Showing papers by "University of Düsseldorf published in 2010"

International network of cancer genome projects

Abstract: The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.

Abstract: BACKGROUND: Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. METHODS: In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. RESULTS: A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. CONCLUSIONS: This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

Abstract: By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.

A link between the systems: functional differentiation and integration within the human insula revealed by meta-analysis.

Abstract: Whether we feel sympathy for another, listen to our heartbeat, experience pain or negotiate, the insular cortex is thought to integrate perceptions, emotions, thoughts, and plans into one subjective image of “our world”. The insula has hence been ascribed an integrative role, linking information from diverse functional systems. Nevertheless, various anatomical and functional studies in humans and non-human primates also indicate a functional differentiation of this region. In order to investigate this functional differentiation as well as the mechanisms of the functional integration in the insula, we performed activation-likelihood-estimation (ALE) meta-analyses of 1,768 functional neuroimaging experiments. The analysis revealed four functionally distinct regions on the human insula, which map to the social-emotional, the sensorimotor, the olfacto-gustatory, and the cognitive network of the brain. Sensorimotor tasks activated the mid-posterior and social-emotional tasks the anterior-ventral insula. In the central insula activation by olfacto-gustatory stimuli was found, and cognitive tasks elicited activation in the anterior-dorsal region. A conjunction analysis across these domains revealed that aside from basic somatosensory and motor processes all tested functions overlapped on the anterior-dorsal insula. This overlap might constitute a correlate for a functional integration between different functional systems and thus reflect a link between them necessary to integrate different qualities into a coherent experience of the world and setting the context for thoughts and actions.

The energetics of genome complexity

Abstract: All complex life is composed of eukaryotic (nucleated) cells. The eukaryotic cell arose from prokaryotes just once in four billion years, and otherwise prokaryotes show no tendency to evolve greater complexity. Why not? Prokaryotic genome size is constrained by bioenergetics. The endosymbiosis that gave rise to mitochondria restructured the distribution of DNA in relation to bioenergetic membranes, permitting a remarkable 200,000-fold expansion in the number of genes expressed. This vast leap in genomic capacity was strictly dependent on mitochondrial power, and prerequisite to eukaryote complexity: the key innovation en route to multicellular life.

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease

Abstract: Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.

Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: Implications for classification of gliomas

Abstract: WHO grading of human brain tumors extends beyond a strictly histological grading system by providing a basis predictive for the clinical behavior of the respective neoplasm. For example, patients with glioblastoma WHO grade IV usually show a less favorable clinical course and receive more aggressive first-line treatment than patients with anaplastic astrocytoma WHO grade III. Here we provide evidence that the IDH1 status is more prognostic for overall survival than standard histological criteria that differentiate high-grade astrocytomas. We sequenced the isocitrate dehydrogenase 1 gene (IDH1) at codon 132 in 382 patients with anaplastic astrocytoma and glioblastoma from the NOA-04 trial and from a prospective translational cohort study of the German Glioma Network. Patients with anaplastic astrocytomas carried IDH1 mutations in 60%, and patients with glioblastomas in 7.2%. IDH1 was the most prominent single prognostic factor (RR 2.7; 95% CI 1.6–4.5) followed by age, diagnosis and MGMT. The sequence from more favorable to poorer outcome was (1) anaplastic astrocytoma with IDH1 mutation, (2) glioblastoma with IDH1 mutation, (3) anaplastic astrocytoma without IDH1 mutation and (4) glioblastoma without IDH1 mutation (p < 0.0001). In this combined set of anaplastic astrocytomas and glioblastomas both, IDH1 mutation and IDH1 expression status were of greater prognostic relevance than histological diagnosis according to the current WHO classification system. Our data indicate that much of the prognostic significance of patient age is due to the predominant occurrence of IDH1 mutations in younger patients. Immunohistochemistry using a mutation-specific antibody recognizing the R132H mutation yielded similar results. We propose to complement the current WHO classification and grading of high-grade astrocytic gliomas by the IDH1 mutation status and to use this combined histological and molecular classification in future clinical trials.

Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene

Abstract: Germline mutations in a number of genes involved in the recombinational repair of DNA double-strand breaks are associated with predisposition to breast and ovarian cancer. RAD51C is essential for homologous recombination repair, and a biallelic missense mutation can cause a Fanconi anemia-like phenotype. In index cases from 1,100 German families with gynecological malignancies, we identified six monoallelic pathogenic mutations in RAD51C that confer an increased risk for breast and ovarian cancer. These include two frameshift-causing insertions, two splice-site mutations and two nonfunctional missense mutations. The mutations were found exclusively within 480 pedigrees with the occurrence of both breast and ovarian tumors (BC/OC; 1.3%) and not in 620 pedigrees with breast cancer only or in 2,912 healthy German controls. These results provide the first unambiguous evidence of highly penetrant mutations associated with human cancer in a RAD51 paralog and support the 'common disease, rare allele' hypothesis.

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

Abstract: The DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either up-front or at recurrence Standardization of MGMT testing requires comparison of different technologies across laboratories and prospectively validated cut-off values for prognostic or predictive effects Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice

Rodin: an open toolset for modelling and reasoning in Event-B

Abstract: Event-B is a formal method for system-level modelling and analysis. Key features of Event-B are the use of set theory as a modelling notation, the use of refinement to represent systems at different abstraction levels and the use of mathematical proof to verify consistency between refinement levels. In this article we present the Rodin modelling tool that seamlessly integrates modelling and proving. We outline how the Event-B language was designed to facilitate proof and how the tool has been designed to support changes to models while minimising the impact of changes on existing proofs. We outline the important features of the prover architecture and explain how well-definedness is treated. The tool is extensible and configurable so that it can be adapted more easily to different application domains and development methods.

EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs

Abstract: Objectives To develop recommendations for the diagnosis, prevention and treatment of neuropsychiatric systemic lupus erythematosus (NPSLE) manifestations. Methods The authors compiled questions on prevalence and risk factors, diagnosis and monitoring, therapy and prognosis of NPSLE. A systematic literature search was performed and evidence was categorised based on sample size and study design. Results Systemic lupus erythematosus (SLE) patients are at increased risk of several neuropsychiatric manifestations. Common (cumulative incidence >5%) manifestations include cerebrovascular disease (CVD) and seizures; relatively uncommon (1–5%) are severe cognitive dysfunction, major depression, acute confusional state (ACS), peripheral nervous disorders psychosis. Strong risk factors (at least fi vefold increased risk) are previous or concurrent severe NPSLE (for cognitive dysfunction, seizures) and antiphospholipid antibodies (for CVD, seizures, chorea). The diagnostic work-up of suspected NPSLE is comparable to that in patients without SLE who present with the same manifestations, and aims to exclude causes unrelated to SLE. Investigations include cerebrospinal fl uid analysis (to exclude central nervous system infection), EEG (to diagnose seizure disorder), neuropsychological tests (to assess cognitive dysfunction), nerve conduction studies (for peripheral neuropathy) and MRI (T1/T2, fl uid-attenuating inversion recovery, diffusion-weighted imaging, enhanced T1 sequence). Glucocorticoids and immunosuppressive therapy are indicated when NPSLE is thought to refl ect an infl ammatory process (optic neuritis, transverse myelitis, peripheral neuropathy, refractory seizures, psychosis, ACS) and in the presence of generalised lupus activity. Antiplatelet/anticoagulation therapy is indicated when manifestations are related to antiphospholipid antibodies, particularly thrombotic CVD. Conclusions Neuropsychiatric manifestations in SLE patients should be fievaluated and treated as in patients without SLE, and secondarily attributed to SLE and treated accordingly.

Fungal endophytes from higher plants: a prolific source of phytochemicals and other bioactive natural products

Abstract: Bioactive natural products from endophytic fungi, isolated from higher plants, are attracting considerable attention from natural product chemists and biologists alike as indicated by the steady increase of publications devoted to this topic during recent years (113 research articles on secondary metabolites from endophytic fungi in the period of 2008–2009, 69 in 2006–2007, 36 in 2004–2005, 14 in 2002–2003, and 18 in 2000–2001). This overview will highlight the chemical potential of endophytic fungi with focus on the detection of pharmaceutically valuable plant constituents, e.g. paclitaxel, camptothecin and podophyllotoxin, as products of fungal biosynthesis. In addition, it will cover new bioactive metabolites reported in recent years (2008–2009) from fungal endophytes of terrestrial and mangrove plants. The presented compounds are selected based on their antimicrobial, antiparasitic, cytotoxic as well as neuroprotective activities. Furthermore, possible factors influencing natural product production in endophytes cultivated in vitro and hence the success of bioprospecting from endophytes are likewise discussed in this review.

Molecular Poltergeists: Mitochondrial DNA Copies (numts) in Sequenced Nuclear Genomes

Abstract: The natural transfer of DNA from mitochondria to the nucleus generates nuclear copies of mitochondrial DNA (numts) and is an ongoing evolutionary process, as genome sequences attest. In humans, five different numts cause genetic disease and a dozen human loci are polymorphic for the presence of numts, underscoring the rapid rate at which mitochondrial sequences reach the nucleus over evolutionary time. In the laboratory and in nature, numts enter the nuclear DNA via non-homolgous end joining (NHEJ) at double-strand breaks (DSBs). The frequency of numt insertions among 85 sequenced eukaryotic genomes reveal that numt content is strongly correlated with genome size, suggesting that the numt insertion rate might be limited by DSB frequency. Polymorphic numts in humans link maternally inherited mitochondrial genotypes to nuclear DNA haplotypes during the past, offering new opportunities to associate nuclear markers with mitochondrial markers back in time.

Centenary of Brodmann's map--conception and fate.

Abstract: To celebrate the centenary of Brodmann's brain map, Zilles and Amunts review his pioneering work and its legacy. This article reconsiders the original concepts described by Brodmann and the use of his map for interpreting functional and structural neuroimaging data today. Rarely in the history of neuroscience has a single illustration been as influential as the cytoarchitectonic map of the human brain published by Korbinian Brodmann in his monograph from 1909. The map presents the segregation of the cerebral cortex into 43 areas, as visible in cell body-stained histological sections. More importantly, Brodmann provided a comparative neuroanatomical approach and discussed ontogenetic and pathological aspects as well as structural–functional correlations. One hundred years later, a large number of neuroscientists still use Brodmann's map for localizing neuroimaging data obtained in the living human brain.

A Within-Subject Analysis of Other-Regarding Preferences

Abstract: We assess the predictive power of a model of other-regarding preferences, inequality aversion, using a within-subjects design. We run four different experiments (ultimatum game, dictator game, sequential prisoner's dilemma and public-good game) with the same sample of subjects. From the data we estimate parameters of aversion to disadvantageous and advantageous inequality. We then use these estimates to test several hypotheses across games. Our data show that results from within-subject tests can differ markedly from aggregate-level analysis. The inequality-aversion model has predictive power at the aggregate level but performs less well at the individual level.

Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema

Abstract: BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

Facets of visual aesthetics

Abstract: Visual aesthetics has been shown to critically affect a variety of constructs such as perceived usability, satisfaction, and pleasure. Given the importance of visual aesthetics in human-computer interaction, it is vital that it is adequately assessed. The present research aimed at providing a precise operational definition and to develop a new measure of perceived visual aesthetics of websites. Construction of the Visual Aesthetics of Website Inventory (VisAWI) was based on a comprehensive and broad definition of visual aesthetics so that the resulting instrument would completely describe the domain of interest. Four interrelated facets of perceived visual aesthetics of websites were identified and validated in a series of seven studies. Simplicity and Diversity have repeatedly been treated as formal parameters of aesthetic objects throughout the history of empirical aesthetics, Colors are a critical property of aesthetic objects, and Craftsmanship addresses the skillful and coherent integration of the relevant design dimensions. These four facets jointly represent perceived visual aesthetics, but are still distinguishable from each other and carry unique meaning. The subscales contained in the VisAWI demonstrate good internal consistencies. Evidence for the convergent, divergent, discriminative, and concurrent validity of the VisAWI is provided. Overall, the present research suggests that the VisAWI appears to be a sound measure of visual aesthetics of websites comprising facets of both practical and theoretical interest.

A European Evidence-Based Guideline for the Prevention of Type 2 Diabetes

Abstract: BACKGROUND: The prevalence and socioeconomic burden of type 2 diabetes (T2DM) and associated co-morbidities are rising worldwide. AIMS: This guideline provides evidence-based recommendations for preventing T2DM. METHODS: A European multidisciplinary consortium systematically reviewed the evidence on the effectiveness of screening and interventions for T2DM prevention using SIGN criteria. RESULTS: Obesity and sedentary lifestyle are the main modifiable risk factors. Age and ethnicity are non-modifiable risk factors. Case-finding should follow a step-wise procedure using risk questionnaires and oral glucose tolerance testing. Persons with impaired glucose tolerance and/or fasting glucose are at high-risk and should be prioritized for intensive intervention. Interventions supporting lifestyle changes delay the onset of T2DM in high-risk adults (number-needed-to-treat: 6.4 over 1.8-4.6 years). These should be supported by inter-sectoral strategies that create health promoting environments. Sustained body weight reduction by >or= 5 % lowers risk. Currently metformin, acarbose and orlistat can be considered as second-line prevention options. The population approach should use organized measures to raise awareness and change lifestyle with specific approaches for adolescents, minorities and disadvantaged people. Interventions promoting lifestyle changes are more effective if they target both diet and physical activity, mobilize social support, involve the planned use of established behaviour change techniques, and provide frequent contacts. Cost-effectiveness analysis should take a societal perspective. CONCLUSIONS: Prevention using lifestyle modifications in high-risk individuals is cost-effective and should be embedded in evaluated models of care. Effective prevention plans are predicated upon sustained government initiatives comprising advocacy, community support, fiscal and legislative changes, private sector engagement and continuous media communication.

Prevalence and Heterogeneity of KRAS, BRAF, and PIK3CA Mutations in Primary Colorectal Adenocarcinomas and Their Corresponding Metastases

Abstract: Purpose: Epidermal growth factor receptor (EGFR) antibody therapy is established in patients with wild-type KRAS colorectal carcinoma; however, up to 50% of these patients do not respond to this therapy. To identify the possible causes of this therapy failure, we searched for mutations in different EGFR-dependent signaling proteins and analyzed their distribution patterns in primary tumors and corresponding metastases. Experimental Design: Tumor tissues, macrodissected from tumor centers, invasion fronts ( n = 100), lymph nodes ( n = 55), and distant metastases ( n = 20), respectively, were subjected to DNA extraction and mutation analysis of KRAS, BRAF , and PIK3CA . Results: Activating mutations were detected in 41% ( KRAS ), 7% ( BRAF ), and 21% ( PIK3CA ) of the primary tumors. By comparing tumor centers and invasion fronts, the intratumoral heterogeneity of KRAS, BRAF , and PIK3CA mutations was observed in 8%, 1%, and 5% of primary tumors, respectively. Heterogeneity between primary tumors and lymph node metastases was found in 31% ( KRAS ), 4% ( BRAF ), and 13% ( PIK3CA ) of the cases. Heterogeneity between primary tumors and distant metastases was present in two patients (10%) for KRAS and one patient for PIK3CA (5%), but not for BRAF . Discordant results between primary tumors and metastases could markedly be reduced by testing the additional tumor samples. Conclusions: Failure of EGFR antibody therapy in patients with wild-type KRAS colorectal cancer may result from activating BRAF or PIK3CA mutations and false-negative sequencing results caused by intratumoral heterogeneity. Due to the particularly high rates of heterogeneity between primary tumors and lymph node metastases, the latter are least suitable for diagnostic mutation analysis. Clin Cancer Res; 16(3); 790–9

A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2α

Abstract: Glioma growth and progression depend on a specialized subpopulation of tumour cells, termed tumour stem cells. Thus, tumour stem cells represent a critical therapeutic target, but the molecular mechanisms that regulate them are poorly understood. Hypoxia plays a key role in tumour progression and in this study we provide evidence that the hypoxic tumour microenvironment also controls tumour stem cells. We define a detailed molecular signature of tumour stem cell genes, which are overexpressed by tumour cells in vascular and perinecrotic/hypoxic niches. Mechanistically, we show that hypoxia plays a key role in the regulation of the tumour stem cell phenotype through hypoxia-inducible factor 2α and subsequent induction of specific tumour stem cell signature genes, including mastermind-like protein 3 (Notch pathway), nuclear factor of activated T cells 2 (calcineurin pathway) and aspartate beta-hydroxylase domain-containing protein 2. Notably, a number of these genes belong to pathways regulating the stem cell phenotype. Consistently, tumour stem cell signature genes are overexpressed in newly formed gliomas and are associated with worse clinical prognosis. We propose that tumour stem cells are maintained within a hypoxic niche, providing a functional link between the well-established role of hypoxia in stem cell and tumour biology. The identification of molecular regulators of tumour stem cells in the hypoxic niche points to specific signalling mechanisms that may be used to target the glioblastoma stem cell population.

β-Carotene Is an Important Vitamin A Source for Humans

Abstract: Experts in the field of carotenoids met at the Hohenheim consensus conference in July 2009 to elucidate the current status of β-carotene research and to summarize the current knowledge with respect to the chemical properties, physiological function, and intake of β-carotene. The experts discussed 17 questions and reached an agreement formulated in a consensus answer in each case. These consensus answers are based on published valid data, which were carefully reviewed by the individual experts and are justified here by background statements. Ascertaining the impact of β-carotene on the total dietary intake of vitamin A is complicated, because the efficiency of conversion of β-carotene to retinol is not a single ratio and different conversion factors have been used in various surveys and following governmental recommendations within different countries. However, a role of β-carotene in fulfilling the recommended intake for vitamin A is apparent from a variety of studies. Thus, besides elucidating the various functions, distribution, and uptake of β-carotene, the consensus conference placed special emphasis on the provitamin A function of β-carotene and the role of β-carotene in the realization of the required/recommended total vitamin A intake in both developed and developing countries. There was consensus that β-carotene is a safe source of vitamin A and that the provitamin A function of β-carotene contributes to vitamin A intake.

Circulating microRNAs as blood-based markers for patients with primary and metastatic breast cancer

Abstract: Introduction MicroRNAs (miRs) are interesting new diagnostic targets that may provide important insights into the molecular pathogenesis of breast cancer. Here we evaluated, for the first time, the feasibility and clinical utility of circulating miRs as biomarkers for the detection and staging of breast cancer.

Mutation of the RAD51C gene in a Fanconi anemia-like disorder

Abstract: Fanconi anemia (FA) is a rare chromosomal-instability disorder associated with a variety of developmental abnormalities, bone marrow failure and predisposition to leukemia and other cancers. We have identified a homozygous missense mutation in the RAD51C gene in a consanguineous family with multiple severe congenital abnormalities characteristic of FA. RAD51C is a member of the RAD51-like gene family involved in homologous recombination-mediated DNA repair. The mutation results in loss of RAD51 focus formation in response to DNA damage and in increased cellular sensitivity to the DNA interstrand cross-linking agent mitomycin C and the topoisomerase-1 inhibitor camptothecin. Thus, biallelic germline mutations in a RAD51 paralog are associated with an FA-like syndrome.

Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study

Abstract: The diagnostic reliability of skin biopsy in small fiber neuropathy depends on the availability of normative reference values We performed a multicenter study to assess the normative values of intraepidermal nerve fiber (IENF) density at distal leg stratified by age deciles Eight skin biopsy laboratories from Europe, USA, and Asia submitted eligible data Inclusion criteria of raw data were healthy subjects 18 years or older; known age and gender; 3-mm skin biopsy performed 10-cm above the lateral malleolus; bright-field immunohistochemistry protocol, and quantification of linear IENF density in three 50-µm sections according to published guidelines Data on height and weight were recorded, and body mass index (BMI) was calculated in subjects with both available data Normative IENF density reference values were calculated through quantile regression analysis; influence of height, weight, or BMI was determined by regression analyses IENF densities from 550 participants (285 women, 265 men) were pooled We found a significant age-dependent decrease of IENF density in both genders (women p < 0001; men p = 0002) Height, weight, or BMI did not influence the calculated 5th percentile IENF normative densities in both genders Our study provides IENF density normative reference values at the distal leg to be used in clinical practice

Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease.

Abstract: We report the 5 to 6 year follow-up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinson's disease (PD) patients. Thirty-live STN patients and 16 GPi patienis were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinson's Disease Rating Scale (UPDRS) assessed with a prospective cross-over double-blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off- and on-medication states with and without stimulation, activities of daily living (ADL), anti-PD medications, and dyskinesias. In double-blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN. P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with of regardless of the sequence of stimulation. In open assessment. both STN- and GPi-DBS significantly improved the off-medication motor UPDRS when compared with before surgery (STN. P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti-PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long-term efficacy of STN and GPi DBS advanced PD. Although the surgical targets were not randomized, there was a trend to 1 better outcome of motor signs in the STN-DBS patients and fewer adverse events in the GPi-DBS group. (C) 2010 Movement Disorder Society