Simultaneous Translocation of Both TCR Loci (14q11) with Rare Partner Loci (Xq22 and 12p13) in a Case of T-lymphoblastic Leukemia

The most common recurrent cytogenetic abnormalities in T-lymphoblastic leukemia (T-acute lymphoblastic leukemia [T-ALL]) involve T-cell receptor (TCR) loci and a variety of partner genes, including HOX11, HOX11L2, MYC, and TAL1. In this report, we present a rare case involving simultaneous translocation of the TCR α/δ loci with different partner loci (Xq22 and 12p13); this resulted in a poor prognosis. Chromosomal analysis showed 46,Y,t(X;14)(q22;q11.2),t(12;14)(p13;q11.2) and FISH analysis by using a T-cell receptor alpha delta DNA probe, Split Signal (DakoCytomation, Denmark), showed translocations at the same TCR α/δ locus on both chromosomes. FISH with 2 bacterial artificial chromosome clones showed break apart signal, which suggests involvement of the IRS4 gene. To our knowledge, this is the first report of T-ALL in which both TCR α/δ loci were translocated with different partner loci, and 1 of the partner loci, Xq22, was a rare translocation partner locus that included IRS4 gene

Numerical Computation of approximate Generalized Polarization Tensors

In this paper we describe a method to compute Generalized Polarization Tensors. These tensors are the coefficients appearing in the multipolar expansion of the steady state voltage perturbation caused by an inhomogeneity of constant conductivity. As an alternative to the integral equation approach, we propose an approximate semi-algebraic method which is easy to implement. This method has been integrated in a Myriapole, a matlab routine with a graphical interface which makes such computations available to non-numerical analysts

Genetic Characterization of Pediatric T-cell Acute Lymphoblastic Leukemia

The aim of my thesis has been to characterize genetically pediatric T-cell acute lymphoblastic leukemia (T-ALL). Articles I and II focus on molecular characterization of translocations involving T-cell receptor (TCR) loci. These types of aberration are characteristic for T-ALL and have previously proved pivotal in the identification of genes implicated in leukemogenesis. The translocation t(12;14)(p13;q11) was shown to result in overexpression of CCND2. The t(12;14) is the first neoplasia-associated translocation shown to result in overexpression of CCND2 and the first example of a targeted deregulation of a member of the cyclin-encoding gene family in T-ALL. Cyclin D proteins are crucial to the cell cycle machinery and hence potential oncogenes. The second translocation cloned, t(X;7)(q22;q34), had not previously been reported in a neoplastic disorder. Breakpoint analysis revealed IRS4 as a novel translocation partner to a TCR locus, resulting in deregulated IRS4 expression, both at the gene and protein level. IRS4 plays an important part in several intracellular signalling cascades, including PI3K-AKT, known to be activated in T-ALL. In a subsequent work, I showed that IRS4 can also be targeted by alternative mechanisms in T-ALL, apart from TCR translocations, namely by mutations (Article IV). In Article III, clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a large, population-based Nordic series of 285 pediatric T-ALLs. Survival analyses revealed a correlation between rare TCR translocations and inferior outcome, an association that awaits confirmation in a separate study. Finally, I used several different techniques – fluorescence in situ hybridization, single nucleotide polymorphism (SNP) array, and deep sequencing of 75 selected candidate genes – to characterize co-operative genetic aberrations in a consecutive series of paediatric T-ALL (Article V). One common change identified by SNP array was segemtal uniparental isodisomy (sUPID). This aberration was seen in 44% of the investigated cases, with most being sUPID9p that always were associated with homozygous CDKN2A deletions, with a heterozygous deletion occurring prior to the sUPID9p in all instances. Among the 75 genes investigated by deep sequencing, 14 were mutated in 28 cases. The genes targeted are involved in signalling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse, showing that such mutations also can be secondary events. These findings support a multistep leukemogenic process in pediatric T-ALL. In summary, through different approaches and by various methods, the articles included in this thesis have deciphered genetic aberrations in pediatric T-ALL, contributing to a better understanding of leukemogenesis

Epistemonikos and KSR Evidence

This article presents an evaluation of the two databases Epistemonikos and KSR Evidence, in the context of conducting evidence maps at the Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU).   Methods: 36 systematic reviews included in published SBU Evidence Maps were used as a gold standard records (GSR). Title searches, as well as subject searches, were performed. Result: Title searches showed that Epistemonikos covers 97% of the GSR, and KSR Evidence covers 94%. Structured subject searches retrieved a part of the references, 58% from KSR Evidence and 48% from Epistemonikos. Conclusion: Epistemonikos and KSR Evidence are valuable resources for identifying systematic reviews, but not sufficient to replace any of the databases usually used for SBUs Evidence Maps. Mesh: Databases, Bibliographic; Information Storage and Retrieval; Review Literature as Topic; Evidence-Based Medicine &nbsp

Mind the gap: Can we explain declining male reproductive health with known antiandrogens?

This article has been made available through the Brunel Open Access Publishing Fund.Several countries have experienced rises in cryptorchidisms, hypospadias and testicular germ cell cancer. The reasons for these trends are largely unknown, but Skakkebaek has proposed that these disorders form a testicular dysgenesis syndrome and can be traced to androgen insufficiency in foetal life. This suggests that antiandrogenic chemicals might contribute to risks, but few chemicals have been linked to these diseases in epidemiological studies. In animal studies with p,p0-dichlorodiphenyldichloroethylene, effects typical of disruptions of male sexual differentiation became apparent when the foetal levels of this androgen receptor (AR) antagonist approached values associated with responses in in vitro assays. This prompted us to analyse whether the 22 chemicals with AR antagonistic properties would produce mixture effects in an in vitro AR antagonism assay when combined at concentrations found in human serum. Other antiandrogenic modalities could not be considered. Two scenarios were investigated, one representative of average serum levels reported in European countries, the other in line with levels towards the high exposures. In both situations, the in vitro potency of the 22 selected AR antagonists was too low to produce combined AR antagonistic effects at the concentrations found in human serum, although the high exposure scenario came quite close to measurable effects. Nevertheless, our analysis exposes an explanation gap which can only be bridged by conjuring up as yet undiscovered high potency AR antagonists or, alternatively, high exposures to unknown agents of average potency

Environ Sci Pollut Res

The sorption processes of persistent organic pollutants on microplastics particles are poorly understood. Therefore, the present study investigated the sorption processes of perfluorooctanesulfonate (PFOS) on polyethylene (PE) microplastic particles (MPs) which are representing a prominent environmental pollutant and one of the most abundant microplastic polymers in the aquatic environment, respectively. The focus was set on the investigation of the impact of the particle size on PFOS sorption using four different PE MPs size ranges. The sorption kinetics for 6 months was studied with one selected size range of PE MPs. Besides, the desorption of PFOS from PE MPs under simulated digestive conditions was carried out by using artificial gut fluid mimicking the intestinal juice of fish. The investigation of the size effects of particles over 6 months demonstrated a linear increase of PFOS concentration sorbed onto PE with a decrease of the particle size. Thus, our findings implicate efficient sorption of PFOS onto PE MPs of different sizes. The results showed that PFOS desorbed from the PE MPs into the artificial gut fluid with a rate of 70 to 80%. Besides, a longer exposure of PE MPs to PFOS leads to a higher concentration adsorbed by PE MPs, which may favor the ingestion of higher concentration of PFOS, and thus represents a higher risk to transfer relevant concentrations of PFOS during digestion

Pediatric T-cell acute lymphoblastic leukemia

The most common pediatric malignancy is acute lymphoblastic leukemia (ALL), of which T-cell ALL (T-ALL) comprises 10–15% of cases. T-ALL arises in the thymus from an immature thymocyte as a consequence of a stepwise accumulation of genetic and epigenetic aberrations. Crucial biological processes, such as differentiation, self-renewal capacity, proliferation, and apoptosis, are targeted and deranged by several types of neoplasia-associated genetic alteration, for example, translocations, deletions, and mutations of genes that code for proteins involved in signaling transduction, epigenetic regulation, and transcription. Epigenetically, T-ALL is characterized by gene expression changes caused by hypermethylation of tumor suppressor genes, histone modifications, and miRNA and lncRNA abnormalities. Although some genetic and gene expression patterns have been associated with certain clinical features, such as immunophenotypic subtype and outcome, none has of yet generally been implemented in clinical routine for treatment decisions. The recent advent of massive parallel sequencing technologies has dramatically increased our knowledge of the genetic blueprint of T-ALL, revealing numerous fusion genes as well as novel gene mutations. The challenges now are to integrate all genetic and epigenetic data into a coherent understanding of the pathogenesis of T-ALL and to translate the wealth of information gained in the last few years into clinical use in the form of improved risk stratification and targeted therapies. Here, we provide an overview of pediatric T-ALL with an emphasis on the acquired genetic alterations that result in this disease

Cytogenetic and Molecular Predictors of Outcome in Acute Lymphocytic Leukemia: Recent Developments

During the last decade a tremendous technologic progress based on genome-wide profiling of genetic aberrations, structural DNA alterations, and sequence variations has allowed a better understanding of the molecular basis of pediatric and adult B/T- acute lymphoblastic leukemia (ALL), contributing to a better recognition of the biological heterogeneity of ALL and to a more precise definition of risk factors. Importantly, these advances identified novel potential targets for therapeutic intervention. This review will be focused on the cytogenetic/molecular advances in pediatric and adult ALL based on recently published articles