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There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

GLPG1972/S201086 is a disintegrin and metalloproteinase with thrombospondin motif-5 (ADAMTS-5) inhibitor in development as an osteoarthritis disease-modifying therapy. We report the safety, tolerability, pharmacokinetics, and pharmacodynamics (turnover of plasma/serum ARGS-aggrecan neoepitope fragments [ARGS]) of GLPG1972 in 3 randomized, double-blind, placebo-controlled phase 1 trials. Study A, a first-in-human trial of single (≤2100 mg [fasted] and 300 mg [fed]) and multiple (≤1050 mg once daily [fed]; 14 days) ascending oral (solution) doses, investigated GLPG1972 in healthy men (N = 41; NCT02612246). Study B investigated multiple ascending oral (tablet) doses of GLPG1972 (≤300 mg once daily [fed]; 4 weeks) in male and female participants with osteoarthritis (N = 30; NCT03311009). Study C investigated single (Japanese: ≤1500 mg; White: 300 mg [fasted]) and multiple (Japanese, ≤1050 mg once daily; White, 300 mg once daily [fed]; 14 days) ascending oral (tablet) doses of GLPG1972 in healthy Japanese and White men (N = 88). The pharmacokinetic profile of GLPG1972 was similar between healthy participants and participants with osteoarthritis, with low to moderate interindividual variability. GLPG1972 was rapidly absorbed (median time to maximum concentration, 4 hours), and eliminated with a mean apparent terminal elimination half-life of ≈10 hours. Steady state was achieved within 2 days of dosing, with minimal accumulation. Steady-state plasma exposure after 300 mg of GLPG1972 showed no or minor differences between populations. Area under the plasma concentration-time curve (56.8-67.6 μg · h/mL) and time to maximum concentration (4 hours) were similar between studies. Urinary excretion of GLPG1972 (24 hours) was low (

Purpose Noninvasive prenatal screening (NIPS) using cell-free DNA has transformed prenatal care. Belgium was the first country to implement and fully reimburse NIPS as a first-tier screening test offered to all pregnant women. A consortium consisting of all Belgian genetic centers report the outcome of two years genome-wide NIPS implementation. Methods The performance for the common trisomies and for secondary findings was evaluated based on 153,575 genome-wide NIP tests. Furthermore, the evolution of the number of invasive tests and the incidence of Down syndrome live births was registered. Results Trisomies 21, 18, and 13 were detected in respectively 0.32%, 0.07%, and 0.06% of cases, with overall positive predictive values (PPVs) of 92.4%, 84.6%, and 43.9%. Rare autosomal trisomies and fetal segmental imbalances were detected in respectively 0.23% and 0.07% of cases with PPVs of 4.1% and 47%. The number of invasive obstetric procedures decreased by 52%. The number of trisomy 21 live births dropped to 0.04%. Conclusion Expanding the scope of NIPS beyond trisomy 21 fetal screening allows the implementation of personalized genomic medicine for the obstetric population. This genome-wide NIPS approach has been embedded successfully in prenatal genetic care in Belgium and might serve as a framework for other countries offering NIPS.

GLPG1690 is a novel autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis (IPF). We report phase 1 studies investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GLPG1690 in healthy subjects. We performed a first‐in‐human randomized, double‐blind, placebo‐controlled trial of single (20, 60, 150, 300, 600, 1000, 1500 mg) and multiple (14 days: 150 mg twice daily; 600 and 1000 mg once daily) ascending oral doses of GLPG1690 ({"type":"clinical-trial","attrs":{"text":"NCT02179502","term_id":"NCT02179502"}}NCT02179502), and a randomized, open‐label, crossover relative bioavailability study to compare the PK of tablet and capsule formulations of GLPG1690 600 mg and to assess the effect of food on PK of the tablet formulation ({"type":"clinical-trial","attrs":{"text":"NCT03143712","term_id":"NCT03143712"}}NCT03143712). Forty and 13 subjects were randomized in the first‐in‐human and relative bioavailability studies, respectively. GLPG1690 was well tolerated, with no dose‐limiting toxicity at all single and multiple doses. GLPG1690 was rapidly absorbed and eliminated, with a median tmax and mean t1/2 of approximately 2 and 5 hours, respectively. GLPG1690 exposure increased with increasing dose (mean Cmax, 0.09‐19.01 µg/mL; mean AUC0‐inf, 0.501‐168 µg·h/mL, following single doses of GLPG1690 20‐1500 mg). PD response, evidenced by rapid reduction in plasma lysophosphatidic acid (LPA) C18:2 levels, increased with increasing GLPG1690 plasma levels, plateauing at approximately 80% reduction in LPA C18:2 at around 0.6 µg/mL GLPG1690. Tablet and capsule formulations had similar PK profiles, and no clinically significant food effect was observed when comparing tablets taken in fed and fasted states. The safety, tolerability, and PK/PD profiles of GLPG1690 support continued clinical development for IPF.

OBJECTIVE: To evaluate the accuracy and diagnostic value of genome-wide noninvasive prenatal testing (NIPT) for the detection of fetal aneuploidies in multiple gestations, with a focus on dichorionic-diamniotic twin pregnancies. METHODS: We performed a retrospective cohort study including data from pregnant women with a twin or higher-order gestation who underwent genome-wide NIPT at one of the eight Belgian genetic centers between November 1, 2013, and March 1, 2020. Chorionicity and amnionicity were determined by ultrasonography. Follow-up invasive testing was carried out in the event of positive NIPT results. Sensitivity and specificity were calculated for the detection of trisomy 21, 18, and 13 in the dichorionic-diamniotic twin cohort. RESULTS: Unique NIPT analyses were performed for 4,150 pregnant women with a multiple gestation and an additional 767 with vanishing gestations. The failure rate in multiple gestations excluding vanishing gestations ranged from 0% to 11.7% among the different genetic centers. Overall, the failure rate was 4.8%, which could be reduced to 1.2% after single resampling. There were no common fetal trisomies detected among the 86 monochorionic-monoamniotic and 25 triplet cases. Two monochorionic-diamniotic twins had an NIPT result indicative of a trisomy 21, which was confirmed in both fetuses. Among 2,716 dichorionic-diamniotic twin gestations, a sensitivity of 100% (95% CI 74.12-100%) and a specificity of 100% (95% CI 99.86-100%) was reached for trisomy 21 (n=12). For trisomy 18 (n=3), the respective values were 75% (95% CI 30.06-95.44%) sensitivity and 100% (95% CI 99.86-100%) specificity, and for trisomy 13 (n=2), 100% (95% CI 20.65-100%) sensitivity and 99.96% (95% CI 99.79-99.99%) specificity. In the vanishing gestation group, 28 NIPT results were positive for trisomy 21, 18, or 13, with only five confirmed trisomies. CONCLUSION: Genome-wide NIPT performed accurately for detection of aneuploidy in dichorionic-diamniotic twin gestations.

The 6-min walk test (6MWT) is an important measure of functional capacity in idiopathic pulmonary fibrosis (IPF) and has been an endpoint of several IPF clinical trials. However, current guidance for the 6MWT offers insufficient advice on standardization, particularly oxygen supplementation, for clinical trials. Three physicians experienced with the 6MWT and IPF developed a standardized protocol for the 6MWT based on existing clinical guidelines and published literature. The protocol comprises guidance on test conditions, pre-defined parameters to measure at specified timepoints, and step-by-step instructions on conducting the test. The standardized test will be evaluated in the large-scale phase 3 ISABELA trials ( NCT03711162 ; NCT03733444 ). The test is conducted indoors, using standardized equipment, along a flat, straight, 30-m unobstructed corridor; tests for each individual are performed by the same administrators at the same time of day; warm-up prior to testing is prohibited; supplemental oxygen tanks are permitted and moved by the patient in the same manner for each test; precise wording is used to instruct and encourage patients. Contraindications and stopping criteria are specified. Key assessments include: 6-min walk distance, distance walked at 1 and 3 min, the Borg CR10 scale, heart rate, blood pressure, and oxygen desaturation levels. A standardized 6MWT for IPF will enable more reliable comparisons between clinical trials and limit variability, optimizing use as an endpoint. Application of the standardized 6MWT in the ISABELA program will allow its correlation with other clinically important endpoints and may lead to novel composite endpoints for use in future trials. Submission category: Study Design, Statistical Design, Study Protocols. Submission classifications: Clinical study methodology; Clinical trial design; Clinical trials; Pulmonary disease; Pulmonary disease clinical trial; Respiratory medicine.

BACKGROUND Chronic lung allograft dysfunction (CLAD) is the leading cause of mortality in lung transplant recipients. CLAD is characterized by respiratory failure owing to the accumulation of fibrotic cells in small airways and alveoli, inducing tissue contraction and architectural destruction. However, the source of the fibroblastic cells and the mechanism(s) underlying the accumulation and activation remain unexplained. Mesenchymal stromal cells (MSCs) are multipotent progenitors that are normally located in the lung tissue but can be isolated from the alveolar space in lung transplant recipients, where they have a profibrotic phenotype. Our objective was to identify the mediator(s) inducing migration and contractile differentiation of lung tissue MSCs. METHODS Bronchoalveolar lavage (BAL) (7 healthy controls and 21 lung transplant recipients), CCL2, HGF, TGFB, EGF, and PDGF-BB and autotaxin were measured by enzyme-linked immunosorbent assay. BAL (7 healthy controls and 31 lung transplant recipients) lysophosphatidic acid (LPA) (16:0, 18:0, 18:1, 22:4) was measured by liquid chromatography with tandem mass spectrometry. The effect of inhibition of candidate mediators on BAL-mediated chemoattraction of MSCs and contraction of MSC-spiked collagen gel assays was assessed. BAL cells from a lung transplant recipient with CLAD were analyzed by single-cell RNA sequencing. RESULTS We first demonstrate that BAL fluid from lung transplant recipients and particularly those with CLAD is potently chemoattractive to human lung tissue‒derived MSCs and induces a contractile phenotype. After excluding several candidate mediators, we show that LPA blockade completely abrogated transplant recipient BAL‒mediated chemoattraction of MSCs and contraction of MSC-spiked collagen gels. Furthermore, LPA levels were enriched in transplant recipient BAL, and LPA replicated the observed in vitro profibrotic effects of transplant recipient BAL. Finally, we identify BAL monocyte‒derived macrophages with autotaxin (ENPP2) and fibrotic transcriptional signature. CONCLUSIONS Autotaxin-expressing alveolar macrophages are present in CLAD BAL. These cells potentially provide a local source of autotaxin/LPA that drives MSC recruitment and tissue contraction in CLAD. These cells are analogous to an aberrant macrophage population recently identified in idiopathic pulmonary fibrosis, suggesting an overlap in pathogenesis between CLAD and other forms of lung fibrosis.

OBJECTIVE: Belgian genetic centers established a database containing data on all chromosomal microarrays (CMA) performed in a prenatal context. A study was initiated to evaluate postnatal development in children diagnosed prenatally with a non-benign copy number variant (CNV). METHODS: All children diagnosed with a prenatally detected non-benign CNV in a Belgian genetic center between May 2013 and February 2015 were included in the patient population. The control population consisted of children who had undergone an invasive procedure during pregnancy, with no or only benign CNVs. Child development was evaluated at 36 months using three (3) questionnaires: Ages and Stages Questionnaire Third edition, Ages and Stages Questionnaire Social-Emotional Second Edition and a general questionnaire. RESULTS: A significant difference in communication and personal-social development was detected between children with a reported susceptibility CNV and both children with an unreported susceptibility CNV and the control population. The outcome of children with a particular CNV is discussed in a case-by-case manner. CONCLUSION: Our postnatal follow-up project of children with a prenatally detected non-benign CNV is the first nationwide project of its kind. A higher number of cases for each CNV category is however needed to confirm our findings.

OBJECTIVE: With the replacement of karyotyping by chromosomal microarray (CMA) in invasive prenatal diagnosis, new challenges have arisen. By building a national database, we standardize the classification and reporting of prenatally detected copy number variants (CNVs) across Belgian genetic centers. This database, which will link genetic and ultrasound findings with postnatal development, forms a unique resource to investigate the pathogenicity of variants of uncertain significance and to refine the phenotypic spectrum of pathogenic and susceptibility CNVs. METHODS: The Belgian MicroArray Prenatal (BEMAPRE) consortium is a collaboration of all genetic centers in Belgium. We collected data from all invasive prenatal procedures performed between May 2013 and July 2016. RESULTS: In this three-year period, 13 266 prenatal CMAs were performed. By national agreement, a limited number of susceptibility CNVs and no variants of uncertain significance were reported. Added values for using CMA versus conventional karyotyping were 1.8% in the general invasive population and 2.7% in cases with an ultrasound anomaly. Of the reported CNVs, 31.5% would have remained undetected with non-invasive prenatal test as the first-tier test. CONCLUSION: The establishment of a national database for prenatal CNV data allows for a uniform reporting policy and the investigation of the prenatal and postnatal genotype-phenotype correlation. ispartof: PRENATAL DIAGNOSIS vol:38 issue:13 pages:1120-1128 ispartof: location:England status: published

Background and Objectives GLPG1690 is an autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis. Several publications suggested a role of autotaxin in the control of disease-affected lung function and of lysophosphatidic acid in lung remodeling processes. The aim of the current article was to describe the exposure–response relationship of GLPG1690 and further develop a rational basis to support dose selection for clinical trials in patients with idiopathic pulmonary fibrosis. Methods Two trials were conducted in healthy volunteers: in the first trial, GLPG1690 was administered as single doses from 20 mg up to 1500 mg, and subsequently in multiple daily doses of 300–1000 mg. In a second trial, the interaction of rifampin with 600 mg of GLPG1690 was evaluated. A third trial was conducted in patients with idiopathic pulmonary fibrosis administered 600 mg of GLPG1690 once daily for 12 weeks. The exposure–response (lysophosphatidic acid C18:2 reduction) relationship of GLPG1690 was first described using non-linear mixed-effects modeling and the model was subsequently deployed to simulate a lysophosphatidic acid C18:2 reduction as a biomarker of autotaxin inhibition in the dose range from 50 to 1000 mg once or twice daily. Results The population pharmacokinetics and lysophosphatidic acid C18:2 response of GLPG1690 were adequately described by a combined population pharmacokinetic and pharmacokinetic/pharmacodynamic model. Dose, formulation, rifampin co-administration, health status (healthy volunteer vs. patient with idiopathic pulmonary fibrosis), and baseline lysophosphatidic acid C18:2 were identified as covariates in the model. The effect of dose on systemic clearance indicated that GLPG1690 followed a more than dose-proportional increase in exposure over the simulated dose range of 50–1000 mg once daily. Model-based simulations showed reductions in lysophosphatidic acid C18:2 of at least 80% with doses greater or equal to 200 mg once daily. Conclusion Based on these results, 200 and 600 mg once-daily doses were selected for future clinical trials in patients with idiopathic pulmonary fibrosis. Electronic supplementary material The online version of this article (10.1007/s40262-019-00755-3) contains supplementary material, which is available to authorized users.

IntroductionWhile current standard of care (SOC) for idiopathic pulmonary fibrosis (IPF) slows disease progression, prognosis remains poor. Therefore, an unmet need exists for novel, well-tolerated agents that reduce lung function decline and improve quality of life. Here we report the design of two phase III studies of the novel IPF therapy, GLPG1690.Methods and analysisTwo identically designed, phase III, international, randomised, double-blind, placebo-controlled, parallel-group, multicentre studies (ISABELA 1 and 2) were initiated in November 2018. It is planned that, in each study, 750 subjects with IPF will be randomised 1:1:1 to receive oral GLPG1690 600 mg, GLPG1690 200 mg or placebo, once daily, on top of local SOC, for at least 52 weeks. The primary endpoint is rate of decline of forced vital capacity (FVC) over 52 weeks. Key secondary endpoints are week 52 composite endpoint of disease progression or all-cause mortality (defined as composite endpoint of first occurrence of ≥10% absolute decline in per cent predicted FVC or all-cause mortality at week 52); time to first respiratory-related hospitalisation until end of study; and week 52 change from baseline in the St George’s Respiratory Questionnaire total score (a quality-of-life measure).Ethics and disseminationStudies will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication.Trial registration numbersNCT03711162; NCT03733444.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) causes irreversible loss of lung function. People with IPF have increased concentrations of autotaxin in lung tissue and lysophosphatidic acid (LPA) in bronchoalveolar lavage fluid and exhaled condensate. GLPG1690 (Galapagos, Mechelen, Belgium) is a novel, potent, selective autotaxin inhibitor with good oral exposure. We explored the effects of GLPG1690 in patients with IPF. METHODS: This was a randomised, double-blind, placebo-controlled phase 2a study done in 17 centres in Italy, Ukraine and the UK. Eligible patients were aged 40 years or older, non-smokers, not taking pirfenidone or nintedanib, and had a centrally confirmed diagnosis of IPF. We used a computer-generated randomisation schedule to assign patients 1:3 to receive placebo or 600 mg oral GLPG1690 once daily for 12 weeks. The primary outcomes were safety (adverse events), tolerability, pharmacokinetics, and pharmacodynamics. Spirometry was assessed as a secondary outcome. This trial is registered with ClinicalTrials.gov, number NCT02738801. FINDINGS: Between March 24, 2016, and May 2, 2017, 72 patients were screened., of whom 49 were ineligible and 23 were enrolled in eight centres (six in Ukraine and two in the UK). Six patients were assigned to receive placebo and 17 to receive GLPG1690. 20 patients completed the study after one in each group discontinued because of adverse events and one in the GLPG1690 group withdrew consent. Four (67%) patients in the placebo group and 11 (65%) in the GLPG1690 group had treatment-emergent adverse events, most of which were mild to moderate. The most frequent events in the GLPG1690 group were infections and infestations (ten events) and respiratory, thoracic, and mediastinal disorders (eight events) with no apparent differences from the placebo group. Two (12%) patients in the GLPG1690 group had events that were judged to be related to treatment. Serious adverse events were seen in two patients in the placebo group (one had a urinary tract infection, acute kidney injury, and lower respiratory tract infection and the other had atrioventricular block, second degree) and one in the GLPG1690 group (cholangiocarcinoma that resulted in discontinuation of treatment). No patients died. The pharmacokinetic and pharmacodynamic profiles of GLPG1690 were similar to those previously shown in healthy controls. LPA C18:2 concentrations in plasma were consistently decreased. Mean change from baseline in forced vital capacity at week 12 was 25 mL (95% CI -75 to 124) for GLPG1690 and -70 mL (-208 to 68 mL) for placebo. INTERPRETATION: Our findings support further development of GLPG1690 as a novel treatment for IPF. FUNDING: Galapagos. ispartof: LANCET RESPIRATORY MEDICINE vol:6 issue:8 pages:627-635 ispartof: location:England status: published

Many Belgian postgraduate students in occupational medicine already work in the field although they have had little training or experience. To direct their learning in line with professional needs, an interactive web-based program was developed and evaluated. On-line multiple-choice questions and real-life cases were used as an add-on to the master course in occupational medicine. Students' perceptions were obtained by questionnaire. Trainees felt that the multiple-choice questions with immediate feedback and automatic scoring increased their factual knowledge. The case studies were well received because they were realistic and of appropriate difficulty level. Students preferred the combination of face-to-face teaching and e-learning to a whole course online and were in favor of more active communication between teachers and users. These findings may inform further collaborative developments in educational technology in occupational health.

Background Although the throughput of next generation sequencing is increasing and at the same time the cost is substantially reduced, for the majority of laboratories whole genome sequencing of large cohorts of cancer samples is still not feasible. In addition, the low number of genomes that are being sequenced is often problematic for the downstream interpretation of the significance of the variants. Targeted resequencing can partially circumvent this problem; by focusing on a limited number of candidate cancer genes to sequence, more samples can be included in the screening, hence resulting in substantial improvement of the statistical power. In this study, a successful strategy for prioritizing candidate genes for targeted resequencing of cancer genomes is presented. Results Four prioritization strategies were evaluated on six different cancer types: genes were ranked using these strategies, and the positive predictive value (PPV) or mutation rate within the top-ranked genes was compared to the baseline mutation rate in each tumor type. Successful strategies generate gene lists in which the top is enriched for known mutated genes, as evidenced by an increase in PPV. A clear example of such an improvement is seen in colon cancer, where the PPV is increased by 2.3 fold compared to the baseline level when 100 top fitSNP genes are sequenced. Conclusions A gene prioritization strategy based on the fitSNP scores appears to be most successful in identifying mutated cancer genes across different tumor entities, with variance of gene expression levels as a good second best.

Neuroblastoma is an aggressive embryonal tumor that accounts for similar to 15% of childhood cancer deaths. Hitherto, despite the availability of comprehensive genomic data on DNA copy number changes in neuroblastoma, relatively little is known about the genes driving neuroblastoma tumorigenesis. In this study, high resolution array comparative genome hybridization (CGH) was performed on 188 primary neuroblastoma tumors and 33 neuroblastoma cell lines to search for previously undetected recurrent DNA copy number gains and losses. A new recurrent distal chromosome 1q deletion (del(1)(q42.2qter)) was detected in seven cases. Further analysis of available array CGH datasets revealed 13 additional similar distal 1q deletions. The majority of all detected 1q deletions was found in high risk 11q deleted tumors without MYCN amplification (Fisher exact test p = 5.61 x 10-5). Using ultra-high resolution (similar to 115 bp resolution) custom arrays covering the breakpoints on 1q for 11 samples, clustering of nine breakpoints was observed within a 12.5-kb region, of which eight were found in a 7-kb copy number variable region, whereas the remaining two breakpoints were colocated 1.4-Mb proximal. The commonly deleted region contains one miRNA (hsa-mir-1537), four transcribed ultra conserved region elements (uc.43-uc.46) and 130 protein coding genes including at least two bona fide tumor suppressor genes, EGLN1 (or PHD2) and FH. This finding further contributes to the delineation of the genomic profile of aggressive neuroblastoma, offers perspectives for the identification of genes contributing to the disease phenotype and may be relevant in the light of assessment of response to new molecular treatments

Background : With one million new cases of colorectal cancer (CRC) diagnosed annually in the world, CRC is the third most commonly diagnosed cancer in the Western world. Patients with stage I-III CRC can be cured with surgery but are at risk for recurrence. Colorectal cancer is characterized by the presence of chromosomal deletions and gains. Large genomic profiling studies have however not been conducted in this disease. The number of a specific genetic aberration in a tumour sample could correlate with recurrence-free survival or overall survival, possibly leading to its use as biomarker for therapeutic decisions. At this point there are not sufficient markers for prediction of disease recurrence in colorectal cancer, which can be used in the clinic to discriminate between stage II patients who will benefit from adjuvant chemotherapy. For instance, the benefit of adjuvant chemotherapy has been most clearly demonstrated in stage III disease with an approximately 30 percent relative reduction in the risk of disease recurrence. The benefits of adjuvant chemotherapy in stage II disease are less certain, the risk for relapse is much smaller in the overall group and the specific patients at risk are hard to identify. Materials and Methods : In this study, array-comparative genomic hybridization analysis (array-CGH) was applied to study high-resolution DNA copy number alterations in 93 colon carcinoma samples. These genomic data were combined with parameters like KRAS mutation status, microsatellite status and clinicopathological characteristics. Results : Both large and small chromosomal losses and gains were identified in our sample cohort. Recurrent gains were found for chromosome 1q, 7, 8q, 13 and 20 and losses were mostly found for 1p, 4, 8p, 14, 15, 17p, 18, 21 and 22. Data analysis demonstrated that loss of chromosome 4 is linked to a worse prognosis in our patients series. Besides these alterations, two interesting small regions of overlap were identified, which could be associated with disease recurrence. Gain of the 16p13.3 locus (including the RNA binding protein, fox-1 homolog gene, RBFOX1) was linked with a worse recurrence-free survival in our patient cohort. On the other hand, loss of RBFOX1 was only found in patients without disease recurrence. Most interestingly, above mentioned characteristics were also found in stage II patients, for whom there is a high medical need for the identification of new prognostic biomarkers. Conclusions : In conclusion, copy number variation of the 16p13.3 locus seems to be an important parameter for prediction of disease recurrence in colon cancer.

Neuroblastoma is an embryonic tumor arising from immature sympathetic nervous system cells. Recurrent genomic alterations include MYCN and ALK amplification as well as recurrent patterns of gains and losses of whole or large partial chromosome segments. A recent whole genome sequencing effort yielded no frequently recurring mutations in genes other than those affecting ALK. However, the study further stresses the importance of DNA copy number alterations in this disease, in particular for genes implicated in neuritogenesis. Here we provide additional evidence for the importance of focal DNA copy number gains and losses, which are predominantly observed in MYCN amplified tumors. A focal 5 kb gain encompassing the MYCN regulated miR-17~92 cluster as sole gene was detected in a neuroblastoma cell line and further analyses of the array CGH data set demonstrated enrichment for other MYCN target genes in focal gains and amplifications. Next we applied an integrated genomics analysis to prioritize MYCN down regulated genes mediated by MYCN driven miRNAs within regions of focal heterozygous or homozygous deletion. We identified RGS5, a negative regulator of G-protein signaling implicated in vascular normalization, invasion and metastasis, targeted by a focal homozygous deletion, as a new MYCN target gene, down regulated through MYCN activated miRNAs. In addition, we expand the miR-17~92 regulatory network controlling TGFß signaling in neuroblastoma with the ring finger protein 11 encoding gene RNF11, which was previously shown to be targeted by the miR-17~92 member miR-19b. Taken together, our data indicate that focal DNA copy number imbalances in neuroblastoma (1) target genes that are implicated in MYCN signaling, possibly selected to reinforce MYCN oncogene addiction and (2) serve as a resource for identifying new molecular targets for treatment. © 2013 Kumps et al., SCOPUS: ar.j, info:eu-repo/semantics/published

Objectives: BELGICA-STROKE is a longitudinal study to enhance the use of online cardiovascular risk prediction scores based on the SCORE 10-year risk estimates for fatal cardiovascular disease (adapted for Belgium) and the Framingham 10-year stroke risk and to evaluate their impact on the cardiovascular risk profile of hypertensive patients. Methods and baseline characteristics are described here. Design: Prospective, multicenter study in primary care. Methods: General practitioners (N = 810) recruited consecutive hypertensive patients aged >40 years who were not at blood pressure goal and assessed them every 4 months. The estimated 10-year risks for fatal cardiovascular disease and stroke were available on a secured, specially designed study website. The calculated risk profile of a patient was modifiable by adding treatment goals in order to increase awareness and motivation of both physician and patient. An automated feedback on goal-level attainment and both cardiovascular risk scores was provided. Results: Mean age of the 15,744 patients was 66.3 years: 51.9% were men, 77.8% had excess weight, 19.4% were smokers, and 25.9% had diabetes. Left ventricle hypertrophy was present in 20.0%, atrial fibrillation in 5.8%. Mean blood pressure was 153.8/88.2 mmHg, mean cholesterol 211.5 mg/dl. Most patients (89.2%) received antihypertensive medication, of which 36.9% was monotherapy. Mean estimated 10-year stroke risk was 19.1%, and mean estimated 10-year fatal cardiovascular disease risk 5.9%. Conclusions: The 10-year estimated stroke and fatal cardiovascular disease risks were moderate to high in hypertensive patients not at goal blood pressure, emphasizing the importance of global cardiovascular risk factor assessment.

While a growing body of evidence implicates regulatory miRNA modules in various aspects of human disease and development, insights into specific miRNA function remain limited. Here, we present an innovative approach to elucidate tissue-specific miRNA functions that goes beyond miRNA target prediction and expression correlation. This approach is based on a multi-level integration of corresponding miRNA and mRNA gene expression levels, miRNA target prediction, transcription factor target prediction and mechanistic models of gene network regulation. Predicted miRNA functions were either validated experimentally or compared to published data. The predicted miRNA functions are accessible in the miRNA bodymap, an interactive online compendium and mining tool of high-dimensional newly generated and published miRNA expression profiles. The miRNA bodymap enables prioritization of candidate miRNAs based on their expression pattern or functional annotation across tissue or disease subgroup. The miRNA bodymap project provides users with a single one-stop data-mining solution and has great potential to become a community resource.