CD49d Is the strongest flow cytometry–based predictor of overall survival in chronic lymphocytic leukemia

Purpose Although CD49d is an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL), definitive validation evidence is lacking. A worldwide multicenter analysis was performed using published and unpublished CLL series to evaluate the impact of CD49d as an overall (OS) and treatment-free survival (TFS) predictor. Patients and Methods A training/validation strategy was chosen to find the optimal CD49d cutoff. The hazard ratio (HR) for death and treatment imposed by CD49d was estimated by pooled analysis of 2,972 CLLs; Cox analysis stratified by center and stage was used to adjust for confounding variables. The importance of CD49d over other flow cytometry–based prognosticators (eg, CD38, ZAP-70) was ranked by recursive partitioning. Results Patients with ≥ 30% of neoplastic cells expressing CD49d were considered CD49d+. Decrease in OS at 5 and 10 years among CD49d+ patients was 7% and 23% (decrease in TFS, 26% and 25%, respectively). Pooled HR of CD49d for OS was 2.5 (2.3 for TFS) in univariate analysis. This HR remained significant and of similar magnitude (HR, 2.0) in a Cox model adjusted for clinical and biologic prognosticators. Hierarchic trees including all patients or restricted to those with early-stage disease or those age ≤ 65 years always selected CD49d as the most important flow cytometry–based biomarker, with negligible additional prognostic information added by CD38 or ZAP-70. Consistently, by bivariate analysis, CD49d reliably identified patient subsets with poorer outcome independent of CD38 and ZAP-70. Conclusion In this analysis of approximately 3,000 patients, CD49d emerged as the strongest flow cytometry–based predictor of OS and TFS in CLL

Thermal- and Oxidative Stress Causes Enhanced Release of NKG2D Ligand-Bearing Immunosuppressive Exosomes in Leukemia/Lymphoma T and B Cells

Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as an explanation of the high incidence of relapse and fatal outcome of many blood malignancies. In this report we have used Jurkat and Raji cell lines as a model for studies of the NKG2D receptor-ligand system in T-and B cell leukemia/lymphoma. Using real-time quantitative RT-PCR and immunoflow cytometry we show that Jurkat and Raji cells constitutively express mRNA and protein for the stress-inducible NKG2D ligands MICA/B and ULBP1 and 2, and up-regulate the expression in a cell-line specific and stress-specific manner. Furthermore, we revealed by electron microscopy, immunoflow cytometry and western blot that these ligands were expressed and secreted on exosomes, nanometer-sized microvesicles of endosomal origin. Acting as a decoy, the NKG2D ligand-bearing exosomes downregulate the in vitro NKG2D receptor-mediated cytotoxicity and thus impair NK-cell function. Interestingly, thermal and oxidative stress enhanced the exosome secretion generating more soluble NKG2D ligands that aggravated the impairment of the cytotoxic response. Taken together, our results might partly explain the clinically observed NK-cell dysfunction in patients suffering from leukemia/lymphoma. The adverse effect of thermal and oxidative stress, enhancing the release of immunosuppressive exosomes, should be considered when cytostatic and hyperthermal anti-cancer therapies are designed

Post-GWAS Functional Characterization of Susceptibility Variants for Chronic Lymphocytic Leukemia

Recent genome-wide association studies (GWAS) have identified several gene variants associated with sporadic chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Many of these CLL/SLL susceptibility loci are located in non-coding or intergenic regions, posing a significant challenge to determine their potential functional relevance. Here, we review the literature of all CLL/SLL GWAS and validation studies, and apply eQTL analysis to identify putatively functional SNPs that affect gene expression that may be causal in the pathogenesis of CLL/SLL. We tested 12 independent risk loci for their potential to alter gene expression through cis-acting mechanisms, using publicly available gene expression profiles with matching genotype information. Sixteen SNPs were identified that are linked to differential expression of SP140, a putative tumor suppressor gene previously associated with CLL/SLL. Three additional SNPs were associated with differential expression of DACT3 and GNG8, which are involved in the WNT/β-catenin- and G protein-coupled receptor signaling pathways, respectively, that have been previously implicated in CLL/SLL pathogenesis. Using in silico functional prediction tools, we found that 14 of the 19 significant eQTL SNPs lie in multiple putative regulatory elements, several of which have prior implications in CLL/SLL or other hematological malignancies. Although experimental validation is needed, our study shows that the use of existing GWAS data in combination with eQTL analysis and in silico methods represents a useful starting point to screen for putatively causal SNPs that may be involved in the etiology of CLL/SLL

MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis

A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients' data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies

Berechenbarkeit als Sphäre digitaler Medien

Als Beitrag zu den Debatten über digitale Kulturen stellt die mit dem Humboldt-Preis 2017 prämierte Masterarbeit ‚Berechenbarkeit als Sphäre digitaler Medien’ die Frage, was mit digitalen Medien überhaupt möglich ist – und was nicht. Das dabei entwickelte Konzept der Sphäre der Berechenbarkeit legt einen Perspektivenwechsel angesichts digitaler Phänomene nahe. Neu an diesem Ansatz ist, dass die Frage nach den Grenzen des Digitalen von zwei Seiten aus angegangen wird: Zum einen wird die Turingmaschine von 1936 – fons et origo der modernen speicherprogrammierbaren digitalen Computer – minutiös analysiert. Wie dieser Rekurs zeigt, existieren Probleme und Funktionen, deren Lösung mit digitalen Medien schon rein konzeptuell unmöglich ist. Zum anderen wird dieser klassische Zugang zu den Grenzen des Digitalen durch Konzepte aus dem Bereich der Hypercomputation ergänzt. Hypercomputer sind theoretische Modelle, die hinsichtlich der Berechenbarkeit mehr leisten sollen als alle digitalen Geräte. Modelle also, die unberechenbare Probleme – dem begrifflichen Widerspruch zum Trotz – eben doch berechnen. Dieses Heranziehen von Konzepten der Hypercomputation ermöglicht es, das Konzept der digitalen Computer zusätzlich von Außen zu umgrenzen. Ziel dieses doppelten Zugangs ist die Ausarbeitung einer Sphäre der Berechenbarkeit, die all das umfasst und definiert, was mit digitalen Maschinen möglich ist, und die einen tiefgreifenden Perspektivenwechsel ermöglicht: Anstatt das Digitale weiter von der „realen Welt“ aus zu begreifen – d.h. im weitesten Sinne die Frage zu stellen, ob Phänomene der Lebenswelt im Digitalen angemessen repräsentiert werden – bietet sich mittels der Sphäre eine alternative Herangehensweise. Diese kann auf problematische Begriffe wie „Welt“, „Mensch“ oder „Geist“ zumindest temporär verzichten und stattdessen direkt an den allgemeinen Strukturen des Digitalen ansetzen, was eine erhebliche Reduktion des Problems und eine Schärfung des Begriff des Digitalen verspricht.The master’s thesis ‚Computability as the Sphere of Digital Media’ – awarded with the Humboldt-Price 2017 – is a contribution to the debate about digital cultures. It asks the question what can possibly be done with digital media – and what can’t. The turing machine from 1936 can be regarded as the definition of a sphere of computability including everything that could possibly be executed by digital machines. This concept of a sphere of computability can be used to analyze „the digital“ on a fundamental level starting right at the digital sphere itself and its techno-mathematical foundations, instead of starting the analysis by looking at the dichotomy of „real“ world phenomena and their digital representations. This change of focus holds the advantage that insufficiently answered and therefore philosophically problematic assumptions about the „world“ or the human mind need not to be made in advance of the analysis. Moreover this reversed approach makes it possible to scrutinize the representation of „world“ in digital machines from a different angle. (This abstract is not a translation of the german one. It has therefore rather the character of an addendum.

[Stammbuch Joseph Nückel]

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