Biomedical subjects

Sriram Balasubramanian

Publications and source records attributed to Sriram Balasubramanian.

3 recordsLinked to original sources

PubMed2006

CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo.

CRA-024781 is a novel, broad spectrum hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor activity in vitro and in vivo preclinically and is under evaluation in phase I clinical trials for cancer. CRA-024781 inhibited pure recombinant HDAC1 with a K(i) of 0.007 mumol/L, and also inhibited the other HDAC isozymes HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-024781 resulted in the accumulation of acetylated histone and acetylated tubulin, resulting in an inhibition of tumor cell growth and the induction of apoptosis. CRA-024781 parenterally administered to mice harboring HCT116 or DLD-1 colon tumor xenografts resulted in a statistically significant reduction in tumor growth at doses that were well tolerated as measured by body weight. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells, and an alteration in the expression of many genes in the tumors, including several involved in apoptosis and cell growth. These results reveal CRA-024781 to be a novel HDAC inhibitor with potent antitumor activity.

Acetylation↗

PubMed2006

CRA-026440: a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo.

CRA-026440 is a novel, broad-spectrum, hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor and antiangiogenic activities in vitro and in vivo preclinically. CRA-026440 inhibited pure recombinant isozymes HDAC1, HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-026440 resulted in the accumulation of acetylated histone and acetylated tubulin, leading to an inhibition of tumor cell growth and the induction of apoptosis. CRA-026440 inhibited ex vivo angiogenesis in a dose-dependent manner. CRA-026440 parenterally given to mice harboring HCT116 or U937 human tumor xenografts resulted in a statistically significant reduction in tumor growth. CRA-026440, when used in combination with Avastin, achieved greater preclinical efficacy in HCT 116 colorectal tumor model. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells and an alteration in the expression of many genes in the tumors, including several involved in angiogenesis, apoptosis, and cell growth. These results reveal CRA-026440 to be a novel HDAC inhibitor with potent antitumor activity.

Acetylation↗

PubMed2004

Below Knee Impact Responses using Cadaveric Specimens.

Knee injuries represent about 10% of all injuries suffered during car crashes. Efforts to assess the injury risk to the posterior cruciate ligament (PCL) have been based on a study available in the literature (Viano et al., 1978), in which only two of the five knees tested had PCL ruptures. The aims of the current study were to repeat the study with a higher number of samples, study the effects of other soft tissues on knee response, and assess the adequacy of the experimental setup for the identification of a PCL tolerance. A total of 14 knees were tested using a high-speed materials testing machine. Eight were intact knees (with the patella and all the muscular and ligamentous structures), three were PCL-only knees (patella and all the muscular and ligamentous structures other than the PCL removed), and the last three were PCL-only knees with the tibia protected from bending fracture. Of the eight intact knees tested, only one had PCL mid substance rupture, one had a partial articular fracture of the tibia below the plateau, and six had simple transverse fracture of the tibial metaphysis. Of the three PCL-only knees without tibial protection, one had PCL mid substance rupture, one had avulsion at the posterior intercondylar attachment point, and the last one had a simple oblique fracture of the tibial metaphysis. Of the three PCL only knees with tibia protection, two had PCL mid-substance ruptures and the third one had an avulsion at the tibial insertion site with partial articular fracture of the lateral plateau. Overall, the results of the current study were similar to those observed by Viano et al. (1978). The average displacement at failure for all PCL related injuries was 17.2+/-2.8 mm for the current study (n=6) and 16.2+/-3.9 mm for Viano et al. (1978) (n=4). This value is higher than the Injury Assessment Reference Value of 15 mm proposed by Mertz (1984) and used in various regulations. Both studies suggest that the existence of the soft tissues other than the PCL affect the injury outcome and that the intact knee would suffer predominantly tibial metaphyseal fractures possibly due to bending. Consequently, it is concluded that the current experimental setup can produce isolated PCL injuries but the data available are inadequate to characterize PCL tolerance. A Hybrid III knee equipped with a ball bearing knee slider was also tested using a pendulum setup. Apart from the initial higher stiffness, the overall response of this knee lies within the force-deflection corridors defined using the response of the cadaver knees with PCL mid-substance failure.

Journal Article↗