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Biomedical subjects

A Chakraborty

Publications and source records attributed to A Chakraborty.

At least 55 records · Page 3Linked to original sources
PubMed2000

Cryptococcal prostatitis in a patient with chronic lymphocytic leukemia.

Cryptococcosis is a systemic mycosis usually affecting patients of immunodeficiency i.e. transplants recipients, patients on chemotherapy for neoplastic diseases and in those suffering from human immunodeficiency virus infection. We report a 52-year old male suffering from chronic lymphocytic leukemia (CLL) on chemotherapy who presented with fever and features of prostatism. Cryptococcus neoformans infection (CN) was diagnosed on aspiration of a prostatic nodule. Subsequent investigations revealed a disseminated involvement by cryptococcus. The case represents an unusual presentation of disseminated cryptococcosis.

Antifungal Agents↗
PubMed1999

Antibacterial steroid alkaloids from the stem bark of Holarrhena pubescens.

Holarrhena pubescens (syn. H. antidysenterica) (L.) WALL. stem bark was tested for antibacterial efficacy against Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus faecalis, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa using the microdilution broth method as well as the disc diffusion method. The crude methanolic extract was active against all tested bacteria. Further chemical fractionation indicated that the antibacterial activity was mainly associated with the alkaloids. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined for the crude extract, the total alkaloids and the neutral fraction using microdilution broth method. The results were compared with reference antibiotics. The total alkaloids showed remarkable activity against S. aureus (MIC = 95 microg/ml).

Alkaloids↗
PubMed1999

Identification of a novel Stat3 recruitment and activation motif within the granulocyte colony-stimulating factor receptor.

Stat3 is essential for early embryonic development and for myeloid differentiation induced by the cytokines granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6). Two isoforms of Stat3 have been identified, (p92) and beta (p83), which have distinct transcriptional and biological functions. Activation of both Stat3 and Stat3beta requires the distal cytoplasmic domain of the G-CSFR, which contains four Tyr at positions 704, 729, 744, and 764. The studies reported here were undertaken to determine which, if any, of these tyrosine residues participated in Stat3/beta recruitment and activation. We showed that Stat3 and Stat3beta were affinity purified using phosphopeptides containing Y704 and Y744 but not by nonphosphorylated peptide analogues or by phosphopeptides containing Y729 and Y764. Complementary results were obtained in studies examining the ability of these peptides to destabilize and inhibit DNA binding of activated Stat3. Both Y704 and Y744 contributed to optimal activation of Stat3/beta in M1 murine myeloid leukemia cells containing wild-type and Y-to-F mutant G-CSFR constructs. Carboxy-terminal to Y704 at the +3 position is Gln; YXXQ represents a consensus Stat3 recruitment and activation motif. Y744 is followed at the +3 position by Cys (C); YXXC, represents a novel motif implicated in the recruitment and activation of Stat3. Modeling of the SH2 domain of Stat3 based on homologous SH2 domains of known structure revealed polar residues whose side chains contact the +3 position. This substitution may confer specificity for the Y704- and Y744-based ligands by allowing H-bond formation between the binding surface and the Gln or Cys found at the respective +3 position.

Amino Acid Sequence↗
PubMed1999

Pharmacoimmunodynamic interactions of interleukin-10 and prednisone in healthy volunteers.

OBJECTIVE: The pharmacoimmunodynamic interactions of recombinant human interleukin-10 and prednisolone were examined in 12 normal male volunteers. METHODS: Single doses of interleukin-10 (8 microg/kg subcutaneous injection), interleukin-10 with prednisone (15 mg by mouth), placebo with prednisone, or placebo were administered. Drug concentrations yielded pharmacokinetic parameters. Response measurements included whole blood lipopolysaccharide-stimulated cytokine (tumor necrosis factor-alpha, interleukin-1beta) production, phytohemagglutinin-stimulated whole blood lymphocyte proliferation, and differential white blood cell counts (including monocytes, lymphocytes, and neutrophils). Extended indirect-response models were used to deal with diverse drug interactions in assessing single and joint effects of interleukin-10 and prednisolone. RESULTS: No pharmacokinetic alterations in interleukin-10 or prednisolone were found. Dosing with interleukin-10 produced strong inhibition of ex vivo cytokine production for the 24-hour postdosing period, whereas prednisolone, the active form of prednisone, was partly inhibitory for only 3 hours. Prednisolone significantly inhibited (P < .05) ex vivo lymphocyte proliferation for 6 hours, whereas interleukin-10 failed to alter this measure. Their joint effects on these responses were inhibitory consonant with the stronger agent. Marked changes in various leukocyte kinetics occurred. The steroid caused monocytopenia, lymphocytopenia, and neutrophilia, with IC50 or SC50 values of 10 to 20 ng/mL. Interleukin-10 elevated monocytes and neutrophils and lowered lymphocyte counts, with IC50 or SC50 values of 0.7 to 1.3 ng/mL. Dynamic modeling showed loss of prednisolone effects on monocytes and additive steroid/interleukin-10 effects on lymphocytes and neutrophils, with neutrophils exhibiting greater changes in net response. CONCLUSION: Interleukin-10 and prednisolone interacted favorably for the measured pharmacoimmunodynamic indices with no kinetic alterations but net responses that were similar to or greater than effects produced by the more strongly acting agent.

Adult↗
PubMed1999

Mathematical modeling of circadian cortisol concentrations using indirect response models: comparison of several methods.

Six mathematical functions to describe the chronobiology of cortisol concentrations were assessed. Mean data from a dose-proportionality study of inhaled fluticasone propionate were fitted with an indirect response model using various biorhythmic functions (single cosine, dual ramps, dual zero-order, dual cosines, and Fourier series with 2 and n-harmonics) for production rate. Data with known parameters and random variation were also generated and fitted using the ADAPT II program. Fitted parameters, model estimation criteria, and runs tests were compared. Models with preassigned functions: the dual ramps, the dual zero-order and the dual cosines provide maximum and minimum times for cortisol release rate, were suitable for describing asymmetric circadian patterns and yielding IC50 values. Fourier analysis differs from the other methods in that it uses the placebo data to recover equations for cortisol secretion rate rather than by postulation. Nonlinear regression for Fourier analysis, instead of the L2-norm method, was useful to characterize the baseline cortisol data but was restricted to a maximum of two harmonics. Apart from the single cosine function, which predicts symmetrical cortisol concentrations, all methods were satisfactory in describing the baseline and suppressed cortisol concentrations. On the other hand, Fourier series with L2-norm produced the best unbiased estimate for baseline patterns. The Fourier method is flexible, accurate, and can be extended to other drug-induced changes in normal periodic rhythms.

Androstadienes↗
PubMed1999

Lipid A mutant Salmonella with suppressed virulence and TNFalpha induction retain tumor-targeting in vivo.

Systemically administered tumor-targeted Salmonella has been developed as an anticancer agent, although its use could be limited by the potential induction of tumor necrosis factor alpha (TNFalpha)-mediated septic shock stimulated by lipid A. Genetic modifications of tumor-targeting Salmonella that alter lipid A and increase safety must, however, retain the useful properties of this bacteria. We report here that disruption of the Salmonella msbB gene reduces TNFalpha induction and increases the LD50 of this pathogenic bacteria by 10,000-fold. Notwithstanding this enormous difference, Salmonella retains its tumor-targeting properties, exhibiting tumor accumulation ratios in excess of 1000:1 compared with normal tissues. Administration of this bacteria to mice bearing melanoma results in tumors that are less than 6% the size of tumors in untreated controls at day 18. Thus, the antitumor activity previously demonstrated using tumor-targeting Salmonella with normal lipid A is retained. Lipid modification of tumor-specific bacterial vectors provides a means for reducing septic shock and further suggests that the antitumor activity of these bacteria may be independent of TNFalpha.

Acyltransferases↗
PubMed1999

Stimulatory and inhibitory maturation of human macrophage-derived dendritic cells.

Circulating human macrophages are often used to generate dendritic cells (DCs) by culturing them in granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4). As DCs are superb antigen-presenting cells, these types of myeloid DCs are now used in many DC-based vaccination protocols, especially in cancer, with the belief that they are essentially stimulatory or 'immunogenic'. Here we show that just as peripheral macrophage-derived myeloid DCs can be stimulatory, in vitro cultures of myeloid DCs in GM-CSF and IL-4 followed by further maturation in interferon-gamma plus bacterial superantigens (as DC maturing agents) can give rise to DCs that are functionally inhibitory. The stimulatory DCs express higher amounts of costimulatory molecules, synthesize IL-12, and efficiently stimulate naive allogeneic T cells in mixed lymphocyte reaction (MLR). The inhibitory DCs, in contrast, express lower concentrations of the critical costimulatory molecules, synthesize large amounts of IL-10, and are either marginally stimulatory or nonstimulatory in MLR. Moreover, while the stimulatory DCs further amplify proliferation of T cells in lectin-driven proliferation assays, the inhibitory DCs suppress T cell proliferation in similar assays, in vitro. Most interestingly, neutralization of the endogenously derived IL-10 with anti-IL-10 antibody with DC cultures as well as exposure of the inhibitory DCs to CpG oligonucleotides or to in vitro activated autologous CD4+ T helper cells repolarize them into stimulatory phenotype. Accordingly, these observations have important implications in translational research involving myeloid DCs.

Antigen Presentation↗
PubMed1999

Pharmacokinetic and adrenal interactions of IL-10 and prednisone in healthy volunteers.

The pharmacokinetic and adrenal interactions of recombinant human interleukin-10 and prednisolone were examined in this open-label, randomized, four-way crossover study in 12 healthy adult male volunteers. Single doses of IL-10 (8 micrograms/kg s.c.), IL-10 with prednisone (15 mg p.o.), placebo with prednisone, or placebo were administered on four separate occasions with at least 3-week interceding washout periods. Measurements included plasma prednisone, prednisolone and cortisol, unbound prednisolone, and serum IL-10 concentrations. Pharmacokinetic parameters were determined using noncompartmental and model-fitting analysis, while area analysis and an indirect response model were used to assess cortisol dynamics. IL-10 exhibited prolonged serum concentrations owing to dual-absorption processes that were largely unaffected by prednisone. The Cmax values were about 3 ng/mL, while the tmax occurred at 7 to 9 hours. Prednisolone exhibited rapid systemic kinetics with a Cmax of 235 ng/mL, tmax at 1.11 hours, and t1/2 of 2.54 hours with no significant alterations owing to IL-10. Both prednisolone and prednisolone/IL-10 caused marked suppression of cortisol concentrations with similar magnitude and IC50 values; however, IL-10 alone significantly increased the 24-hour AUC of cortisol by 20%. Thus, IL-10 and prednisolone do not interact in disposition or adrenal suppression to a clinically significant degree.

Adrenal Glands↗
PubMed1999

Systemic interferon-alpha (IFN-alpha) treatment leads to Stat3 inactivation in melanoma precursor lesions.

BACKGROUND: In the setting of familial melanoma, the presence of atypical nevi, which are the precursors of melanoma, is associated with a nearly 100% risk of developing primary melanoma by age 70. In patients with sporadic melanoma, it is estimated that 40-60% of melanomas develop in contiguous association with atypical nevi. Currently, the only way to prevent atypical nevi from progressing to melanoma is to monitor and excise them as soon as they exhibit changes in their clinical features. Activation of the transcription factor, Stat3, has been linked to abnormal cell growth and transformation as well as to interferon alpha (IFN-alpha)-mediated growth suppression in vitro. MATERIALS AND METHODS: To determine whether IFN-alpha, used for adjuvant therapy of high-risk, resected melanoma, induces changes in Stat3 in atypical nevi, patients with a clinical history of melanoma who have multiple atypical nevi were treated for 3 months with low-dose IFN-alpha. Thereupon, the new technology of microscopic spectral imaging and biochemical assays such as electrophoretic mobility shift assays (EMSAs) and immunoblot analysis were used for the study of atypical nevi, obtained before and after IFN-alpha treatment. RESULTS: The results of the investigations provided evidence that, as a result of systemic IFN-alpha treatment, Stat1 and Stat3, which are constitutively activated in melanoma precursor lesions, lose their ability to bind DNA, and as shown in the case of Stat3, become dephosphorylated. CONCLUSIONS: Unlike primary and metastatic melanomas, melanoma precursor lesions cannot be established as cell cultures. Thus, the only way to explore pathways and treatment regimens that might help prevent progression to melanoma is within the context of a melanoma precursor lesion study conducted prospectively. The findings presented here suggest that down-regulation of the transcription factors Stat1 and Stat3 by systemic IFN-alpha treatment may represent a potential pathway to prevent the activation of gene(s) whose expression may be required for atypical nevus cells to progress to melanoma.

Aged↗
PubMed1999

Role of closed mitral commissurotomy for mitral restenosis.

Out of 1184 consecutive cases of rheumatic mitral stenosis treated surgically by closed mitral commissurotomy (CMC) at NRS Medical College and Hospital, Calcutta, 20 (1.68%) were mitral valve restenosis. Twelve cases (60%) were females, The median age was 32 years. Duration between the first operation and reappearance of symptoms varied with a mean of 8 years. The previous operations were digital dilatation and instrumental dilatation in 6 and 14 cases respectively. History of thromboembolism was present in 4 cases. On echocardiography, calcification of the mitral valve was present in 2 cases, left atrial clot in 4 cases, associated mild to moderate mitral regurgitation in 6 cases and mild aortic regurgitation in 4 cases. All cases presented with New York Heart Association (NYHA) III and IV symptoms. Critical stenosis (mitral valve orifice less than 0.5 cm2) was present in 12 cases. Re-do CMC was undertaken in all cases with Tubb's dilator. Median operating time was 2.5 hours. Satisfactory split was achieved in 13 cases. One patient died during surgery. Four cases having less than satisfactory split were asymptomatic on follow-up. In one case no split was possible and in another, gross mitral regurgitation was noted postoperatively. These 2 cases had to undergo open heart surgery. It is concluded that re-do CMC is a feasible and suitable alternative in mitral restenosis even in the presence of complications.

Adult↗
PubMed1998

Hair cycle-dependent production of ACTH in mouse skin.

We investigated the functional determinants of the cutaneous expression of elements of the hypothalamic-pituitary-adrenal axis. In the present work, the presence of adrenocorticotropin (ACTH) peptide in skin of C57/BL6 mouse was demonstrated by reversed-phase HPLC analysis combined with specific radioimmunoassay. ACTH concentration that was low in telogen, increased during anagen in two steps: a rapid phase in anagen I, and a slower rise that reached its peak in anagen VI. Immunofluorescence localized the ACTH antigen to the basal layer of epidermis, outer root sheath of hair follicle and subcutaneous muscle of anagen VI skin. At physiological plasma concentration (10-9 M), ACTH selectively stimulated DNA synthesis in dermis, while pharmacological doses (10-7-10-6 M) inhibited DNA synthesis in both dermis and epidermis. In conclusion, we suggest that local production of ACTH may represent a regulatory element in the control of skin functions including hair growth.

Adrenocorticotropic Hormone↗
PubMed1998

Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro.

Stimulation of epidermal growth factor receptor (EGFR) by ligand(s) leads to activation of signaling molecules including Stat1 and Stat3, two members of the signal transducers and activators of transcription (STAT) protein family. Activation of Stat1 and Stat3 was constitutive in transformed squamous epithelial cells, which produce elevated levels of TGF-alpha, and was enhanced by the addition of exogenous TGF-alpha. Targeting of Stat3 using antisense oligonucleotides directed against the translation initiation site, resulted in significant growth inhibition. In addition, cells stably transfected with dominant negative mutant Stat3 constructs failed to proliferate in vitro. In contrast, targeting of Stat1 using either antisense or dominant-negative strategies had no effect on cell growth. Thus, TGF-alpha/EGFR-mediated autocrine growth of transformed epithelial cells is dependent on activation of Stat3 but not Stat1.

Carcinoma, Hepatocellular↗
PubMed1998

Downmodulation of TGF-alpha protein expression with antisense oligonucleotides inhibits proliferation of head and neck squamous carcinoma but not normal mucosal epithelial cells.

Interruption of an autocrine growth pathway involving TGF-alpha and EGFR may inhibit tumor growth and improve survival in head and neck cancer patients. We previously demonstrated that biopsy specimens and established cell lines from patients with squamous cell carcinoma of the head and neck (SCCHN) overexpress TGF-alpha and its receptor, epidermal growth factor receptor (EGFR) at both the mRNA and protein levels. Protein localization studies showed that TGF-alpha and EGFR are produced by the same epithelial cells in tissues from head and neck cancer patients further supporting a role for this ligand-receptor pair in an autocrine growth pathway. To confirm that TGF-alpha contributes to autocrine growth, we examined the effect of down regulation of TGF-alpha protein on SCCHN cell proliferation. Treatment of 6 SCCHN cell lines with antisense oligodeoxynucleotides targeting the translation start site of human TGF-alpha mRNA decreased TGF-alpha protein production by up to 93% and reduced cell proliferation by a mean of 76.2% compared to a 9.7% reduction with sense oligonucleotide (range P = 0.036-0.0001). TGF-alpha antisense oligonucleotide exposure also decreased TGF-alpha protein levels in normal oropharyngeal mucosal epithelial cells, however their growth rate was not affected. These findings indicate that TGF-alpha is participating in an autocrine signaling pathway in transformed, but not in normal mucosal epithelial cells, that promotes proliferation.

Base Sequence↗
PubMed1998

Granulocyte colony-stimulating factor activates a 72-kDa isoform of STAT3 in human neutrophils.

Granulocyte colony-stimulating factor (G-CSF) signaling involves activation of STATs, proteins that serve the dual function of signal transduction and activation of transcription. We previously demonstrated that G-CSF activated a distinct Stat3-like protein in immature and mature normal myeloid cells, StatG. StatG in normal immature human myeloid cells, i.e. adult CD34+ bone marrow cells, was composed of Stat3beta. This investigation was undertaken to determine the composition of StatG in mature normal human myeloid cells, i.e. polymorphonuclear neutrophilic granulocytes (PMN). These studies revealed that the major protein in extracts of PMN activated by G-CSF to bind the high-affinity serum-inducible element (hSIE) is a 72-kDa protein that cross-reacts with Stat3 monoclonal antibody, which we have designated Stat3gamma. Stat3gamma is derived from Stat3alpha by limited proteolysis and lacks the carboxyl-terminal portion of Stat3alpha. Because this region of Stat3alpha is involved in transcriptional activation, our findings suggest the possibility that Stat3gamma may be transcriptionally inactive and may compete with Stat3alpha for Stat3 binding sites in these terminally differentiated myeloid cells.

Adult↗
PubMed1998

Melanoma x macrophage hybrids with enhanced metastatic potential.

Studies were conducted on the hypothesis that melanoma metastasis might be initiated through the generation of hybrids comprised of cells of the primary tumor and tumor-infiltrating leukocytes. Fusion hybrids were generated in vitro between weakly metastatic Cloudman S91 mouse melanoma cells and normal mouse or human macrophages. Hybrids were implanted s.c. in the tail and mice were monitored for metastases. Controls included parental S91 cells, autologous S91 x S91 hybrids, and B16F10 melanoma cells. Of 35 hybrids tested, most were more aggressive than the parental melanoma cells, producing metastases sooner and in more mice. A striking characteristic was heterogeneity amongst hybrids, with some lines producing no metastases and others producing metastases in up to 80% of mice. With few exceptions, hybrids with the highest metastatic potential also had the highest basal melanin content whereas those with the lowest metastatic potential were basally amelanotic, as were the parental melanoma cells. A spontaneous in vivo supermelanotic hybrid between an S91 tumor cell and DBA/2J host cell was one of the most metastatic lines. Hybrids with the highest metastatic potential also exhibited markedly higher chemotaxis to fibroblast-conditioned media. Histologically, the metastatic hybrids demonstrated vascular invasion and spread to distant organs similar to that of metastatic melanomas in mice and humans. Thus previous findings of enhanced metastasis in leukocyte x lymphoma hybrids can now be extended to include leukocyte x melanoma hybrids. Whether such hybridization is a natural cause of metastasis in vivo remains to be determined; however the fusion hybrids with genetically-matched parents described herein so closely resembled naturally-occurring metastatic melanoma cells that they could serve as useful new models for studies of this complex and deadly phenomenon.

Animals↗