Phenotypic Detection of Clonotypic B Cells in Multiple Myeloma by Specific Immunoglobulin Ligands Reveals their Rarity in Multiple Myeloma

In multiple myeloma, circulating “clonotypic” B cells, that express the immunoglobulin rearrangement of the malignant plasma cell clone, can be indirectly detected by PCR. Their role as potential “feeder” cells for the malignant plasma cell pool remains controversial. Here we established for the first time an approach that allows direct tracking of such clonotypic cells by labeling with patient-specific immunoglobulin ligands in 15 patients with myeloma. Fifty percent of patients showed evidence of clonotypic B cells in blood or bone marrow by PCR. Epitope-mimicking peptides from random libraries were selected on each patient's individual immunoglobulin and used as ligands to trace cells expressing the idiotypic immunoglobulin on their surface. We established a flow cytometry and immunofluorescence protocol to track clonotypic B cells and validated it in two independent monoclonal B cell systems. Using this method, we found clonotypic B cells in only one out of 15 myeloma patients. In view of the assay's validated sensitivity level of 10−3, this surprising data suggests that the abundance of such cells has been vastly overestimated in the past and that they apparently represent a very rare population in myeloma. Our novel tracing approach may open perspectives to isolate and analyze clonotypic B cells and determine their role in myeloma pathobiology

Mechanochemical Solvent-Free Catalytic C—H Methylation

The mechanochemical, solvent-free, highly regioselective, rhodium-catalyzed C-H methylation of (hetero)arenes is reported. The reaction shows excellent functional-group compatibility and is demonstrated to work for the late-stage C-H methylation of biologically active compounds. The method requires no external heating and benefits from considerably shorter reaction times than previous solution-based C-H methylation protocols. Additionally, the mechanochemical approach is shown to enable the efficient synthesis of organometallic complexes that are difficult to generate conventionally

Arynes and Their Precursors from Arylboronic Acids via Catalytic C–H Silylation

A new, operationally simple approach is presented to access arynes and their fluoride-activated precursors based on Ru-catalyzed C–H silylation of arylboronates. Chromatographic purification may be deferred until after aryne capture, rendering the arylboronates <i>de facto</i> precursors. Access to various new arynes and their derivatives is demonstrated, including, for the first time, those based on a 2,3-carbazolyne and 2,3-fluorenyne core, which pave the way for novel derivatizations of motifs relevant to materials chemistry

Respostas fisiológicas da tilápia-do-nilo e variáveis limnológicas após decomposição de macrófitas utilizando herbicidas.

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A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men

Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD

Common genetic variants of fetal hemoglobin modify hematological phenotypes in MDS/MPN/Myeloma patients receiving cytotoxic drugs

Genetic studies identify common variants within the HBS1L-MYB intergenic region (HMIP), BCL11A, and Xmn1-HBG2 as associated with elevated fetal hemoglobin (HbF) levels and other clinically important human hematological traits. Recent studies suggest HbF is a predictor of outcome in MDS/AML patients receiving decitabine. We assessed effects of HbF genetic variants on hematological traits in myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS) and myeloma on HbF-inducing therapy to determine potential for variants predicting treatment response. Seven common HbF variants at HMIP, BCL11A, Xmn1-HGB2 loci were genotyped in 89 patients with MPN on Hydroxyurea (HU), myeloma on Lenalidomide, and MDS on Azacytidine. HbF genetic association was seen with rs9494142 (HMIP) in MPN on HU (p = 0.04) and rs1427407 (BCL11A) in myeloma on Lenalidomide (p = 0.002). HMIP variants rs9494142 and rs6920211 influenced baseline platelets (p = 0.04) and hemoglobin treatment response (p = 0.02). rs1427407 (BCL11A) was significantly associated with increased platelets (p = 0.04) negating thrombocytopenic tendency of Lenalidomide. These HbF variants showed significantly discordant minor allele frequencies in MDS/MPN/myeloma compared to wider European population data. This small study findings together suggest the implication of these variants in treatment response and disease biology in MDS/MPN/myeloma warranting larger prospective genotype-phenotype association studies

Proceedings of the first workshop on Peripheral Machine Interfaces: going beyond traditional surface electromyography

One of the hottest topics in rehabilitation robotics is that of proper control of prosthetic devices. Despite decades of research, the state of the art is dramatically behind the expectations. To shed light on this issue, in June, 2013 the first international workshop on Present and future of non-invasive PNS-Machine Interfaces was convened, hosted by the International Conference on Rehabilitation Robotics. The keyword PNS-Machine Interface (PMI) has been selected to denote human-machine interfaces targeted at the limb-deficient, mainly upper-limb amputees, dealing with signals gathered from the peripheral nervous system (PNS) in a non-invasive way, that is, from the surface of the residuum. The workshop was intended to provide an overview of the state of the art and future perspectives of such interfaces; this paper represents is a collection of opinions expressed by each and every researcher/group involved in it