A Computational Approach to Analyze the Mechanism of Action of the Kinase Inhibitor Bafetinib

Prediction of drug action in human cells is a major challenge in biomedical research. Additionally, there is strong interest in finding new applications for approved drugs and identifying potential side effects. We present a computational strategy to predict mechanisms, risks and potential new domains of drug treatment on the basis of target profiles acquired through chemical proteomics. Functional protein-protein interaction networks that share one biological function are constructed and their crosstalk with the drug is scored regarding function disruption. We apply this procedure to the target profile of the second-generation BCR-ABL inhibitor bafetinib which is in development for the treatment of imatinib-resistant chronic myeloid leukemia. Beside the well known effect on apoptosis, we propose potential treatment of lung cancer and IGF1R expressing blast crisis

Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma

<p>Abstract</p> <p>Background</p> <p>Allergic rhinitis (AR) affects up to 80% of children with asthma and increases asthma severity. Thymic stromal lymphopoietin (TSLP) is a key mediator of allergic inflammation. The role of the TSLP gene (<it>TSLP</it>) in the pathogenesis of AR has not been studied.</p> <p>Objective</p> <p>To test for associations between variants in <it>TSLP</it>, <it>TSLP</it>-related genes, and AR in children with asthma.</p> <p>Methods</p> <p>We genotyped 15 single nucleotide polymorphisms (SNPs) in <it>TSLP, OX40L, IL7R</it>, and <it>RXRα </it>in three independent cohorts: 592 asthmatic Costa Rican children and their parents, 422 nuclear families of North American children with asthma, and 239 Swedish children with asthma. We tested for associations between these SNPs and AR. As we previously reported sex-specific effects for <it>TSLP</it>, we performed overall and sex-stratified analyses. We additionally performed secondary analyses for gene-by-gene interactions.</p> <p>Results</p> <p>Across the three cohorts, the T allele of <it>TSLP </it>SNP rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone. The SNP was associated with reduced odds for AR (odds ratios ranging from 0.56 to 0.63, with corresponding Fisher's combined P value of 1.2 × 10^-4). Our findings were significant after accounting for multiple comparisons. SNPs in <it>OX40L, IL7R</it>, and <it>RXRα </it>were not consistently associated with AR in children with asthma. There were nominally significant interactions between gene pairs.</p> <p>Conclusions</p> <p><it>TSLP </it>SNP rs1837253 is associated with reduced odds for AR in boys with asthma. Our findings support a role for <it>TSLP </it>in the pathogenesis of AR in children with asthma.</p

Occupational Noise, Smoking, and a High Body Mass Index are Risk Factors for Age-related Hearing Impairment and Moderate Alcohol Consumption is Protective: A European Population-based Multicenter Study

A multicenter study was set up to elucidate the environmental and medical risk factors contributing to age-related hearing impairment (ARHI). Nine subsamples, collected by nine audiological centers across Europe, added up to a total of 4,083 subjects between 53 and 67 years. Audiometric data (pure-tone average [PTA]) were collected and the participants filled out a questionnaire on environmental risk factors and medical history. People with a history of disease that could affect hearing were excluded. PTAs were adjusted for age and sex and tested for association with exposure to risk factors. Noise exposure was associated with a significant loss of hearing at high sound frequencies (>1 kHz). Smoking significantly increased high-frequency hearing loss, and the effect was dose-dependent. The effect of smoking remained significant when accounting for cardiovascular disease events. Taller people had better hearing on average with a more pronounced effect at low sound frequencies (<2 kHz). A high body mass index (BMI) correlated with hearing loss across the frequency range tested. Moderate alcohol consumption was inversely correlated with hearing loss. Significant associations were found in the high as well as in the low frequencies. The results suggest that a healthy lifestyle can protect against age-related hearing impairment

Efectos analgésicos de la clonidina epidural en la cirugía de tórax.

Introducción: Se realizó un estudio sobre los efectos de la Clonidina extradural en la analgesia postoperatoria de la cirugía torácica. Objetivos: Determinar la intensidad del dolor en los pacientes operados de tórax y el comportamiento de las variables hemogasométricas. Material y Método: Se evaluaron 30 pacientes subdivididos en 3 grupos de 10 pacientes cada uno, en los que se emplearon: Morfina (grupo 1), Clonidina másMorfina (grupo 2) y Clonidina (grupo 3) respectivamente en el control del dolor postoracotomía. Se determinó la distribución de pacientes según la cantidad de dosis requeridas y el tratamiento empleado, tiempo promedio entre la primera y segunda dosis por tratamiento, la repercusión farmacodinámica sobre los signos vitales en cada grupo así como el comportamiento de las variables hemogasométricas. Se evaluó la intensidad del dolor según la escala análoga visual, el tratamiento escogido y el número de dosis, así como los efectos indeseables de losmedicamentos administrados. Resultados: El grupo II encontramos un valor medio de intensidad de dolor de 4,5.El número de dosis administradas fue 8 pacientes (1 dosis) y 2 pacientes 2 dosis). Ninguno paciente de este grupo recibió mas de 2 dosis. Existieron escasas variaciones hemodinámicas y hemogasométricas en los grupos I y III. Las reacciones sistémicas fueron nulas en el grupo II. Existieron diferencias estadísticamente significativas p &lt; 0,05 al comparar el grupo II con el I el III. Conclusiones: El grupo en el que se administró morfina-clonidina, presentó un menor puntaje en la escala análoga visual, así como un menor número de dosis. Escasas variaciones hemodinámicas y hemogasométricas. Las reacciones sistémicas fueron nulas.<br /

A haplotype in the inducible T-cell tyrosine kinase is a risk factor for seasonal allergic rhinitis

Background: Identification of disease-associated single nucleotide polymorphisms (SNPs) in seasonal allergic rhinitis (SAR) may be facilitated by focusing on genes in a disease-associated pathway. Objective: To search for SNPs in genes that belong to the T-cell receptor (TCR) pathway and that change in expression in allergen-challenged CD4+ cells from patients with SAR. Methods: CD4+ cells from patients with SAR were analysed with gene expression microarrays. Allele, genotype and haplotype frequencies were compared in 251 patients and 386 healthy controls. Results: Gene expression microarray analysis of allergen-challenged CD4+ cells from patients with SAR showed that 25 of 38 TCR pathway genes were differentially expressed. A total of 62 SNPs were analysed in eight of the 25 genes; ICOS, IL4, IL5, IL13, CSF2, CTLA4, the inducible T-cell tyrosine kinase (ITK) and CD3D. Significant chi-squared values were identified for several markers in the ITK kinase gene region. A total of five SNPs were nominally significant at the 5% level. Haplotype analysis of the five significant SNPs showed increased frequency of a haplotype that covered most of the coding part of ITK. The functional relevance of ITK was supported by analysis of an independent material, which showed increased expression of ITK in allergen-challenged CD4+ cells from patients, but not from controls. Conclusion: Analysis of SNPs in TCR pathway genes revealed that a haplotype that covers a major part of the coding sequence of ITK is a risk factor for SAR

Turner karyotype and childbirth

Turner karyotype and childbirth Anna Hagman, Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, the Sahlgrenska Academy, University of Gothenburg, Sweden, 2013. [email protected] Turner syndrome (TS) is a sex chromosome aberration and occurs in 1/2500 live born girls. One X chromosome is absent or structurally changed in all (monosomy) or some (mosaicism) of the cells. TS is characterized by short stature, ovarian failure and cardiac defects. Mortality is increased, mostly owing to cardiovascular disease and aortic dissection. Pregnancies in women with TS are rare, but have increased owing to oocyte donation (OD) and are reported to be of high risk. The aim of this thesis was to describe characteristics of mothers to girls with TS and characteristics of newborns with TS and to evaluate the obstetric and neonatal outcomes in women with Turner karyotype and whether the pregnancy increased morbidity after delivery. Characteristics of mothers giving birth to girls with TS from 1973-2006 and their newborns with TS were investigated in a study using the Swedish Genetic Turner Register (SGTR) and the Swedish Medical Register (MBR). Mothers to girls with TS were older and shorter than mothers from the general population. More girls with TS were born late preterm and were small for gestational age than controls. In a registry study, using the SGTR, the MBR, and the Cause of Death Register (CDR), 115 women with Turner karyotype who gave birth to 208 children (after both spontaneous and OD pregnancies) born 1973-2007, were studied. One woman had an aortic dissection. Singletons of women with Turner karyotype had lower gestational age, but similar size at birth and the rate of birth defects did not differ. In a Nordic, descriptive study on women with TS who had delivered after OD 106, women and 131 children born from 1992-2011 were included, and data from medical records were registered. The rate of hypertensive disorders during pregnancy was 35%. Life-threatening events occurred in four pregnancies (3.3%) including one with aortic dissection. The rate of preterm birth was 8% and low birth weight 9%. In a population-based registry study, mortality and morbidity in 124 women with Turner karyotype who had given birth from 1973-2010 was compared with women with Turner karyotype without childbirth and a control group from the MBR. The SGTR, the MBR, the National Patient Register, the CDR and Cancer Register were used. Morbidity and mortality in the total Turner group were increased as compared with the controls. Morbidity from cardiovascular diseases was increased before and during pregnancy but similar after more than one year after delivery and no deaths were seen. In conclusion, pregnancies in women with TS are high risk pregnancies owing to hypertensive disorders and aortic dissection. Neonatal outcomes in women with TS are generally reassuring. Women who gave birth to girls with TS were shorter and older. Key words: Turner syndrome, obstetric, neonatal outcome, Turner karyotype, pregnancy, maternal, neonatal characteristics. ISBN 978-91-628-8648-

Obstetric Outcomes in Women With Turner Karyotype EDITORIAL COMMENT

There is concern over the high risk of cardiovascular complications, hypertensive disorders, and other adverse obstetric outcomes among pregnant women with Turner syndrome (TS). A diagnosis of TS is made in some women late in life or not at all. Spontaneous pregnancies are rare in women with TS and are associated with a high rate of complications, especially miscarriage. The use of assisted reproductive techniques is an option for these women; pregnancy and implantation rates after oocyte donation in women with TS seem to be comparable with those without TS who need this treatment. Few data are available on obstetric outcome in pregnant women with TS. The aim of this retrospective population-based cohort study was to compare maternal and neonatal outcomes among singleton pregnancies of women with and without TS. Data on births occurring between 1973 and 2007 from the Swedish Genetic Turner Register and the Swedish Medical Birth Register were cross-linked. Obstetric outcome in infants born to women with TS was compared with a reference group of 56,000 women from the general population. Mean gestational age and birth weight were adjusted for maternal age. Outcome in TS women with twins was described separately. A total of 115 women with TS gave birth to 208 children (202 singletons and 3 sets of twins) during the study period. The TS diagnosis was unknown in 52% of the women before the first delivery. Women in the TS group were older at the first delivery than women in the reference group; median age was 30 years and 26 years, respectively (P < 0.0001). There was a trend toward more women with TS having preeclampsia during their first pregnancy (6.3 vs. 3.0%; P = 0.07). One woman suffered from an aortic dissection during her second spontaneous pregnancy. Compared with the reference group, the median gestational age was shorter in children in the TS group (-6.4 days, P = 0.0067), and median birth weight was lower (-208 g, P = 0.001); however, no significant difference was found in median standard deviation scores for weight and length at birth. The rate of cesarean delivery was higher in the TS group than in the reference group (35.6% vs. 11.8%, respectively, P < 0.0001). There was no significant difference in birth defects between groups. These findings show that women with a TS karyotype have mostly favorable obstetric outcomes. Singletons of women with TS have a shorter gestational age but a similar size at birth. The data also show no difference in birth defects between women with and without TS