The role of the Philadelphia translocation in chronic myeloid leukemia

During the last two decades evidence for a close association between the presence of specific chromosomal abnormalities and the occurrence of several types of cancers and leukemias has accumulated. The Philadelphia (Ph 1) translocation, present in about 90% of the patients with chronic myeloid leukemia (CML), is one of the most typical and best documented examples of such an aberration. Usually this translocation involves chromosome 9 and 22: t(9;22)(q34;q11). The translocation products are designated 9q+ and 22q-. Variant translocations involving an array of translocation sites different from 9 have been described as well, but chromosome 22 is always involved. So far, no clear indications were found for the possible role played by this highly specific chromosomal aberration in the etiology of CML. Moreover, results concerning the exact nature of the Ph1 translocation, obtained by different investigators using different techniques, appeared to be contradictory. In this thesis the application of somatic cell hybridization and gene segregation analyses to these questions has been described. Rodent cells (fibroblasts) were fused with human Ph1 positive leucocytes and, subsequently, hybrid cell 1 ines were isolated. These hybrids appeared to segregate human chromosomes, including the Ph1 translocation products. The segregation of genes, previously assigned to the regions of the chromosomal breakpoints, was studied together with the segregation of the relevant human (translocation) chromosomes. Several genes on chromosome 22 were found to be translocated to the 9q+ chromosome which confirmed, on a molecular level, the translocation of chromosome 22 materia] to chromosome 9. Another gene on chromosome 22 (immunoglobulin A 1 ight chain) stayed on the Ph1 chromosome (22q-). One gene on chromosome 9 (c-abl) appeared to be translocated to 22q-. This latter result provided unequivocal evidence for reciprocity of the Ph 1 translocation. No apparent differences in chromosomal breakpoints could be revealed in the different CML patients used for analysis and no evidence was found for loss of chromosomal material {genes) as a result of the Ph 1 translocation. The clonal origin of the Ph 1 translocation in CML was confirmed using a chromosome 9 encoded polymorphic enzyme (AKI)

Division of labor between dendritic cell subsets in the lung during influenza virus infection

Influenza disease, often referred to as “flu”, is caused by the influenza viruses. These viruses are most only responsible for epidemics of variable severity almost every winter but occasionally cause major pandemic outbreaks. The term “influenza” has been derived from the Italian astrologers in the mid-1300s, who thought the flu was due to the “influence” of the heavenly bodies. Yet, the aetiology of the disease and the explanation for it’s peculiar behavior remained elusive. At the turn of the 19th century, influenza was thought to be due to a bacterial infection with Haemophilus influenzae. It was not until 1931 that Richard Shope showed that the causative agent was a virus. A few years later, Smith and co-workers for the first time isolated an influenza virus from humans with respiratory illness. The burden of influenza virus for the society, not only from a clinical but also from an economic perspective, is often underestimated. This relates particularly to the recurring annual winter epidemics. Fortunately, since the virus was first discovered, efficient means to contain the infection have been developed. Vaccination is the primary method for the prevention of influenza. However, due to the continuous genetic and antigenic variation that influenza viruses undergo, a constant global surveillance is required to identify and select new variants with epidemic or pandemic potential. Therefore, improvement of vaccination strategies against epidemic influenza and development of effective vaccines against potential pandemic viruses are a public health priority. New strategies for influenza vaccines include altering the dose, site or method of delivery of inactivated vaccines, the use of adjuvants or immunomodulators to enhance immune responses, or targeting of viral proteins that may promote broader, cross protective responses

Gebieden met bijzondere ecologische waarden op het Nederlands Continentaal Plat

Coproductie van Rijkswaterstaat RIKZ en Alterra Texel, met medewerking van RIVO en NIOZ, in opdracht van Verkeer en Waterstaat (directie Water) en LNV (directie Natuur). In navolging van wat Nota Ruimte aangeeft, komen de territoriale wateren van Noordzee in aanmerking voor beschermd gebied. Dit onderzoek zal meegenomen worden in het medio 2005 uit te brengen Integraal Beheerplan Noordzee 2015. Dit onderzoek behandelt namelijk de nadere begrenzing van het aan te wijzen gebied, aan de hand van internationaal in EU en OSPAR kader overeengekomen criteri

Early IL-1 signaling promotes iBALT induction after influenza virus infection

Inducible bronchus-associated lymphoid tissue (iBALT) is a long lasting tertiary lymphoid tissue that can be induced following influenza A virus (IAV) infection. Previous studies have shown that iBALT structures containing germinal center (GC) B cells protect against repeated infection by contributing locally to the cellular and humoral immune response. If we are to exploit this in vaccination strategies, we need a better understanding on how iBALT structures are induced. One hypothesis is that the strength of the initial innate response dictates induction of iBALT. In the present study, we investigated the role of interleukin (IL)-1 and IL-1R signaling on iBALT formation. Mice lacking the IL-1R had a delayed viral clearance and, thus, a prolonged exposure to viral replication, leading to increased disease severity, compared to wild-type mice. Contradictorily, iBALT formation following clearance of the virus was heavily compromised in Il1r1-/- mice. Quantification of gene induction after IAV infection demonstrated induction of IL-1α and to a much lesser extent of IL-1β. Administration of recombinant IL-1α to the lungs of wild-type mice, early but not late, after IAV infection led to more pronounced iBALT formation and an increased amount of GC B cells in the lungs. Bone marrow chimeric mice identified the stromal compartment as the crucial IL-1 responsive cell for iBALT induction. Mechanistically, Q-PCR analysis of lung homogenates revealed a strongly diminished production of CXCL13, a B cell-attracting chemokine, in Il1r-/- mice during the early innate phase of IAV infection. These experiments demonstrate that appropriate innate IL-1α-IL-1R signaling is necessary for IAV clearance and at the same time instructs the formation of organized tertiary lymphoid tissues through induction of CXCL13 early after infection. These findings are discussed in the light of recent insights on the pathogenesis of tertiary lymphoid organ formation in the lung in various diseases where the IL-1 axis is hyperactive, such as rheumatoid arthritis and COPD

Rabies virus uniquely reprograms the transcriptome of human monocyte-derived macrophages

Macrophages are amongst the first immune cells that encounter rabies virus (RABV) at virus entry sites. Activation of macrophages is essential for the onset of a potent immune response, but insights into the effects of RABV on macrophage activation are scarce. In this study we performed high-throughput sequencing on RNA extracted from macrophages that were exposed to RABV for 48 hours, and compared their transcriptional profiles to that of non-polarized macrophages (M0), and macrophages polarized towards the canonical M1, M2a and M2c phenotypes. Our analysis revealed that RABV-stimulated macrophages show high expression of several M1, M2a and M2c signature genes. Apart from their partial resemblance to these phenotypes, unbiased clustering analysis revealed that RABV induces a unique and distinct polarization program. Closer examination revealed that RABV induced multiple pathways related to the interferon- and antiviral response, which were not induced under other classical polarization strategies. Surprisingly, our data show that RABV induces an activated rather than a fully suppressed macrophage phenotype, triggering virus-induced activation and polarization. This includes multiple genes with known antiviral (e.g. APOBEC3A, IFIT/OAS/TRIM genes), which may play a role in anti-RABV immunity.</p

A long-lasting, complete hematologic and cytogenetic remission of chronic myelogenous leukemia after treatment with busulfan alone

A 44-year-old man suffering from cytogenetically and molecularly proven Philadelphia translocation-positive chronic myelogenous leukemia in chronic phase was treated with busulfan for 18 months and studied during a follow-up period of 13 years. Hematologically and cytogenetically, he attained a continuing complete remission, although at one point (9.5 years) at least, after attaining complete remission molecular analysis indicated the presence of minimal residual disease

Isolation of anonymous, polymorphic DNA fragments from human chromosome 22q12-qter

A series of 195 random chromosome 22-specific probes, equivalent to approximately 1% of the size of this chromosome, have been isolated from a chromosome 22-specific bacteriophage lambda genomic library. These probes were mapped to four different regions of chromosome 22 on a panel of five somatic cell hybrids. Restriction fragment length polymorphisms were detected by 28 of the probes mapping to 22q12-qter. Evolutionarily conserved sequences in human, mouse, and Chinese hamster DNA were detected by 12% of the isolated probes

Fluorescence in situ hybridization-based approaches for detection of 12p overrepresentation, in particular i(12p), in cell lines of human testicular germ cell tumors of adults

Overrepresentation of the short arm of chromosome 12 is frequently detected in human testicular germ cell tumors of adolescents and adults (TGCT). This overrepresentation mostly results from the formation of an isochromosome i(12p). Whether the overrepresentation consistently involves the complete 12p arm including the centromere is still unclear. We studied five TGCT-derived cell line

Guillain-Barré syndrome following varicella-zoster virus infection

We describe the frequency, clinical features, and electrophysiological and immunological phenotypes of Guillain-Barré Syndrome (GBS) patients treated at a single institution in Bangladesh who had preceding chicken pox (primary Varicella-zoster virus [VZV] infection) within 4 weeks of GBS onset. A literature review of GBS cases preceding VZV infection is also provided. Diagnosis of GBS was based on the National Institute of Neurological Disorders and Stroke criteria for GBS. Serum anti-VZV IgM and IgG antibodies were quantified by indirect chemiluminescence immunoassay (CLIA); anti-Campylobacter jejuni IgG, IgM, and IgA antibodies and anti-ganglioside GM1 IgM and IgG antibodies, by enzyme-linked immunosorbent assays. Neurophysiologic subtypes were categorized following the Hadden criteria. Of 536 patients with GBS, 7 (1.3%) had chicken pox within 4 weeks before GBS onset. Four of the seven cases were male (age range, 23 to 40 years old). All seven patients were bed-bound, six had sensory symptoms, and three required mechanical ventilation for respiratory failure. All seven patients had CSF albuminocytologic dissociation and evidence of demyelination in nerve conduction studies. Anti-VZV IgM antibodies were present and anti-GM1 and anti-Campylobacter jejuni lipo-oligosaccharides (LOS) were negative in all cases. All patients had excellent outcome at 1 year (able to run). A systematic literature review of GBS cases related to VZV revealed 39 previously reported patients with comparable clinical presentations and outcomes, of which 36 had neurophysiologic evidence of demyelination. VZV infection is associated with the demyelinating subtype of GBS, clearly distinct from the axonal form of GBS that predominate in countries like Bangladesh