Experimental African trypanosome infection suppresses the development of multiple myeloma in mice by inducing intrinsic apoptosis of malignant plasma cells

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow (BM). Recently, several studies have highlighted the role of pathogens in either promoting or dampening malignancies of unrelated origin. Trypanosoma brucei is an extracellular protozoan parasite which causes sleeping sickness. Our group has previously demonstrated that trypanosome infection affects effector plasma B cells. Therefore, we hypothesized that T. brucei infection could have an impact on MM development. Using the immunocompetent 5T33MM model, we demonstrated a significant reduction in BM-plasmacytosis and M-protein levels in mice infected with T. brucei, resulting in an increased survival of these mice. Blocking IFN. could only partially abrogate these effects, suggesting that other mechanisms are involved in the destruction of malignant plasma cells. We found that T. brucei induces intrinsic apoptosis of 5T33MM cells in vivo, and that this was associated with reduced endogenous unfolded protein response (UPR) activation. Interestingly, pharmacological inhibition of IRE1 alpha and PERK was sufficient to induce apoptosis in these cells. Together, these results demonstrate that trypanosome infections can interfere with MM development by suppressing endogenous UPR activation and promoting intrinsic apoptosis

Patient-specific image-based computer simulation for theprediction of valve morphology and calcium displacement after TAVI with the Medtronic CoreValve and the Edwards SAPIEN valve

AIMS: Our aim was to validate patient-specific software integrating baseline anatomy and biomechanical properties of both the aortic root and valve for the prediction of valve morphology and aortic leaflet calcium displacement after TAVI. METHODS AND RESULTS: Finite element computer modelling was performed in 39 patients treated with a Medtronic CoreValve System (MCS; n=33) or an Edwards SAPIEN XT (ESV; n=6). Quantitative axial frame morphology at inflow (MCS, ESV) and nadir, coaptation and commissures (MCS) was compared between multislice computed tomography (MSCT) post TAVI and a computer model as well as displacement of the aortic leaflet calcifications, quantified by the distance between the coronary ostium and the closest calcium nodule. Bland-Altman analysis revealed a strong correlation between the observed (MSCT) and predicted frame dimensions, although small differences were detected for, e.g., Dmin at the inflow (mean±SD MSCT vs. MODEL: 21.6±2.4 mm vs. 22.0±2.4 mm; difference±SD: -0.4±1.3 mm, p<0.05) and Dmax (25.6±2.7 mm vs. 26.2±2.7 mm; difference±SD: -0.6±1.0 mm, p<0.01). The observed and predicted calcium displacements were highly correlated for the left and right coronary ostia (R2=0.67 and R2=0.71, respectively p<0.001). CONCLUSIONS: Dedicated software allows accurate prediction of frame morphology and calcium displacement after valve implantation, which may help to improve outcome

Regional heterogeneity and firms’ innovation: the role of regional factors in industrial R&D in India

This study makes an early attempt to estimate the magnitude and intensity of manufacturing firms’ R&D by Indian states during the period 1991‒2008 and analyses the role of regional factors on firm-level R&D activities. As there is little research on state-wise R&D performance of firms in India, this study serves an important contribution to the academic and policy realm. It has brought out the fact the total manufacturing R&D investment in India is unevenly distributed regionally with a few states accounting for disproportionate share of it. Regional heterogeneity or inter-state disparities in R&D has increased between the 1990s and the first decade of the twenty-first century. In view of this persistent regional heterogeneity in R&D, the study has developed and estimated an empirical model for a sample of 4545 Indian manufacturing firms with R&D facilities located in single state and that explicitly includes regional factors as probable factors affecting R&D. The three-step Censored Quantitle Regression results confirm that regional factors play an important role in shaping the R&D intensity of the sample of firms. This led us to some useful policy suggestions for regional governments to promote local firms’ R&D activities