Prevalence and risk factors of radial ray deficiencies: A population-based case-control study.

Radial ray deficiency is the most common congenital deficiency of the upper limb. The aim of our study was to investigate maternal risk factors for radial ray deficiencies. We conducted a nationwide population-based case-control study using national registers. All cases with a radial ray deficiency born between 1996 and 2008 were included in the study and compared with five controls without limb deficiency. In total, 115 (10 isolated, 18 with multiple congenital anomalies, and 87 syndromic) cases with radial ray deficiencies were identified and compared with 575 matched controls. The total prevalence in Finland was 1.22 per 10,000 births. No significant risk factors were observed for nonsyndromic cases. In the syndromic group, advanced maternal age (≥35 years) increased the risk of radial aplasia (aOR 2.45, 95% CI 1.37-4.36), and a similar association was observed with multiple pregnancy (aOR 2.97, 1.16-7.62) and male sex (aOR 1.96, 1.18-3.25). Valproic acid was also a risk factor (p = .002). In conclusion, novel associations in the syndromic group of advanced maternal age and multiple pregnancy and increased risk of radial ray deficiencies were observed. Also, early reports on increased risk of RRD associated with valproate and male sex were supported by our results.

Risk Factors and Prevalence of Limb Deficiencies Associated With Amniotic Band Sequence: A Population-based Case-control Study.

BACKGROUND: Limb deficiencies associated with amniotic bands comprise a wide range of congenital anomalies. The association of maternal medication and the risk of amniotic band sequence (ABS) has not yet been addressed. METHODS: This nationwide population-based case-control study used national registers on congenital anomalies, births and induced abortions, cross-linked with information on maternal prescription medicine use obtained from the registers on Reimbursed Drug Purchases and Medical Special Reimbursements. All cases with congenital limb deficiency associated with amniotic bands born between 1996 and 2008 were included in the study. Five controls without limb deficiency matched for residency and time of conception were randomly selected from the Medical Birth Register. RESULTS: In total, 106 children with limb deficiency associated with ABS were identified and compared with 530 matched controls. Young maternal age (less than 25 y) increased the risk of limb deficiencies [odds ratio=1.72; 95% confidence interval (CI): 1.06, 2.80]. Primiparity was also associated with increased risk [adjusted odds ratio (aOR)=2.42; 95% CI: 1.52, 3.88]. After adjusting for maternal age, pregestational diabetes, and parity, maternal use of beta-blockers (adjusted OR=24.2; 95% CI: 2.57, 228) and progestogens (adjusted OR=3.79; 95% CI: 1.38, 10.4) during the first trimester of pregnancy significantly increased the risk of limb deficiencies associated with amniotic bands. CONCLUSIONS: Primiparity significantly increased the risk of limb defects associated with amniotic bands. Also, a novel association on increased risk of ABS with maternal use of progestogens or beta-blockers during the first trimester of pregnancy was observed. LEVEL OF EVIDENCE: Level III.

Maternal hyperthyroidism and pregnancy outcomes: A population-based cohort study.

OBJECTIVE: Maternal hyperthyroidism and antithyroid medications have been associated with adverse pregnancy and perinatal outcomes. This nationwide register-based study investigated the association of maternal hyperthyroidism and antithyroid drug (ATD) use with pregnancy outcomes and included all singleton births in Finland between 2004 and 2013 (N = 571 785). DESIGN, PATIENTS AND MEASUREMENTS: Hyperthyroid mothers were identified in the Medical Birth Register, and data on ATD use before and/or during pregnancy were collected from the Prescription Register. The odds ratios, with 95% confidence intervals, for adverse outcomes among hyperthyroid mothers and mothers without thyroid disease were compared using logistic regression. RESULTS: In total, 2144 (0.37%) of all the women had diagnoses of hyperthyroidism, and 580 (27%) of these women had used ATDs before and/or during pregnancy. Compared to the mothers without thyroid disease, maternal hyperthyroidism was associated with older age, multiparity, smoking, previous miscarriages, and overweight or obesity. The mothers diagnosed with hyperthyroidism also had increased odds of gestational hypertensive disorders, caesarean sections, placental abruptions, preterm births, small-for-gestational-age newborns and neonatal intensive care unit treatment. The odds of pregnancy and/or perinatal complications were higher among those who had used ATDs (indicative of active disease), but those who had not received ATD treatment also had increased odds of such complications compared to the mothers without thyroid disease. CONCLUSIONS: Women with active hyperthyroidism and those with histories of hyperthyroidism should be considered at risk of developing pregnancy and perinatal complications and should therefore be monitored during pregnancy.

Placental transporter-mediated drug interactions and offspring congenital anomalies.

AIMS: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are efflux transporters expressed in the placenta, limiting their substrates from reaching the foetus. Our aim was to investigate if concomitant prenatal exposure to several substrates or inhibitors of these transporters increases the risk of congenital anomalies. METHODS: The national Drugs and Pregnancy database, years 1996-2014, was utilized in this population-based birth cohort study. In the database, the Medical Birth Register, the Register on Induced Abortions, the Malformation register and the Register on Reimbursed Drug Purchases have been linked. The University of Washington Metabolism and Transport Drug Interaction Database was used to identify substrates and inhibitors of P-gp and BCRP. We included singleton pregnancies ending in birth or elective termination of pregnancy due to foetal anomaly. Known teratogens were excluded. We identified women exposed 1 month before pregnancy or during the first trimester to P-gp/BCRP polytherapy (n = 21 186); P-gp/breast cancer resistance protein monotherapy (n = 97 906); non-P-gp/BCRP polytherapy (n = 78 636); and unexposed (n = 728 870). We investigated the association between the exposure groups and major congenital anomalies using logistic regression adjusting for several confounders. RESULTS: The prevalence of congenital anomalies was higher in the P-gp/BCRP polytherapy group (5.5%) compared to the P-gp/BCRP monotherapy (4.7%, OR 1.13; 95% CI 1.05-1.21), the non-P-gp/BCRP polytherapy (4.9%, OR 1.14; 95% CI 1.06-1.22), and to the unexposed groups (4.2%, OR 1.23; 95% CI 1.15-1.31). CONCLUSION: The results suggest a role of placental transporter-mediated drug interactions in teratogenesis.

Second-generation antipsychotics and pregnancy complications.

PURPOSE: To study if second-generation antipsychotic (S-GA) use during pregnancy is associated with an increased risk of pregnancy and neonatal complications. METHODS: A population-based birth cohort study using national register data extracted from the "Drugs and Pregnancy" database in Finland, years 1996-2016. The sampling frame included 1,181,090 pregnant women and their singleton births. Women were categorized into three groups: exposed to S-GAs during pregnancy (n = 4225), exposed to first-generation antipsychotics (F-GAs) during pregnancy (n = 1576), and unexposed (no purchases of S-GAs or F-GAs during pregnancy, n = 21,125). Pregnancy outcomes in S-GA users were compared with those in the two comparison groups using multiple logistic regression models. RESULTS: Comparing S-GA users with unexposed ones, the risk was increased for gestational diabetes (adjusted odds ratio, OR 1.43; 95% CI 1.25-1.65), cesarean section (OR 1.35; 95% CI 1.18-1.53), being born large for gestational age (LGA) (OR 1.57; 95% CI 1.14-2.16), and preterm birth (OR 1.29; 95% CI 1.03-1.62). The risk for these outcomes increased further with continuous S-GA use. Infants in the S-GA group were also more likely to suffer from neonatal complications. Comparing S-GA users with the F-GA group, the risk of cesarean section and LGA was higher (OR 1.25, 95% CI 1.03-1.51; and OR 1.89, 95% CI 1.20-2.99, respectively). Neonatal complications did not differ between the S-GA and F-GA groups. CONCLUSIONS: Prenatal exposure to S-GAs is associated with an increased risk of pregnancy complications related to impaired glucose metabolism. Neonatal problems are common and occur similarly in S-GA and F-GA users.

Anti-TNF treatment during pregnancy and birth outcomes: A population-based study from Denmark, Finland, and Sweden.

PURPOSE: To study the risk of preterm birth, caesarean section, and small for gestational age after anti-tumor necrosis factor agent treatment (anti-TNF) in pregnancy. METHODS: Population-based study including women with inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis, and their infants born 2006 to 2013 from the national health registers in Denmark, Finland, and Sweden. Women treated with anti-TNF were compared with women with nonbiologic systemic treatment. Adalimumab, etanercept, and infliximab were compared pairwise. Continuation of treatment in early pregnancy was compared with discontinuation. Odds ratios with 95% confidence intervals were calculated in logistic regression models adjusted for country and maternal characteristics. RESULTS: Among 1 633 909 births, 1027 infants were to women treated with anti-TNF and 9399 to women with nonbiologic systemic treatment. Compared with non-biologic systemic treatment, women with anti-TNF treatment had a higher risk of preterm birth, odds ratio 1.61 (1.29-2.02) and caesarean section, 1.57 (1.35-1.82). The odds ratio for small for gestational age was 1.36 (0.96-1.92). In pairwise comparisons, infliximab was associated with a higher risk of severely small for gestational age for inflammatory joint and skin diseases but not for inflammatory bowel disease. Discontinuation of anti-TNF had opposite effects on preterm birth for inflammatory bowel disease and inflammatory joint and skin diseases. CONCLUSIONS: Anti-TNF agents were associated with increased risks of preterm birth, caesarean section, and small for gestational age. However, the diverse findings across disease groups may indicate an association related to the underlying disease activity, rather than to agent-specific effects.

ß-Blocker Use in Pregnancy and the Risk for Congenital Malformations: An International Cohort Study.

Background: ß-Blockers are a class of antihypertensive medications that are commonly used in pregnancy. Objective: To estimate the risks for major congenital malformations associated with first-trimester exposure to ß-blockers. Design: Cohort study. Setting: Health registries in the 5 Nordic countries and the U.S. Medicaid database. Patients: Pregnant women with a diagnosis of hypertension and their offspring. Measurements: First-trimester exposure to ß-blockers was assessed. Outcomes were any major congenital malformation, cardiac malformations, cleft lip or palate, and central nervous system (CNS) malformations. Propensity score stratification was used to control for potential confounders. Results: Of 3577 women with hypertensive pregnancies in the Nordic cohort and 14 900 in the U.S. cohort, 682 (19.1%) and 1668 (11.2%), respectively, were exposed to ß-blockers in the first trimester. The pooled adjusted relative risk (RR) and risk difference per 1000 persons exposed (RD1000) associated with ß-blockers were 1.07 (95% CI, 0.89 to 1.30) and 3.0 (CI, -6.6 to 12.6), respectively, for any major malformation; 1.12 (CI, 0.83 to 1.51) and 2.1 (CI, -4.3 to 8.4) for any cardiac malformation; and 1.97 (CI, 0.74 to 5.25) and 1.0 (CI, -0.9 to 3.0) for cleft lip or palate. For CNS malformations, the adjusted RR was 1.37 (CI, 0.58 to 3.25) and the RD1000 was 1.0 (CI, -2.0 to 4.0) (based on U.S. cohort data only). Limitation: Analysis was restricted to live births, exposure was based on dispensed medication, and cleft lip or palate and CNS malformations had few outcomes. Conclusion: The results suggest that maternal use of ß-blockers in the first trimester is not associated with a large increase in the risk for overall malformations or cardiac malformations, independent of measured confounders. Primary Funding Source: The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Söderström König Foundation.

Dectin-1 pathway activates robust autophagy-dependent unconventional protein secretion in human macrophages.

Dectin-1 is a membrane-bound pattern recognition receptor for ß-glucans, which are the main constituents of fungal cell walls. Detection of ß-glucans by dectin-1 triggers an effective innate immune response. In this study, we have used a systems biology approach to provide the first comprehensive characterization of the secretome and associated intracellular signaling pathways involved in activation of dectin-1/Syk in human macrophages. Transcriptome and secretome analysis revealed that the dectin-1 pathway induced significant gene expression changes and robust protein secretion in macrophages. The enhanced protein secretion correlated only partly with increased gene expression. Bioinformatics combined with functional studies revealed that the dectin-1/Syk pathway activates both conventional and unconventional, vesicle-mediated, protein secretion. The unconventional protein secretion triggered by the dectin-1 pathway is dependent on inflammasome activity and an active autophagic process. In conclusion, our results reveal that unconventional protein secretion has an important role in the innate immune response against fungal infections.

Atomoxetine in Early Pregnancy and the Prevalence of Major Congenital Malformations: A Multinational Study.

Objective: Most research on safety of attention-deficit/hyperactivity disorder (ADHD) medications during pregnancy concerns central nervous system stimulants, while little is known about the safety of atomoxetine, a primary treatment alternative. We assessed the prevalence of major congenital malformations overall, and cardiac malformations and limb malformations specifically, after first-trimester exposure.Methods: In this cohort study, we included all approximately 2.4 million pregnancies ending in live births recorded in the population-based nationwide health registers of Denmark, Iceland, Norway, and Sweden (2003-2017) and approximately 1.8 million publicly insured pregnancies ending in live births recorded in the US Medicaid Analytic eXtract (MAX, 2001-2013) health care claims database. We compared the prevalence of major congenital malformations in the newborn among pregnancies exposed and unexposed to atomoxetine. For each country, we calculated prevalence ratios (PRs), crude and stratified by propensity scores (PSs). We pooled the country-specific PS strata to obtain a PR adjusted for potential confounding factors.Results: We identified 368 pregnancies exposed to atomoxetine during the first trimester in the 4 Nordic countries and 622 in the US. The pooled crude PR for any major congenital malformation was 1.18 (95% CI, 0.88-1.60), and the adjusted PR was 0.99 (95% CI, 0.74-1.34). For cardiac malformations, the adjusted PR was 1.34 (95% CI, 0.86-2.09). For limb malformations, the adjusted PR was 0.90 (95% CI, 0.38-2.16).Conclusions: After atomoxetine exposure in early pregnancy, we observed no increase in major congenital malformations overall and, although with some uncertainty due to sample size, no statistically increased risk estimates for cardiac malformations and limb malformations.

Integrated data management and validation platform for phosphorylated tandem mass spectrometry data.

MS/MS is a widely used method for proteome-wide analysis of protein expression and PTMs. The thousands of MS/MS spectra produced from a single experiment pose a major challenge for downstream analysis. Standard programs, such as MASCOT, provide peptide assignments for many of the spectra, including identification of PTM sites, but these results are plagued by false-positive identifications. In phosphoproteomic experiments, only a single peptide assignment is typically available to support identification of each phosphorylation site, and hence minimizing false positives is critical. Thus, tedious manual validation is often required to increase confidence in the spectral assignments. We have developed phoMSVal, an open-source platform for managing MS/MS data and automatically validating identified phosphopeptides. We tested five classification algorithms with 17 extracted features to separate correct peptide assignments from incorrect ones using over 2600 manually curated spectra. The naïve Bayes algorithm was among the best classifiers with an AUC value of 97% and PPV of 97% for phosphotyrosine data. This classifier required only three features to achieve a 76% decrease in false positives as compared with MASCOT while retaining 97% of true positives. This algorithm was able to classify an independent phosphoserine/threonine data set with AUC value of 93% and PPV of 91%, demonstrating the applicability of this method for all types of phospho-MS/MS data. PhoMSVal is available at http://csbi.ltdk.helsinki.fi/phomsval.

Pregnancy and Perinatal Outcome Among Hypothyroid Mothers: A Population-Based Cohort Study.

BACKGROUND: Maternal hypothyroidism has been associated with adverse pregnancy outcomes. A large nationwide register-based cohort with data on medication purchases was established to study the associations between maternal hypothyroidism, levothyroxine (LT4) use, and pregnancy and perinatal complications. METHODS: The data included all singleton births between 2004 and 2013 (N = 571,785) in Finland. Hypothyroid mothers (n = 16,364) were identified in the Finnish Medical Birth Register. Of these women, 95.8% used LT4 medication, and 37.5% had consistent LT4 use during pregnancy. Hypothyroid mothers were compared to mothers without thyroid disease (N = 550,860) using logistic regression. The main outcome measures were pregnancy and perinatal complications. RESULTS: Maternal hypothyroidism was associated with several pregnancy and perinatal complications, including gestational diabetes mellitus (odds ratio [OR] = 1.19 [confidence interval (CI) 1.13-1.25]), gestational hypertension (OR = 1.20 [CI 1.10-1.30]), severe preeclampsia (OR = 1.38 [CI 1.15-1.65]), cesarean section (OR = 1.22 [CI 1.17-1.27]), preterm births (OR = 1.25 [CI 1.16-1.34]), large-for-gestational age newborns (OR = 1.30 [CI 1.19-1.42]), major congenital anomalies (OR = 1.14 [CI 1.06-1.22]), and neonatal intensive care unit admission (OR = 1.23 [CI 1.17-1.29]). However, among mothers with consistent LT4 purchases, only the associations between gestational diabetes mellitus (OR = 1.12 [CI 1.03-1.22]), cesarean section (OR = 1.13 [CI 1.06-1.21]), neonatal intensive care unit admission (OR = 1.09 [CI 1.01-1.29]), and large-for-gestational age newborns (OR = 1.26 [CI 1.10-1.45]) and maternal hypothyroidism remained. CONCLUSIONS: Maternal hypothyroidism is associated with several pregnancy and perinatal complications, but consistent LT4 use may reduce many of the risks.

Maternal asthma is associated with increased risk of perinatal mortality.

BACKGROUND: Asthma is the most common chronic disease during pregnancy and it may have influence on pregnancy outcome. OBJECTIVES: Our goal was to assess the association between maternal asthma and the perinatal risks as well as possible effects of asthma medication. METHODS: The study was based on a nationwide Finnish register-based cohort between the years 1996 and 2012 in the Drug and Pregnancy Database. The register data comprised 962 405 singleton live and stillbirths, 898 333 (93.3%) pregnancies in mothers with neither confirmed asthma nor use of asthma medication (controls), and 26 674 (2.8%) pregnancies with confirmed maternal asthma. 71% of mothers with asthma used asthma medication. The diagnosis of asthma was based on the mothers' right for subsidised medication which is carefully evaluated by strict criteria including pulmonary function testing. Odds ratio was used in comparison. Premature birth (PB), low birth weight, small for gestational age (SGA), neonatal death were the main outcome measures. RESULTS: Maternal asthma was associated with adjusted odds ratios (aORs) for perinatal mortality 1.24 (95% CI 1.05 to 1.46), preterm birth 1.18 (1.11 to 1.25), low birth weight 1.29 (1.21 to 1.37), fetal growth restriction (SGA) 1.32, (1.24 to 1.40), and asphyxia 1.09 (1.02 to 1.17). Asthma treatment reduced the increased risk of preterm birth aOR 0.85 (95% CI 0.76 to 0.96) but mothers with treated asthma had higher risks of fetal growth restriction (SGA) aOR 1.26 (1.10 to 1.45), and asphyxia aOR 1.37 (1.17 to 1.61) than mothers with untreated asthma. CONCLUSION: Asthma is associated with increased risks of perinatal mortality, preterm birth, low birth weight, fetal growth restriction (SGA), and asphyxia. Asthma treatment reduces the risk of preterm delivery, but it does not seem to reduce other complications such as perinatal mortality.

Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital Malformations: A Cohort Study From the International Pregnancy Safety Study Consortium.

Importance: Given the rapidly increasing use of stimulant medications during pregnancy and among women of reproductive age who may become pregnant inadvertently, there is a need to better understand their safety. Objective: To examine the risk of congenital malformations associated with intrauterine exposure to stimulants. Design, Setting, and Participants: Cohort study of the Medicaid-insured population in the United States nested in the 2000-2013 US Medicaid Analytic eXtract, with follow-up of safety signals detected in the Medicaid Analytic eXtract data using the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden). A total of 1 813 894 publicly insured pregnancies in the United States and 2 560 069 singleton pregnancies in the 5 Nordic countries ending in live births were included. Relative risks were estimated accounting for underlying psychiatric disorders and other potential confounders. Relative risk estimates for the US and Nordic data were pooled using a fixed-effects meta-analytic approach. The study was conducted from July 1, 2015, to March 31, 2017. Exposures: Methylphenidate and amphetamines dispensed during the first trimester. Main Outcomes and Measures: Major congenital malformations and subgroup of cardiac malformations. Results: In the US data, of the 1 813 894 pregnancies evaluated, 35.0 per 1000 infants not exposed to stimulants were diagnosed as having congenital malformations, compared with 45.9 per 1000 infants for methylphenidate and 45.4 for amphetamines. For cardiac malformations, the risks were 12.7 (95% CI, 12.6-12.9), 18.8 (95% CI, 13.8-25.6), and 15.4 (95% CI, 12.5-19.0) per 1000 infants, respectively. The adjusted relative risks for methylphenidate were 1.11 (95% CI, 0.91-1.35) for any malformation and 1.28 (95% CI, 0.94-1.74) for cardiac malformations. No increased risks were observed for amphetamines: 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. Findings were confirmed in sensitivity analyses accounting for proxies of unmeasured confounders and increasing the specificity of the exposure and outcome definitions. Replication of the analyses for methylphenidate using the Nordic data including 2 560 069 pregnancies yielded a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations, resulting in a pooled estimate of 1.28 (95% CI, 1.00-1.64). Conclusions and Relevance: These findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy.

Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies.

OBJECTIVE: To test previous signals of a risk of orofacial cleft (OC) and clubfoot with exposure to the antiepileptic lamotrigine, and to investigate risk of other congenital anomalies (CA). METHODS: This was a population-based case-malformed control study based on 21 EUROCAT CA registries covering 10.1 million births (1995-2011), including births to 2005 in which the clubfoot signal was generated and a subsequent independent study population of 6.3 million births. A total of 226,806 babies with CA included livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. First-trimester lamotrigine monotherapy exposure in OC cases and clubfoot cases was compared to other nonchromosomal CA (controls). Odds ratios (OR) were adjusted for registry. An exploratory analysis compared the proportion of each standard EUROCAT CA subgroup among all babies with nonchromosomal CA exposed to lamotrigine monotherapy with non-AED exposed pregnancies. RESULTS: There were 147 lamotrigine monotherapy-exposed babies with nonchromosomal CA. For all OC, ORadj was 1.31 (95% confidence interval [CI] 0.73-2.33), isolated OC 1.45 (95% CI 0.80-2.63), isolated cleft palate 1.69 (95% CI 0.69-4.15). Overall ORadj for clubfoot was 1.83 (95% CI 1.01-3.31) and 1.43 (95% CI 0.66-3.08) in the independent study population. No other specific CA were significantly associated with lamotrigine monotherapy. CONCLUSIONS: The risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.

Phosphoprotein profiling predicts response to tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients.

Tyrosine kinase inhibitors (TKIs) have dramatically improved treatment outcomes in chronic myeloid leukemia (CML), but a proportion of patients fail to achieve optimal molecular response. By using a phosphoproteomic approach, we aimed to discover aberrant signaling pathways and putative biomarkers in bone marrow samples of suboptimally responding patients, which could be used to guide treatment selection at the diagnosis. The study consisted of 20 chronic-phase CML patients (10 optimal and 10 suboptimal response patients based on 18 months European-Leukemia-Net criteria) and healthy bone marrow cells, and CML cell lines were used as controls. The phosphorylation profile of normal bone marrow cells diverged from CML patients expectedly but, interestingly, CML cell lines (such as K562) also showed marked difference with primary CML cells. Several phosphoproteins were elevated in suboptimal patients compared to optimal response group. Most prominent differences were seen in signal transducers and activators of transcription 5b, phospholipase C γ-1, proline-rich tyrosine kinase 2, Hck, and Paxillin. These phosphoproteins were also increased in three additional nonresponder patients studied, but each of them also had unique phosphorylation patterns, such as highly active HSP27 protein in one patient. In conclusion, suboptimal imatinib response is related to increased phosphorylation of several proteins at diagnosis, which might guide the selection of TKI therapy. Furthermore, the activation of additional BCR-ABL-independent pathways in nonresponder patients (such as the anti-apoptotic HSP27 pathway) may reveal novel therapy targets.

Large-scale data integration framework provides a comprehensive view on glioblastoma multiforme.

BACKGROUND: Coordinated efforts to collect large-scale data sets provide a basis for systems level understanding of complex diseases. In order to translate these fragmented and heterogeneous data sets into knowledge and medical benefits, advanced computational methods for data analysis, integration and visualization are needed. METHODS: We introduce a novel data integration framework, Anduril, for translating fragmented large-scale data into testable predictions. The Anduril framework allows rapid integration of heterogeneous data with state-of-the-art computational methods and existing knowledge in bio-databases. Anduril automatically generates thorough summary reports and a website that shows the most relevant features of each gene at a glance, allows sorting of data based on different parameters, and provides direct links to more detailed data on genes, transcripts or genomic regions. Anduril is open-source; all methods and documentation are freely available. RESULTS: We have integrated multidimensional molecular and clinical data from 338 subjects having glioblastoma multiforme, one of the deadliest and most poorly understood cancers, using Anduril. The central objective of our approach is to identify genetic loci and genes that have significant survival effect. Our results suggest several novel genetic alterations linked to glioblastoma multiforme progression and, more specifically, reveal Moesin as a novel glioblastoma multiforme-associated gene that has a strong survival effect and whose depletion in vitro significantly inhibited cell proliferation. All analysis results are available as a comprehensive website. CONCLUSIONS: Our results demonstrate that integrated analysis and visualization of multidimensional and heterogeneous data by Anduril enables drawing conclusions on functional consequences of large-scale molecular data. Many of the identified genetic loci and genes having significant survival effect have not been reported earlier in the context of glioblastoma multiforme. Thus, in addition to generally applicable novel methodology, our results provide several glioblastoma multiforme candidate genes for further studies.Anduril is available at http://csbi.ltdk.helsinki.fi/anduril/The glioblastoma multiforme analysis results are available at http://csbi.ltdk.helsinki.fi/anduril/tcga-gbm/