Biomedical subjects

B Bhardwaj

Publications and source records attributed to B Bhardwaj.

14 recordsLinked to original sources

PubMed1995

Antiestrogens: mechanisms and actions in target cells.

Antiestrogens, acting via the estrogen receptor (ER) evoke conformational changes in the ER and inhibit the effects of estrogens as well as exerting anti-growth factor activities. Although the binding of estrogens and antiestrogens is mutually competitive, studies with ER mutants indicate that some of the contact sites of estrogens and antiestrogens are likely different. Some mutations in the hormone-binding domain of the ER and deletions of C-terminal regions result in ligand discrimination mutants, i.e. receptors that are differentially altered in their ability to bind and/or mediate the actions of estrogens vs antiestrogens. Studies in a variety of cell lines and with different promoters indicate marked cell context- and promoter-dependence in the actions of antiestrogens and variant ERs. In several cell systems, estrogens and protein kinase activators such as cAMP synergize to enhance the transcriptional activity of the ER in a promoter-specific manner. In addition, cAMP changes the agonist/antagonist balance of tamoxifen-like antiestrogens, increasing their agonistic activity and reducing their efficacy in reversing estrogen actions. Estrogens, and antiestrogens to a lesser extent, as well as protein kinase activators and growth factors increase phosphorylation of the ER and/or proteins involved in the ER-specific response pathway. These changes in phosphorylation alter the biological effectiveness of the ER. Multiple interactions among different cellular signal transduction systems are involved in the regulation of cell proliferation and gene expression by estrogens and antiestrogens.

Cyclic AMP↗

PubMed1993

Electrocardiographic diagnosis of left ventricular hypertrophy in the presence of left bundle branch block: an echocardiographic correlation.

Surface electrocardiographic findings of 10 cases of left bundle branch block with echocardiographically determined left ventricular hypertrophy were compared with another 10 cases of left bundle branch block without left ventricular hypertrophy. Horizontal plane QRS- and T-wave angle > or = 150 degrees was highly sensitive (70%) and specific (90%) in diagnosing left ventricular hypertrophy in the presence of left bundle branch block. This diagnosis criterion was better than any other conventional criterion described before.

Adult↗

PubMed1993

Hormone binding and transcription activation by estrogen receptors: analyses using mammalian and yeast systems.

We have used affinity labeling, site-directed mutagenesis and regional chemical mutagenesis in order to determine regions of the human estrogen receptor (ER) important in hormone binding, ligand discrimination between estrogens and antiestrogens, and transcriptional activation. Affinity labeling studies with the antiestrogen, tamoxifen aziridine and the estrogen, ketononestrol aziridine have identified cysteine 530 in the ER hormone binding domain as the primary site of labeling. In the absence of a cysteine at 530 (i.e. C530 mutant), C381 becomes the site of estrogen-compatible tamoxifen aziridine labeling. Hence these two residues, although far apart in the primary linear sequence of the ER protein, must be close in the three-dimensional structure of the protein, in the ER ligand binding pocket, so that the ligand can reach either site. Site-directed mutagenesis of selected residues in the ER and region-specific chemical mutagenesis of the ER hormone binding domain with initial phenotypic screening in yeast have enabled the identification of a region near C530 important in discrimination between estrogens and antiestrogens and of other residues important in hormone-dependent transcriptional activation. Some ER mutants with alterations in the carboxy-terminal portion of the hormone binding domain are transcriptionally inactive yet bind hormone and also function as potent dominant negative ERs, suppressing the activity of wild-type ER at low concentrations. These studies reveal a separation of the hormone binding and transcription activation functions of the ER. They are also beginning to provide a more detailed picture of the ER hormone binding domain and amino acids important in ligand binding and discrimination between different categories of agonist and antagonist ligands. Such information will be important in the design of maximally effective antiestrogens. In addition, since there is now substantial evidence for a mixture of wild-type and variant ERs in breast cancers, our studies should provide insight about the bioactivities of these variant receptors and their roles in modulating the activity of wild type ER, and should lead to a better understanding of the possible role of variant receptors in altered response or resistance to antiestrogen and endocrine therapy in breast cancer. In addition, some dominant negative receptors may prove useful in examining ER mechanisms of action and in suppressing the estrogen-dependent growth of breast cancer cells.

Affinity Labels↗

PubMed1992

Acute lymphoblastic leukaemia presenting as breast mass.

A 14 year old girl presented with bilateral symmetrical involvement of the breast with acute lymphoblastic leukaemia (ALL). Treatment with combined therapy of adriamycin, vincristine and prednisolone produced a remission in the leukaemia with complete resolution of the breast mass.

Adolescent↗

PubMed1991

Rat as a potential model for hearing loss in biotinidase deficiency.

Biotinidase deficiency is an inborn error of metabolism that is transmitted as an autosomal recessive disorder. Symptoms include hearing loss, ataxia, blindness, mental retardation, and seizures. The metabolic defect is an inability to recycle the vitamin biotin, which is an important cofactor in key enzymes. We therefore sought to develop an animal model for this disorder by inducing biotin deficiency. Rat pups were divided into control and experimental groups. Control rats were fed a normal diet whereas experimental animals were given a diet deficient in biotin. Animals from both groups underwent brain stem auditory evoked potential testing at various ages. Wave I thresholds at various ages were similar in both groups. Latencies for wave I, however, and interpeak latencies (I-IV) were prolonged in the biotin-deficient groups compared to controls. Scanning electron microscopy of the organ of Corti in biotin-deficient animals showed no significant hair cell loss. The biotin-deficient developing rat appears to acquire functional changes in the auditory brain stem. These effects may be caused by defective myelination, since biotin is important in fatty acid metabolism.

Amidohydrolases↗

PubMed1986