SPROUTY 2: A Novel Attenuator of B Cell Receptor and MAPK Signaling in Chronic Lymphocytic Leukemia

Clinical heterogeneity is a major barrier to effective treatment of Chronic Lymphocytic Leukemia (CLL). Emerging evidence suggests that constitutive activation of various signaling pathways plays a role in the heterogeneous clinical outcome of CLL patients. MAPK-Erk signaling represents one such pathway with a demonstrated role in CLL pathogenesis. In this study, we have investigated the role of Sprouty2 (SPRY2) as a negative regulator of receptor and non-receptor tyrosine kinase signaling in the pathogenesis of CLL. We show that SPRY2 expression is significantly decreased in CLL cells, particularly from poor prognosis patients compared to those from good prognosis patients. Over-expression of SPRY2 in CLL cells from poor prognosis patients decreased their proliferation while increasing their apoptosis. Conversely, down-regulation of SPRY2 in CLL cells from good prognosis patients resulted in increased proliferation. Furthermore, CLL cells with low SPRY2 expression grew more rapidly in a xenograft model of CLL. Strikingly, B-cell specific transgenic over-expression of spry2 in mice led to a decrease in the frequency of B1 cells, the precursors of CLL cells in rodents. Mechanistically, we show that SPRY2 attenuates the BCR and MAPK-Erk signaling by binding to and antagonizing the activities of RAF1, BRAF and SYK in normal B cells and CLL cells. We identified that SPRY2 is targeted by miR-21 which in turn leads to increased activity of Syk and Erk in CLL cells. We also show that the activation of miR-21 is mediated by IL-10 induced STAT3 signaling in CLL cells. Taken together, these results establish SPRY2 as a critical negative regulator of BCR-mediated MAPK-Erk signaling in CLL, thereby providing one of the molecular mechanisms to explain the clinical heterogeneity of CLL

Stromal Tumor Microenvironment in Chronic Lymphocytic Leukemia: Regulation of Leukemic Progression

Chronic Lymphocytic Leukemia (CLL), the most prevalent adult leukemia in western countries, which is highly heterogeneous with a very variable clinical outcome. Emerging evidence indicates that the stromal tumor microenvironment (STME) and stromal associated genes (SAG) play important roles in the pathogenesis and progression of CLL. However, the precise mechanisms by which STME and SAG are involved in this process remain unknown. In an attempt to explore the role of STME in this process, we examined the expression levels of stromal associated genes using gene expression profiling (GEP) of CLL cells from lymph nodes (LN) (n=15), bone marrow (BM) (n=18), and peripheral blood (PB) (n=20). Interestingly, LUM, MMP9, MYLK, ITGA9, CAV1, CAV2, FBN1, PARVA, CALD1, ITGB5 and EHD2 were found to be overexpressed while ITGB2, DLC1 and ITGA6 were under expressed in LN-CLL compared to BM-CLL and PB-CLL. This is suggestive of a role for LN-mediated TME in CLL cell survival/progression. Among these genes, expression of MYLK, CAV1 and CAV2 correlated with clinical outcome as determined by time to first treatment. Together, our studies show that members of the stromal signature, particularly in the CLL cells from lymph nodes, regulate CLL cell survival and proliferation and thus leukemic progression

Relationships of surface ozone with its precursors, particulate matter and meteorology over Delhi

The paper presents the temporal variations of surface ozone (O-3) and its precursors (oxides of nitrogen (NOX), carbon monoxide (CO), methane (CH4) and non-methane hydrocarbons (NMHCs)) along with particulate matter (PM10 and PM2.5) and their relationship with meteorology during January 2012 to December 2014 at an urban site of Delhi, India. The mean mixing ratio of surface O-3, NOX, CO, CH4 and NMHCs were 29.5 +/- 7.3 ppb, 34.7 +/- 11.2 ppb, 1.82 +/- 0.52 ppm, 3.07 +/- 0.37 ppm and 0.53 +/- 0.17 ppm, respectively. This study also comprises an analysis of the relation between UV irradiance and surface O-3. A relationship between the total oxidant concentrations (OX) and NOX has been used to identify the regional background O-3 values and the local levels of primary pollution. An attempt has been made to identify the existence of NOX or NMHC sensitive regime by charting out relationships between O-3, NOX and NMHCs. The respective high pollution periods of surface O-3 and PM differ on a seasonal timescale. Linear regression analysis has been used to quantify the negative influence of the chemical constituents of PM (elemental carbon, NO3-, SO42-) on O-3 values. Statistical validation using bivariate correlation analysis, multiple linear regression (MLR) analysis and principal component analysis (PCA) strongly describes the intricate relationships among the aforesaid variables and meteorology. Potential Source Contribution Function (PSCF) and Concentration Weighted Trajectory (CWT) analysis indicated upper Indo-Gangetic Plain (IGP) as a significant source region of O-3 precursor gases contributing for O-3 values at the study site

author response efficacy of β lactam β lactamase inhibitor combination is linked to whib4 mediated changes in redox physiology of mycobacterium tuberculosis

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Efficacy of β-lactam/β-lactamase inhibitor combination is linked to WhiB4-mediated changes in redox physiology of Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) expresses a broad-spectrum β-lactamase (BlaC) that mediates resistance to one of the highly effective antibacterials, β-lactams. Nonetheless, β-lactams showed mycobactericidal activity in combination with β-lactamase inhibitor, clavulanate (Clav). However, the mechanistic aspects of how Mtb responds to β-lactams such as Amoxicillin in combination with Clav (referred as Augmentin [AG]) are not clear. Here, we identified cytoplasmic redox potential and intracellular redox sensor, WhiB4, as key determinants of mycobacterial resistance against AG. Using computer-based, biochemical, redox-biosensor, and genetic strategies, we uncovered a functional linkage between specific determinants of β-lactam resistance (e.g. β-lactamase) and redox potential in Mtb. We also describe the role of WhiB4 in coordinating the activity of β-lactamase in a redox-dependent manner to tolerate AG. Disruption of WhiB4 enhances AG tolerance, whereas overexpression potentiates AG activity against drug-resistant Mtb. Our findings suggest that AG can be exploited to diminish drug-resistance in Mtb through redox-based interventions