Role of Superficial CD200 Marker in Differential Diagnosis of Malignant B-Cell Lymphoproliferative Diseases

Background & Aims. Flow cytometry is successfully used for diagnosis of malignant lymphoproliferative disorders. However, there are atypical cases that are difficult to interpret; thus, new markers relevant for the differential diagnosis are to be searched for. The aim is to analyze CD200 expression in patients with B-cell lymphoproliferative disorders. Materials & Methods. 187 patients with chronic lymphocytic leukemia (CLL), 14 patients with mantle cell lymphoma (MCL), 9 patients with marginal zone lymphoma (MZL), and 5 patients with hairy cell leukemia (HCL) were enrolled in the study. Neoplasm was not confirmed in 12 subjects. The patients underwent the following tests: CBC, immunophenotyping of peripheral blood or bone marrow lymphocytes, and a cytogenetic test. In some cases, an additional immunohistochemical test of bone marrow trepanobiopsy or lymph node biopsy samples was required. Results. In all cases of CLL and HCL, the CD200 expression was positive; mean fluorescence intensity was higher in these cases as compared to other groups. Negative expression of CD200 prevailed in MCL patients; however, at the same time 2 cases of intermediate and positive expression were reported, both showing moderate fluorescence intensity values. CD200 expression was heterogeneous in MZL patients. Conclusion. The CD200 negative expression excludes typical HCL and CLL. Additional cytogenetic and immunnohistoсhemical tests should be performed in such cases to verify the diagnosis, first of all, MCL or MZL

Minimal Residual Disease and IGHV-Genes Mutational Status as the Main Predictors of Response to Bendamustine-Rituximab Therapy in Previously Untreated Chronic Lymphocytic Leukemia

Background. In patients with chronic lymphocytic leukemia (CLL) the eradication of minimal residual disease (MRD) is a prognostic factor of overall survival (OS) and progression-free survival (PFS). IGHV mutational status has also independent prognostic value. Aim. To analyse the impact of mutational status and MRD eradication in CLL patients after first-line standard BR (bendamustine + rituximab) immunochemotherapy. Materials & Methods. The prospective study included patients with immunophenotypically confirmed CLL who had not previously received anticancer therapy. All patients were treated by BR combination from 2012 to 2015. MRD level was determined in 109 patients after completing the 3rd and the 6th treatment courses. IGHV mutational status data were available for 98 patients. IGHV mutational status was evaluated in accordance with ERIC recommendations. MRD was assessed by standardized method of 4-color flow cytometry. Results. MRD negativity was achieved in 37 (34 %) out of 109 patients. MRD eradication correlated with the best PFS (p = 0.04). IGHV mutational status had a statistically significant impact on PFS (p = 0.02). In patients with MRD-negative response and IGHV mutation no unfavorable events occurred during the period of monitoring. Conversely, PFS rates in MRD-negative patients having no IGHV mutation and in MRD-positive patients with mutation were significantly worse. MRD eradication resulted in statistically significant improvement of PFS rates after completing 3 treatment courses, compared with the cases with MRD persistence regardless of residual malignant clone level (p = 0.01). Conclusion. BR therapy as first-line treatment statistically improved PFS in patients who achieved MRD-negative remission after completing the 3rd treatment course. PFS was significantly higher in MRD-negative patients with IGHV mutation after 6 treatment courses. MRD negativity resulting from 6 BR therapies in patients having no IGHV mutation was not accompanied by PFS improvement. It follows that by itself MRD negativity cannot be considered to be a universal prognostic factor

Structural Similarity and Classification of Protein Interaction Interfaces

Interactions between proteins play a key role in many cellular processes. Studying protein-protein interactions that share similar interaction interfaces may shed light on their evolution and could be helpful in elucidating the mechanisms behind stability and dynamics of the protein complexes. When two complexes share structurally similar subunits, the similarity of the interaction interfaces can be found through a structural superposition of the subunits. However, an accurate detection of similarity between the protein complexes containing subunits of unrelated structure remains an open problem

Novel Peptide-Mediated Interactions Derived from High-Resolution 3-Dimensional Structures

Many biological responses to intra- and extracellular stimuli are regulated through complex networks of transient protein interactions where a globular domain in one protein recognizes a linear peptide from another, creating a relatively small contact interface. These peptide stretches are often found in unstructured regions of proteins, and contain a consensus motif complementary to the interaction surface displayed by their binding partners. While most current methods for the de novo discovery of such motifs exploit their tendency to occur in disordered regions, our work here focuses on another observation: upon binding to their partner domain, motifs adopt a well-defined structure. Indeed, through the analysis of all peptide-mediated interactions of known high-resolution three-dimensional (3D) structure, we found that the structure of the peptide may be as characteristic as the consensus motif, and help identify target peptides even though they do not match the established patterns. Our analyses of the structural features of known motifs reveal that they tend to have a particular stretched and elongated structure, unlike most other peptides of the same length. Accordingly, we have implemented a strategy based on a Support Vector Machine that uses this features, along with other structure-encoded information about binding interfaces, to search the set of protein interactions of known 3D structure and to identify unnoticed peptide-mediated interactions among them. We have also derived consensus patterns for these interactions, whenever enough information was available, and compared our results with established linear motif patterns and their binding domains. Finally, to cross-validate our identification strategy, we scanned interactome networks from four model organisms with our newly derived patterns to see if any of them occurred more often than expected. Indeed, we found significant over-representations for 64 domain-motif interactions, 46 of which had not been described before, involving over 6,000 interactions in total for which we could suggest the molecular details determining the binding

Main results of the first experimental campaign in the stellarator W7-X

A summary of the first operational phase (OP1.1) at the stellarator W7-X is given. The operational setup of heating and diagnostics as well the results of experiments are briefly described. Plasma parameters and confinement are better than expected: Te > 8 keV and Ti > 2 keV at ne ≈ 3×1019 m-3 yielding β0 ≈ 2.5 %. The results for ECR heating with X2-mode as well the ECCD are in good agreement with the theory predictions. The heating scenario with the O2-mode alone was successfully first time performed. Stellarator specific regime of core “electron root” confinement was obtained

Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups

Background: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). Methods: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. Results: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). Conclusions: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease

The complex variability of blazars: time-scales and periodicity analysis in S4 0954+65

Among active galactic nuclei, blazars show extreme variability properties. We here investigate the case of the BL Lac object S4 0954+65 with data acquired in 2019-2020 by the Transiting Exoplanet Survey Satellite (TESS) and by the Whole Earth Blazar Telescope (WEBT) Collaboration. The 2-min cadence optical light curves provided by TESS during three observing sectors of nearly 1 month each allow us to study the fast variability in great detail. We identify several characteristic short-term time-scales, ranging from a few hours to a few days. However, these are not persistent, as they differ in the various TESS sectors. The long-term photometric and polarimetric optical and radio monitoring undertaken by the WEBT brings significant additional information, revealing that (i) in the optical, long-term flux changes are almost achromatic, while the short-term ones are strongly chromatic; (ii) the radio flux variations at 37 GHz follow those in the optical with a delay of about 3 weeks; (iii) the range of variation of the polarization degree and angle is much larger in the optical than in the radio band, but the mean polarization angles are similar; (iv) the optical long-term variability is characterized by a quasi-periodicity of about 1 month. We explain the source behaviour in terms of a rotating inhomogeneous helical jet, whose pitch angle can change in time