CNS tumors or one of the morphological subgroups. Therefore, our results suggest that aspects of the prenatal and neonatal period play only a minor role in the etiology of pediatric CNS tumors.

High-birth weight and other risk factors for Wilms tumour: results of a population-based case-control study.

UNLABELLED: Wilms tumour, or nephroblastoma, is one of the childhood cancers included in two recent population-based case-control studies in West Germany. Altogether, 177 children under the age of 10 years with Wilms tumour diagnosed between 1988 and 1994 and 2006 control children sampled from population registration files participated. Information on potential risk factors was obtained from the parents using a questionnaire and by subsequent telephone interview. We found an association with a high birth weight >4000 g (odds ratio 1.58; 95% confidence interval 1.01-2.48), which was somewhat stronger for children aged 2 years or older. Findings for young maternal age at birth and certain parental occupationally related exposures were not reported by previous studies and thus may be chance findings. As opposed to previous studies, we failed to confirm associations with high parental age at birth, maternal coffee and tea consumption during pregnancy, and exposure to pesticides. CONCLUSION: Based on this large population-based case-control study, high birth weight may play a role in the aetiology of Wilms tumour, but many risk factors previously suggested are of less importance.

A randomized trial of treatment for multisystem Langerhans' cell histiocytosis.

OBJECTIVE: To compare 2 active agents, vinblastine and etoposide, in the treatment of multisystem Langerhans' cell histiocytosis (LCH) in an international randomized study. STUDY DESIGN: One hundred forty-three untreated patients were randomly assigned to receive 24 weeks of vinblastine (6 mg/m(2), given intravenously every week) or etoposide (150 mg/m(2)/d, given intravenously for 3 days every 3 weeks), and a single initial dose of corticosteroids. RESULTS: Vinblastine and etoposide were equivalent (P > or = .2) in all respects: response at week 6 (57% and 49%); response at the last evaluation (58% and 69%); toxicity (47% and 58%); and probability of survival (76% and 83%) [corrected], of disease reactivation (61% and 55%), and of developing permanent consequences (39% and 51%) including diabetes insipidus (22% and 23%). LCH reactivations were usually mild, as was toxicity. All children > or = 2 years old without risk organ involvement (liver, lungs, hematopoietic system, or spleen) survived. With such involvement, lack of rapid (within 6 weeks) response was identified as a new prognostic indicator, predicting a high (66%) mortality rate. CONCLUSIONS: Vinblastine and etoposide, with one dose of corticosteroids, are equally effective treatments for multisystem LCH, but patients who do not respond within 6 weeks are at increased risk for treatment failure and may require different therapy.

Survival of children with neuroblastoma. time trends and regional differences in Europe, 1978--1992.

Neuroblastoma is one of the most common solid cancers in children. We present the data collected for the EUROCARE II study, describing survival patterns for children diagnosed in Europe 1985--1989 in detail, and exploring time trends from 1978 to 1992. On average, the mean 5-year survival rate was considerably higher in infants (79%) compared with older children (30--33%). The risk of death has dropped by 37% from 1978--1981 to 1990--1992. There is a pronounced difference between countries, with Scotland and England and Wales having two of the lowest survival rates (28% (95% confidence interval (CI) 14--48) and 36% (95% CI 31--41) 5-year survival rates, respectively). The survival rates in France, Germany and Italy (48--66% 5-year survival rate) were among the highest. This pattern corresponds to the incidence rates for these countries. It can be assumed that in neuroblastoma, both incidence and survival are related to the frequency of diagnosing asymptomatic cases with good prognosis among infants. However, one cannot ignore possible intercountry differences in the effectiveness of therapy.

Residential magnetic fields as a risk factor for childhood acute leukaemia: results from a German population-based case-control study.

Our objective was to investigate whether exposure to residential power-frequency (50 Hz) magnetic fields above 0.2 microT increases a child's risk of leukaemia and to confirm or reject a finding from a previous German study on this topic, which reported increased leukaemia risk with exposure to stronger magnetic fields during the night. A population-based case-control study was used, covering the whole of the former West Germany. Residential magnetic fields were measured over 24 hr for 514 children with acute leukaemia identified by the German Childhood Cancer Registry and 1,301 control children taken from population registration files. Magnetic fields above 0.2 microT were relatively rare in Germany (only 1.5% of the study population). Childhood leukaemia and 24 hr median magnetic fields were only weakly related (OR = 1.55, 95% CI 0.65-3.67). A significant association was seen between childhood leukaemia and magnetic field exposure during the night (OR = 3.21, 95% CI 1.33-7.80). A dose-response-relationship was observed after combining the data of all German studies on magnetic fields and childhood leukaemia. The evidence for an association between childhood leukaemia and magnetic field exposure in our study comes from a measure of exposure during the night. Despite the large size of our study, the results are based on small numbers of exposed children. If the observed association stands, the effect on a population level in Germany would be small.

Childhood acute leukaemia and residential 16.7 Hz magnetic fields in Germany.

We observed a moderate but statistically non-significant association between magnetic fields (MF) and childhood leukaemia. This is the first such study to cover residential exposure to 16.7 Hz (railway frequency) MF though based on few exposed subjects. Our study does not exclude a small excess risk, but the attributable risk must be very low. It is reassuring that neglecting 16.7 Hz MF in childhood cancer studies appears to have little effect on findings.

Population-based and controlled study to evaluate neuroblastoma screening at one year of age in Germany: interim results.

BACKGROUND: The German Neuroblastoma Screening Project is the first controlled and population-based screening study to evaluate the presumed benefit of neuroblastoma mass screening at 1 year of age (10-18 months). PROCEDURE: Screening takes place in 6 of the 16 German states; children from the remainder serve as controls. The German Childhood Cancer Registry enables a mostly complete follow-up and detection of false-negative patients. RESULTS: Up to December, 1999, 1,199,165 children were examined for urinary catecholamine metabolites and 124 cases of neuroblastoma were detected preclinically, giving a detection rate of 10.3/100,000. Within this cohort, 33 false-negative cases were found. CONCLUSIONS: The results of this screening program will be crucial for further implementation of neuroblastoma screening.

Prevention of childhood leukemia by BCG vaccination in newborns? A population-based case-control study in Lower Saxony, Germany.

Data from a case-control study in Lower Saxony, Germany, were used to assess whether the risk for childhood cancer may be reduced by bacille Calmette-Guérin (BCG) vaccination in the neonatal period. There were 420 newly diagnosed childhood cancer cases from the German cancer registry and 613 controls eligible for this study. A mailed questionnaire was completed during a telephone interview with parents. Details on the perinatal history were abstracted from the birth charts by nurses blinded to the children's case-control status. Complete information was available for 259 cases and for 323 controls. A total of 85% of the controls had been BCG vaccinated in the newborn period. The adjusted odds ratios for BCG vaccination were 0.90 (95% confidence interval; 0.51-1.61) for leukemia and 0.61 (95% confidence interval; 0.25-1.50) for other cancers. Based on these data the probability of a 50% or more reduction of more reduction of the cancer risk by BCG vaccination in the newborn period is small. The statistical power of this study, however, was not high enough to rule out a smaller, still relevant reduction in cancer risk.