The 5T mouse multiple myeloma model: absence of c-myc oncogene rearrangement in early transplant generations.

Consistent chromosomal translocations involving the c-myc cellular oncogene and one of the three immunoglobin loci are typical for human Burkitt's lymphoma, induced mouse plasmacytoma (MPC) and spontaneously arising rat immunocytoma (RIC). Another plasma cell malignancy, multiple myeloma (MM), arising spontaneously in the ageing C57BL/KaLwRij mice, was investigated in order to see whether the MM cells contain c-myc abnormalities of the MPC or RIC type. Rearrangement of the c-myc oncogene was found in the bone marrow cells only in 5T2 MM transplantation line in a mouse of the 24th generation and in none of the seven other MM of the 5T series which were of earlier generations. Since the mouse 5T MM resembles the human MM very closely, including the absence of consistent structural c-myc oncogene abnormalities, it can serve as a useful experimental model for studies on the aetiopathogenesis of this disease

Impact of high carbon amendments and pre-crops on soil bacterial communities

A 2-year outdoor mesocosm experiment was carried out to determine the effects of high C amendments (HCAs; wheat straw and sawdust) compared to a control with no addition of HCAs (no-HCA) and 2 different crop rotation systems (spring barley/winter barley and faba bean/winter barley) on soil bacterial communities using a molecular barcoding approach. Samples were analyzed after pre-crop harvest (T1) and harvest of winter barley (T2). Our data demonstrate a clear drop in bacterial diversity after winter barley harvest in the no-HCA and wheat straw treatment compared to the pre-crops. Sawdust application had a stabilizing effect on bacterial diversity compared to the pre-crops and induced an increase in carbon (C) stocks in soil which were however negatively correlated with yields. Main responders in the no-HCA and wheat straw treatment compared to the pre-crops were bacteria of the phyla Actinobacteria and Bacteroidetes which were enriched and bacteria belonging to Firmicutes, Gemmatimonadetes, Proteobacteria, and Gemmatimonadaceae which were depleted. Overall differences between wheat straw-amended and no-HCA control samples were small and included single ASVs from various phyla. In sawdust-amended samples, only a shift of some Proteobacteria families was observed compared to the no-HCA control. Overall, pre-crop plant species had small influence on the observed response pattern of the soil microbiome towards the amendments and was only visible for wheat straw

The Testing by Fire of the Builders' Works: 1 Corinthians 3.10-15

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A geometric analysis of hallux valgus: correlation with clinical assessment of severity

<p>Abstract</p> <p>Background</p> <p>Application of plane geometry to the study of bunion deformity may represent an interesting and novel approach in the research field of hallux valgus. For the purpose of contributing to development of a different perspective in the assessment of hallux valgus, this study was conducted with three objectives: a) to determine the position on the intersection point of the perpendicular bisectors of the longitudinal axes of the first metatarsal and proximal phalanx (IP), b) to correlate the location of this point with hallux valgus deformity according to angular measurements and according to visual assessment of the severity carried out by three independent observers, and c) to assess whether this IP correlated with the radius of the first metatarsophalangeal arc circumference.</p> <p>Methods</p> <p>Measurements evaluated were intermetatarsal angle (IMA), hallux valgus angle (HVA), and proximal phalangeal articular angle (PPAA). The Autocad^®program computed the location of the IP inside or outside of the foot. Three independent observers rated the severity of hallux valgus in photographs using a 100-mm visual analogue scale (VAS).</p> <p>Results</p> <p>Measurements of all angles except PPAA showed significantly lower values when the IP was located out of the foot more distantly and vice versa, significantly higher values for severe deformities in which the IP was found inside the foot (<it>p </it>< 0.001). The IP correlated significantly with VAS scores and with the length of the radius of the circle that included the first metatarsophalangeal arc circumference (<it>p </it>< 0.001)</p> <p>Conclusion</p> <p>The IP is a useful indicator of hallux valgus deformity because correlated significantly with IMA and HVA measurements, VAS scores obtained by visual inspection of the degree of deformity, and location of the center of the first metatarsophalangeal arc circumference.</p

Polycomb Target Genes Are Silenced in Multiple Myeloma

Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies

Tracking human multiple myeloma xenografts in NOD-Rag-1/IL-2 receptor gamma chain-null mice with the novel biomarker AKAP-4

<p>Abstract</p> <p>Background</p> <p>Multiple myeloma (MM) is a fatal malignancy ranking second in prevalence among hematological tumors. Continuous efforts are being made to develop innovative and more effective treatments. The preclinical evaluation of new therapies relies on the use of murine models of the disease.</p> <p>Methods</p> <p>Here we describe a new MM animal model in NOD-Rag1null IL2rgnull (NRG) mice that supports the engraftment of cell lines and primary MM cells that can be tracked with the tumor antigen, AKAP-4.</p> <p>Results</p> <p>Human MM cell lines, U266 and H929, and primary MM cells were successfully engrafted in NRG mice after intravenous administration, and were found in the bone marrow, blood and spleen of tumor-challenged animals. The AKAP-4 expression pattern was similar to that of known MM markers, such as paraproteins, CD38 and CD45.</p> <p>Conclusions</p> <p>We developed for the first time a murine model allowing for the growth of both MM cell lines and primary cells in multifocal sites, thus mimicking the disease seen in patients. Additionally, we validated the use of AKAP-4 antigen to track tumor growth <it>in vivo </it>and to specifically identify MM cells in mouse tissues. We expect that our model will significantly improve the pre-clinical evaluation of new anti-myeloma therapies.</p