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Biomedical subjects

D Sinha

Publications and source records attributed to D Sinha.

At least 19 recordsLinked to original sources
PubMed2002

Haemophilus influenzae type b vaccine formulation and risk of childhood leukaemia.

Incidence of childhood leukaemia was studied among subjects of a vaccine trial in Finland comparing the polysaccharide-diptheria toxoid conjugate and oligosaccharide-CRM197 conjugate Haemophilus influenzae type b conjugate vaccine formulations. Eighty cases of childhood leukaemia were detected: 35 among children on the polysaccharide-diptheria toxoid conjugate arm, and 45 among children on the oligosaccharide-CRM197 conjugate arm, which was not statistically significant.

Adolescent↗
PubMed2001

Haemophilus influenzae type b serology in childhood leukaemia: a case-control study.

Antibody to Haemophilus influenzae type b (Hib) polysaccharide (PRP) was measured in 42 children with acute lymphoblastic leukaemia (ALL) and 42 non-leukaemic hospital controls. Modelling anti-PRP concentrations as a function of age revealed that the slopes of the trend lines differed significantly between cases and controls (P = 0.05); anti-PRP concentrations were lower among younger cases, and higher among older cases, than among controls of the same ages.

Adolescent↗
PubMed2001

Bayesian semiparametric models for survival data with a cure fraction.

We propose methods for Bayesian inference for a new class of semiparametric survival models with a cure fraction. Specifically, we propose a semiparametric cure rate model with a smoothing parameter that controls the degree of parametricity in the right tail of the survival distribution. We show that such a parameter is crucial for these kinds of models and can have an impact on the posterior estimates. Several novel properties of the proposed model are derived. In addition, we propose a class of improper noninformative priors based on this model and examine the properties of the implied posterior. Also, a class of informative priors based on historical data is proposed and its theoretical properties are investigated. A case study involving a melanoma clinical trial is discussed in detail to demonstrate the proposed methodology.

Bayes Theorem↗
PubMed2000

A temperature-sensitive mutation of Crygs in the murine Opj cataract.

In Opj, an inherited cataract in mice, opacity is associated with a mutation in Crygs, the gene for gammaS-crystallin, the first mutation to be associated with this gene. A single base change causes replacement of Phe-9, a key hydrophobic residue in the core of the N-terminal domain, by serine. Despite this highly non-conservative change, mutant protein folds normally at low temperature. However, it exhibits a marked, concentration-dependent decrease in solubility, associated with loss of secondary structure, at close to physiological temperatures. This is reminiscent of processes thought to occur in human senile cataracts in which normal proteins become altered and aggregate. The Opj cataract is progressive and more severe in Opj/Opj than in Opj/+. Lens histology shows that whereas fiber cell morphology in Opj/+ mice is essentially normal, in Opj/Opj, cortical fiber cell morphology and the loss of maturing fiber cell nuclei are both severely disrupted from early stages. This may indicate a loss of function of gammaS-crystallin which would be consistent with ideas that members of the betagamma-crystallin superfamily may have roles associated with maintenance of cytoarchitecture.

Amino Acid Sequence↗
PubMed2000

Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells.

17beta-Estradiol (E(2)) is a rapid activator of endothelial nitric oxide synthase (eNOS). The product of this activation event, NO, is a fundamental determinant of cardiovascular homeostasis. We previously demonstrated that E(2)-stimulated endothelial NO release can occur without an increase in cytosolic Ca(2+). Here we demonstrate for the first time, to our knowledge, that E(2) rapidly induces phosphorylation and activation of eNOS through the phosphatidylinositol 3 (PI3)-kinase-Akt pathway. E(2) treatment (10 ng/mL) of the human endothelial cell line, EA.hy926, resulted in increased NO production, which was abrogated by the PI3-kinase inhibitor, LY294002, and the estrogen receptor antagonist ICI 182, 780. E(2) stimulated rapid Akt phosphorylation on serine 473. As has been shown for vascular endothelial growth factor, eNOS is an E(2)-activated Akt substrate, demonstrated by rapid eNOS phosphorylation on serine 1177, a critical residue for eNOS activation and enhanced sensitivity to resting cellular Ca(2+) levels. Adenoviral-mediated EA.hy926 transduction confirmed functional involvement of Akt, because a kinase-deficient, dominant-negative Akt abolished E(2)-stimulated NO release. The membrane-impermeant E(2)BSA conjugate, shown to bind endothelial cell membrane sites, also induced rapid Akt and consequent eNOS phosphorylation. Thus, engagement of membrane estrogen receptors results in rapid endothelial NO release through a PI3-kinase-Akt-dependent pathway. This explains, in part, the reduced requirement for cytosolic Ca(2+) fluxes and describes an important pathway relevant to cardiovascular pathophysiology.

Adenoviridae↗
PubMed2000

Human vascular endothelial cells contain membrane binding sites for estradiol, which mediate rapid intracellular signaling.

Estrogen induces both rapid and delayed effects on the cardiovascular system. The early effects take place within minutes (e.g., changes in vasomotor tone) and are mediated through rapid intracellular signaling pathways; whereas the delayed effects (e.g., remodeling or lipid alterations) require hours to days to occur and require transcriptional effects with subsequent modulation of protein expression. To study the acute effects of 17beta-estradiol (E2) treatment on vascular function, we have investigated the rapid (on the order of minutes) effects of E2 treatment on intracellular signaling in human endothelial cells (EC). Our previous data have shown that E2 induces rapid release of NO from and activation of guanylate cyclase in human EC. In this study, we demonstrate that E2 also activates mitogen-activated protein kinase (extracellular signal-related kinase) signaling within minutes in EC. We hypothesized that this effect might be mediated by estrogen receptors (ER) localized to the cell surface. Our data show that membrane-impermeant forms of E2 also activate EC mitogen-activated protein kinase as well as stimulate cGMP production and NO release. The ER antagonist ICI 182,780 blocks this effect. Using confocal microscopy and flow cytometric analysis, we demonstrate that EC contain surface binding sites for E2, detectable by cell-impermeant ligand binding and equally with an anti-ERalpha antibody. Immunoreactive bands of 66 and 45 kDa are detectable with an anti-ERalpha mAb in human EC, and their individual presence correlates functionally with E2-stimulated genomic and rapid nongenomic responses, respectively. Membrane ERs may provide key molecular switches in these novel, rapid signaling pathways induced by E2 in EC.

Antibodies, Monoclonal↗
PubMed1999

Enzyme activity of macrophage migration inhibitory factor toward oxidized catecholamines.

Macrophage migration inhibitory factor (MIF) is a relatively small, 12.5-kDa protein that is structurally related to some isomerases and for which multiple immune and catalytic roles have been proposed. MIF is widely expressed in tissues with particularly high levels in neural tissues. Here we show that MIF is able to catalyze the conversion of 3,4-dihydroxyphenylaminechrome and norepinephrinechrome, toxic quinone products of the neurotransmitter catecholamines 3,4-dihydroxyphenylamine and norepinephrine, to indoledihydroxy derivatives that may serve as precursors to neuromelanin. This raises the possibility that MIF participates in a detoxification pathway for catecholamine products and could therefore have a protective role in neural tissues, which as in Parkinson's disease, may be subject to catecholamine-related cell death.

Aging↗
PubMed1999

15-Deoxy-delta(12,14) prostaglandin J2: a putative endogenous promoter of adipogenesis suppresses the ob gene.

Leptin is considered a key factor in the regulation of appetite and energy expenditure, but little is known about the control of its synthesis and release. Thiazolidinediones (TZDs) have recently been shown to downregulate leptin expression, and it has been speculated that downregulation of the ob gene occurs through activation of the transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma). However, there are no studies using an endogenous PPARgamma ligand. We examined the effect of 15-deoxy-delta(12,14) prostaglandin J2 (15d-PGJ2), a putative natural ligand of PPARgamma, on ob gene expression in fully differentiated 3T3-L1 adipocytes and compared its effect with that of two other PPARgamma activators, the TZD troglitazone (Trog) and indomethacin (Indo). 15d-PGJ2, Trog, and Indo all inhibited leptin expression at concentrations at which they activate PPARgamma. The inhibition of leptin expression of PPARgamma activators was surprising, since PPARgamma is known to induce adipogenesis during which the ob gene is expressed. To address the possibility that PPARgamma plays different roles before and after the induction of adipogenesis, we examined the effects of the three PPARgamma ligands on the expression of leptin and the glucose transporter protein GLUT4, both of which are expressed during differentiation of 3T3-L1 preadipocytes to adipocytes. In the absence of PPARgamma ligands, leptin and GLUT4 synthesis increased from day 3 to day 9 or 10 during differentiation. However, in the presence of any of the three PPARgamma ligands, GLUT4 expression was unaffected, while ob gene expression was inhibited. We hypothesize that PPARgamma may be essential for induction of adipocyte differentiation but then needs to be inactivated to allow expression of the ob gene.

Adipose Tissue↗
PubMed1999

Development of a simple, blood based lymphoproliferation assay to assess the clinical status of patients with acute lymphoblastic leukemia.

Although childhood acute lymphoblastic leukemia (ALL) is highly responsive to chemotherapy, reliable techniques are needed to determine treatment outcome and predict relapse. Employing a 9-O-acetyl sialic acid binding lectin, ATN(H), we have identified two 9-O-acetylated sialogycoconjugates (9-OAcSGs) as novel biomarkers expressed selectively on leukemic blasts of ALL patients. Presently, we report a non-invasive, blood based lymphoproliferation assay, which employs the maximal lymphoproliferative dose of ATN(H) (MLD) to assess the status of 9-OAcSGs with progressive therapy. A low MLD (0.18 +/- 0.01 microg) in untreated patients reflects increased expression of 9-OAcSGs which decline following therapy (MLD = 2.10 +/- 0.60 microg), persist during maintenance therapy (MLD = 4.50 +/- 1.60 microg)/follow-up (MLD = 5.50 +/- 0.85 microg) and are re-induced with relapse (MLD = 0.25 +/- 0.01 microg). Since the assay detects lymphoblasts with a sensitivity of 10(-4), shows no cross-reactivity with other hematological disorders (n = 48) and has been tested in 212 patients, it meets clinical consideration.

Child↗
PubMed1999

A colorimetric assay to evaluate the chemotherapeutic response of children with acute lymphoblastic leukemia (ALL) employing achatininH: a 9-O-acetyl sialic acid binding lectin.

Employing a 9-O-acetyl sialic acid binding lectin, Achatinin(H) (ATNH), we have reported a non-invasive, blood based lymphoproliferation assay which measures the maximal lymphoproliferative dose (MLD) of ATN(H) to assess the status of 9-O-acetylated sialoglycoconjugates (9-OAcSGs) in patients with Acute lymphoblastic leukemia (ALL) (Mandal C, Sinha D, Sharma V, Bhattacharya DK. O-acetyl sialic acid binding lectin, as a probe for detection of subtle changes on the cell surface induced during acute lymphoblastic leukemia [ALL] and its clinical application. Ind J Biochem Biophys 1997;34:82; Sinha D, Mandal C, Bhattacharya DK. Development of a simple blood based lymphoproliferation assay to assess the clinical status of patients with acute lymphoblastic leukemia. Leuk Res 1999;13:309-312; Sinha D, Mandal C, Bhattacharya DK. A novel method for prognostic evaluation of childhood acute lymphoblastic leukemia. Leukemia 1999;13[in press]). Although the expression of 9-OAcSGs clearly serves as an index of treatment outcome, the assay has limitations in that it requires radioisotopes, i.e. [3H]-TdR. Therefore a colorimetric assay was developed as an alternative approach. The pre-treatment MLD, as measured by the colorimetric assay, was 0.15 +/- 0.02 microg which progressively increased during consolidation therapy (1.40 +/- 0.39 microg), maintenance therapy (4.20 +/- 1.60 microg) and in followed-up cases (5.20 +/- 0.43 microg) but sharply declined following relapse (0.25 +/- 0.02 microg). The colorimetric assay also showed a good correlation with radiometric assay (r = + 0.93) and their mean coefficient of inter-assay precision were also comparable (15.53% versus 14.86%). We therefore propose that the colorimetric assay is a safe, non-radiometric, user-friendly alternative for assessing individual chemotherapeutic responses in childhood ALL.

Acetylation↗
PubMed1999

Identification of 9-O acetyl sialoglycoconjugates (9-OAcSGs) as biomarkers in childhood acute lymphoblastic leukemia using a lectin, AchatininH, as a probe.

Neoplastic transformation causes changes in cell surface architecture, most notably, aberrant sialylation. Exploiting the restricted specificity of a 9-O acetyl sialic acid (9-OAcSA) binding lectin, AchatininH (ATN(H)), we have identified two 9-O acetyl sialoglyconjugates (9-OAcSGs) on lymphoblasts of 87 children suffering from acute lymphoblastic leukemia (ALL). The preferential binding of ATN(H) to lymphoblasts induces their 11-fold increased agglutination (81 +/- 7.8%) compared to peripheral blood mononuclear cells (PBMC) of normal donors (8 +/- 4.3%) which corroborates with flow cytometry studies. Agglutination of MOLT-4 (87 +/- 4.8%), a lymphoblastoid cell line and MDCK (91.25 +/- 0.01%), a cell line expressing surface 9-OAcSA, confirms the preferential binding of ATN(H) to lymphoblasts through their surface 9-OAcSGs. Furthermore, fluorometric quantitation reveals a 4.6-fold increase in % of 9-OAcSA on lymphoblasts of ALL patients (42.1 +/- 4.1%) compared to normal donors (9.2 +/- 3.4%). Western blotting confirms that ATN(H) recognizes two membrane sialoglycoconjugates, of MW 120 kDa and 90 kDa, both having 9-OAcSA alpha2 --> 6 GalNAc terminal sugar moiety as their lectinogenic epitope. We propose that these 9-OAcSGs may serve as biomarkers for detection and monitoring of lymphoblasts in ALL and accordingly merit therapeutic considerations.

Agglutination Tests↗
PubMed1999

Bayesian analysis and model selection for interval-censored survival data.

Interval-censored data occur in survival analysis when the survival time of each patient is only known to be within an interval and these censoring intervals differ from patient to patient. For such data, we present some Bayesian discretized semiparametric models, incorporating proportional and nonproportional hazards structures, along with associated statistical analyses and tools for model selection using sampling-based methods. The scope of these methodologies is illustrated through a reanalysis of a breast cancer data set (Finkelstein, 1986, Biometrics 42, 845-854) to test whether the effect of covariate on survival changes over time.

Algorithms↗
PubMed1999

Carboplatin and paclitaxel, alone and in combination: dose escalation, measurement of renal function, and role of the p53 tumor suppressor gene.

In this pharmacokinetic and dose-escalation study of the carboplatin/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combination, patients were randomly assigned to receive paclitaxel either as a 1-hour or a 3-hour infusion. The 1-hour infusion was feasible, with maximum tolerated doses similar to those previously reported for a 3-hour infusion. Using patients' age, height, plasma creatinine, and plasma creatine kinase provided an improved estimate of the glomerular filtration rate compared with the more traditional creatinine-based formulas according to population analysis of data derived from glomerular filtration rate estimates performed by an isotope method. Studies of the p53 gene sequence of ovarian tumors at diagnosis suggest that p53 mutations are a potent predictor of response to subsequent treatment with carboplatin.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Macrophage migration inhibitory factor (MIF)--its role in catecholamine metabolism.

Macrophage migration inhibitory factor (MIF) was originally identified several decades ago as a lymphokine-derived protein that inhibited monocyte migration. Recently, it has been reported that MIF has D-dopachrome tautomerase, phenylpyruvate tautomerase and thiol protein oxidoreductase activities, although the physiological significance of those activities is not yet clear. Here we show that MIF is able to catalyze the conversion of dopaminechrome and norepinephrinechrome, toxic quinone products of the neurotransmitters dopamine and norepinephrine, respectively, to indole derivatives that may serve as precursors to neuromelanin. Since MIF is highly expressed in human brain, these observations raise the possibility that MIF participates in a detoxification pathway for catecholamine products and could therefore have an important role for neural tissues. The potential role of MIF in the formation of neuromelanin from catecholamines is also an extremely interesting possibility.

Animals↗
PubMed1998

Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice.

We have been developing a series of nonpeptidic, small molecule farnesyl protein transferase inhibitors that share a common tricyclic nucleus and compete with peptide/protein substrates for binding to farnesyl protein transferase. Here, we report on pharmacological and in vivo studies with SCH 66336, a lead compound in this structural class. SCH 66336 potently inhibits Ha-Ras processing in whole cells and blocks the transformed growth properties of fibroblasts and human tumor cell lines expressing activated Ki-Ras proteins. The anchorage-independent growth of many human tumor lines that lack an activated ras oncogene is also blocked by treatment with SCH 66336. In mouse, rat, and monkey systems, SCH 66336 has excellent oral bioavailability and pharmacokinetic properties. In the nude mouse, SCH 66336 demonstrated potent oral activity in a wide array of human tumor xenograft models including tumors of colon, lung, pancreas, prostate, and urinary bladder origin. Enhanced in vivo efficacy was observed when SCH 66336 was combined with various cytotoxic agents (cyclophosphamide, 5-fluorouracil, and vincristine). In a Ha-Ras transgenic mouse model, prophylactic treatment with SCH 66336 delayed tumor onset, reduced the average number of tumors/mouse, and reduced the average tumor weight/animal. In a therapeutic mode in which gavage treatment was initiated after the transgenic mice had developed palpable tumors, significant tumor regression was induced by SCH 66336 in a dose-dependent fashion. This was associated with increased apoptosis and decreased DNA synthesis in tumors of animals treated with SCH 66336. Enhanced efficacy was also observed in this model when SCH 66336 was combined with cyclophosphamide. SCH 66336 is presently being evaluated in Phase I clinical trials.

3T3 Cells↗