105 research outputs found
Wandel in der russlĂ€ndischen AuĂenpolitik seit dem Amtsantritt von PrĂ€sident Medwedew unter besonderer BerĂŒcksichtigung der euro-atlantischen Beziehungen
Die vorliegende Arbeit beschĂ€ftigt sich mit der Frage, ob seit dem Amtsantritt von PrĂ€sident Dmitri Medwedew eine Neuausrichtung der AuĂenpolitik der RusslĂ€ndischen Föderation stattgefunden hat. Unter Anwendung der (neo-) realistischen Schule und der Autoritarismustheorie kann festgestellt werden, dass die russlĂ€ndische AuĂenpolitik nicht nur von der internationalen Umwelt sondern auch von innenpolitischen Konstellationen beeinflusst wird. Die von der RusslĂ€ndischen Föderation angestrebte Durchsetzung des GroĂmachtstatus wird von der ungĂŒnstigen demografischen Entwicklung, den MĂ€ngeln in der Gesundheitsversorgung und den veralteten BestĂ€nden bei konventionellen Waffen behindert. Ein Vergleich der PrĂ€sidentschaften Jelzins, Putins und Medwedews hat dabei gezeigt, dass nicht nur die (innen-) politische Linie des PrĂ€sidenten, sondern auch das MaĂ, in dem er die von der Verfassung vorgesehene auĂenpolitische Richtlinienkompetenz ausschöpft, fĂŒr die Ausgestaltung der AuĂenpolitik entscheidend sind. WĂ€hrend Jelzin aufgrund von Auseinandersetzungen zwischen den einzelnen fĂŒr die AuĂenpolitik zustĂ€ndigen Organen seine auĂenpolitische Linie oftmals nicht durchsetzen konnte, hat Putin nicht nur innenpolitisch sondern auch auĂenpolitisch eine Konzentration der Macht auf seine Person erwirkt, was eine kohĂ€rentere AuĂenpolitik mit sich bringt. Medwedew jedoch hat mit Putin einen auĂergewöhnlich mĂ€chtigen MinisterprĂ€sidenten an seiner Seite. Ein Vergleich der auĂenpolitischen Interessen Putins mit jenen Medwedews hat gezeigt, dass Medwedew in zentralen Politikbereichen die von einem neorealistischen Weltbild geprĂ€gte AuĂenpolitik Putins fortsetzt. Insgesamt kann festgehalten werden, dass unter Medwedew keine fundamentale Neuorientierung der russlĂ€ndischen AuĂenpolitik stattgefunden hat
Imprecision and DNA break repair biased towards incompatible end joining in leukemia
Cancer is a genetic disease caused by mutations and chromosomal abnormalities that contribute to uncontrolled cell growth. In addition, cancer cells can rapidly respond to conventional and targeted therapies by accumulating novel and often specific genetic lesions leading to acquired drug resistance and relapsing disease. In chronic lymphocytic leukemia (CLL), however, diverse chromosomal aberrations often occur. In many cases, improper repair of DNA double-strand breaks (DSB) is a major source for genomic abnormalities. Therefore, this study examined the repair of DNA DSBs by nonhomologous end joining (NHEJ) in CLL by performing plasmid-based repair assays in primary CLL cells and normal B cells, isolated from patients, as well as TALEN/Cas9âinduced chromosomal deletions in the CLL cell line Mec1. It is demonstrated that DNA repair is aberrant in CLL cells, featuring perturbed DNA break structure preference with efficient joining of noncohesive ends and more deletions at repair junctions. In addition, increased microhomology-mediated end joining (MMEJ) of DNA substrates was observed in CLL together with increased expression of MMEJ-specific repair factors. In summary, these data identify major differences in DNA repair efficiency between CLL cells and normal B cells isolated from patients
TIGIT expressing CD4+T cells represent a tumor-supportive T cell subset in chronic lymphocytic leukemia
While research on T cell exhaustion in context of cancer particularly focuses on CD8C cytotoxic T cells, the
role of inhibitory receptors on CD4C T-helper cells have remained largely unexplored. TIGIT is a recently
identified inhibitory receptor on T cells and natural killer (NK) cells. In this study, we examined TIGIT
expression on T cell subsets from CLL patients. While we did not observe any differences in TIGIT expression
in CD8C T cells of healthy controls and CLL cells, we found an enrichment of TIGITC T cells in the CD4C T
cell compartment in CLL. Intriguingly, CLL patients with an advanced disease stage displayed elevated
numbers of CD4C TIGITC T cells compared to low risk patients. Autologous CLL-T cell co-culture assays
revealed that depleting CD4C TIGITC expressing T cells from co-cultures significantly decreased CLL viability.
Accordingly, a supportive effect of TIGITCCD4C T cells on CLL cells in vitro could be recapitulated by
blocking the interaction of TIGIT with its ligands using TIGIT-Fc molecules, which also impeded the T cell
specific production of CLL-prosurvival cytokines. Our data reveal that TIGITCCD4CT cells provide a
supportive microenvironment for CLL cells, representing a potential therapeutic target for CLL treatment
Management of Solid-pseudopapillary Neoplasms of the Pancreas: a Comparison with Standard Pancreatic Neoplasms
BACKGROUND: Solid-pseudopapillary neoplasms (SPNs) of the pancreas are increasingly diagnosed, but the exact surgical management in terms of extent of the resection is not well defined. MATERIALS AND METHODS: Patients operated on in our hospital between January 1993 and March 2005 formed the study groups. RESULTS: From 659 consecutive resections for pancreatic neoplasms, 12 female patients (1.8%) with a median age of 21 years who underwent resection for (SPN) are compared with the remaining 647 pancreatic resection patients. Jaundice (SPN 0 versus PR 73%, p < 0.001) and weight loss (SPN 0 versus PR 49%, p = 0.001) occurred significantly less often. Neoplasms were distributed equally among the pancreatic head (SPN 5 out of 12 patients versus PR 88%, p < 0.001) and corpus/tail (SPN 6 out of 12 patients versus PR 8%, p < 0.001). The operative time was significantly shorter (SPN 233 min versus PR 280 min, p = 0.012), and there were significantly fewer complications (SPN 1 of 12 patients versus PR 48%, p = 0.007). The mortality was not different (SPN 0 versus PR 1.6%, p = 1.000), and the hospital stay was significantly shorter (SPN 9 days versus PR 15 days, p = 0.012). The median size of the neoplasms was significantly larger (SPN 6.9 cm versus PR 2.5 cm). The median number of lymph nodes harvested was significantly fewer (SPN 1 versus PR 6, p = 0.001), and lymph node metastases occurred significantly less often (SPN 0 versus PR 64%, p < 0.001). The 5-year survival of SPN patients was 100% and is significantly better compared with survival of patients with pancreatic adenocarcinoma (12%, p < 0.001) and ampulla of Vater adenocarcinoma (22%, p = 0.005). CONCLUSIONS: Patients with solid-pseudopapillary neoplasms of the pancreas present differently and the course of the disease is more benign. These patients can be adequately managed by pylorus-preserving pancreatoduodenectomy or spleen-preserving distal pancreatectomy with excellent early and long-term result
Epigenomic modifications mediating antibody maturation
Epigenetic modifications, such as histone modifications, DNA methylation status, and non-coding RNAs (ncRNA), all contribute to antibody maturation during somatic hypermutation (SHM) and class-switch recombination (CSR). Histone modifications alter the chromatin landscape and, together with DNA primary and tertiary structures, they help recruit Activation-Induced Cytidine Deaminase (AID) to the immunoglobulin (Ig) locus. AID is a potent DNA mutator, which catalyzes cytosine-to-uracil deamination on single-stranded DNA to create U:G mismatches. It has been shown that alternate chromatin modifications, in concert with ncRNAs and potentially DNA methylation, regulate AID recruitment and stabilize DNA repair factors. We, hereby, assess the combination of these distinct modifications and discuss how they contribute to initiating differential DNA repair pathways at the Ig locus, which ultimately leads to enhanced antibody-antigen binding affinity (SHM) or antibody isotype switching (CSR). We will also highlight how misregulation of epigenomic regulation during DNA repair can compromise antibody development and lead to a number of immunological syndromes and cancer
APOBEC3 genes: retroviral restriction factors to cancer drivers
The APOBEC3 cytosine deaminases play key roles in innate immunity through their ability to mutagenize viral DNA and restrict viral replication. Recent advances in cancer genomics, together with biochemical characterization of the APOBEC3 enzymes, have now implicated at least two family members in somatic mutagenesis during tumor development. We review the evidence linking these enzymes to carcinogenesis and highlight key questions, including the potential mechanisms that misdirect APOBEC3 activity to the host genome, the links to viral infection, and the association between a common APOBEC3 polymorphism and cancer risk
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