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.

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.

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.

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.

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/