SNX10 gene mutation leading to osteopetrosis with dysfunctional osteoclasts

Acknowledgements We sincerely thank the patients and family members who participated in this study. We would also like to thank Stefan Esher, Umeå University, for help with genealogy, and Anna Westerlund for excellent technical assistance. This work was supported by grants from the FOU, at the Umeå university hospital, and the Medical Faculty at Umeå University. The work at University of Gothenburg was supported by grants from The Swedish Research Council, the Swedish Rheumatism Association, the Royal 80-Year Fund of King Gustav V, ALF/LUA research grant from Sahlgrenska University Hospital in Gothenburg and the Lundberg Foundation. The work at the University of Gothenburg and the University of Aberdeen was supported by Euroclast, a Marie Curie FP7-People-2013-ITN: # 607446.Peer reviewedPublisher PD

Dic(9;20)(p13;q11) in childhood acute lymphoblastic leukaemia is related to low cellular resistance to asparaginase, cytarabine and corticosteroids.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldDic(9;20)(p13;q11) was first described as a nonrandom chromosome abnormality in B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the mid 1990s,1, 2 and 71 dic(9;20)-positive cases have since then been reported.3, 4, 5 Approximately 90% of these cases were children or adolescents, with dic(9;20) occurring in about 2% of childhood BCP ALL.6 The recent review by Forestier et al.5 describes that dic(9;20)-leukaemias are of B-cell precursor immunophenotype, never have a high hyperdiploid modal number, show a female predominance, and have a significant age incidence peak at 3 years. Most patients are allocated to non-standard risk treatment arms due to high WBC (median 24 109/l) and a relatively high frequency of CNS disease or other extra-medullary leukaemia (EML) at diagnosis. The prognostic implications of dic(9;20) are to a large extent unknown. A relatively large proportion of the relapses reported in the literature have been extra-medullary, and post-relapse treatment including block therapy has been successful in several patients, as illustrated by a p-EFS of 0.62 and a predicted overall survival of 0.82 at 5 years for the 24 Nordic cases.

DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL.We used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations ('other' subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5.Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.Swedish Foundation for Strategic Research RBc08-008 Swedish Cancer Society CAN2010/592 Swedish Childhood Cancer Foundation 11098 Swedish Research Council for Science and Technology 90559401 Swedish Research Council FORTE Swedish Research Council FORMAS Swedish Research Council VINNOVA Swedish Research Council VR 259-2012-2

DNA Methylation Analysis of Bone Marrow Cells at Diagnosis of Acute Lymphoblastic Leukemia and at Remission

To detect genes with CpG sites that display methylation patterns that are characteristic of acute lymphoblastic leukemia (ALL) cells, we compared the methylation patterns of cells taken at diagnosis from 20 patients with pediatric ALL to the methylation patterns in mononuclear cells from bone marrow of the same patients during remission and in non-leukemic control cells from bone marrow or blood. Using a custom-designed assay, we measured the methylation levels of 1,320 CpG sites in regulatory regions of 413 genes that were analyzed because they display allele-specific gene expression (ASE) in ALL cells. The rationale for our selection of CpG sites was that ASE could be the result of allele-specific methylation in the promoter regions of the genes. We found that the ALL cells had methylation profiles that allowed distinction between ALL cells and control cells. Using stringent criteria for calling differential methylation, we identified 28 CpG sites in 24 genes with recurrent differences in their methylation levels between ALL cells and control cells. Twenty of the differentially methylated genes were hypermethylated in the ALL cells, and as many as nine of them (AMICA1, CPNE7, CR1, DBC1, EYA4, LGALS8, RYR3, UQCRFS1, WDR35) have functions in cell signaling and/or apoptosis. The methylation levels of a subset of the genes were consistent with an inverse relationship with the mRNA expression levels in a large number of ALL cells from published data sets, supporting a potential biological effect of the methylation signatures and their application for diagnostic purposes

ENERGIANVÄNDING PÅ BYGGARBETSPLATSER : Analys av införandet av energieffektiva bygg­etableringar

This report is the final step in the Bachelor of Science program in Building Construction Engineering, Department of Engineering Sciences, Uppsala University. The purpose of this study is to highlight the difficulties and possibilities that could involve the introduction of new energy efficient technologies and changing work around this technology. This study focuses on energy use at a construction site or other temporary workplace where so-called portacabins are in place to address the need for temporary facilities. The method for obtaining knowledge on the subject was mainly interviews with site managers working in Svevia AB's various activities. In conjunction with the interviews I visited construction sites and portacabins if it was possible. My most important suggestion to Svevia AB concerns a better organization in order to make poratacabins more efficient on energy and costs. The company should also evaluate and monitor the energy efficient portacabins that are in operation. Expected energy savings of new technology may not materialize if there are gaps in information, education, technical services and technical maintenance. It is very important to utilize the experiences of new technology. The experience should be used for the design of training, information and service schedules

Evaluation of New Non-Pharmacological Therapies for Symptomatic Atrial Fibrillation : With Special Emphasis on the Maze Procedure

Atrial fibrillation is a common disease. With pharmacological therapy most patients with atrial fibrillation have moderate or little symptoms, but a number of patients have severely symptomatic disease. This study evaluates two new non-pharmacological therapies for atrial fibrillation, the Maze procedure and atrial overdrive pacing. In the patients planned for Maze surgery the quality of life, assessed with the SF-36 questionnaire, was very low before the operation. The quality of life was markedly improved 6 and 12 months after the Maze operation, and was comparable to values of the general Swedish population. In the patients with sinus rhythm before surgery, the atrial size and transport function was assessed with echocardiography, and the autonomic balance was assessed with heart rate variability (HRV). The sizes of both atria were reduced and the transmitral early filling / atrial filling (E/A) ratio was increased at 6 months after the operation compared to before. A progressive increase of the E/A ratio was seen during the 24 months follow-up period, indicating a progressive decline of the left atrial transport function. All components of HRV, including the parameters expressing sympathetic and parasympathetic modulation, were markedly decreased early after the Maze procedure compared to before. Late after the operation all components of HRV were still markedly depressed. This is interpreted as a partial autonomic denervation of the heart Single-site right atrial overdrive pacing with two different levels of overdriving was compared with no pacing in patients with paroxysmal atrial fibrillation in a cross-over study. Overdrive pacing reduced the median number of episodes of atrial fibrillation with 50% compared to no pacing. There was no difference between medium rate overdrive pacing and high rate overdrive pacing

ENERGIANVÄNDING PÅ BYGGARBETSPLATSER : Analys av införandet av energieffektiva bygg­etableringar

This report is the final step in the Bachelor of Science program in Building Construction Engineering, Department of Engineering Sciences, Uppsala University. The purpose of this study is to highlight the difficulties and possibilities that could involve the introduction of new energy efficient technologies and changing work around this technology. This study focuses on energy use at a construction site or other temporary workplace where so-called portacabins are in place to address the need for temporary facilities. The method for obtaining knowledge on the subject was mainly interviews with site managers working in Svevia AB's various activities. In conjunction with the interviews I visited construction sites and portacabins if it was possible. My most important suggestion to Svevia AB concerns a better organization in order to make poratacabins more efficient on energy and costs. The company should also evaluate and monitor the energy efficient portacabins that are in operation. Expected energy savings of new technology may not materialize if there are gaps in information, education, technical services and technical maintenance. It is very important to utilize the experiences of new technology. The experience should be used for the design of training, information and service schedules