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K Mehta

Publications and source records attributed to K Mehta.

At least 73 records · Page 4Linked to original sources
PubMed1994

High levels of transglutaminase expression in doxorubicin-resistant human breast carcinoma cells.

Tissue type II transglutaminase (TGase) is a member of the TGase family that catalyzes Ca(2+)-dependent covalent cross-linking of several amines to the gamma-carboxamide group of protein-bound glutamine residues. The degree of therapeutic efficacy or toxicity of drugs may be related to their ability to serve as a substrate for TGase and their covalent linkage to glutamine residues of regulatory proteins through the catalytic action of this enzyme. Here, doxorubicin (adriamycin)-resistant human breast carcinoma MCF-7ADR cells exhibited 40- to 6C-fold higher TGase activity than control drug-sensitive MCF-7WT cells. The same was observed in vivo: a small proportion of tumor cells became positive for TGase after administration of adriamycin-based chemotherapy to patients with breast carcinoma. Similarly, continuous culture of MCF-7WT cells in the presence of adriamycin led to the appearance of the drug-resistant phenotype that was in turn associated with increased expression of TGase. This increase in TGase was specific for adriamycin resistance. Like most known TGase, MCF-7ADR TGase was completely dependent on the presence of Ca2+ for its catalytic activity. Based on its immunoreactivity, the TGase in MCF-7ADR cells was identified as an 85-kDa tissue-type TGase and was present only in the soluble form. Immunoblot analysis revealed that the increase in TGase activity was due to accumulation of the protein. Two cytosolic proteins of approximately 20 and 30 kDa in MCF-7 cells served as suitable acyl donor substrates in TGase-catalyzed reactions.

Animals↗
PubMed1994

Retinoic acid-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid receptor-alpha.

CD38 is a leukocyte differentiation antigen that has been thought to be a phenotypic marker of different subpopulations of T- and B-lymphocytes. In myeloid cells, CD38 is expressed during early stages of differentiation. Virtually no information is available on regulation and functions of CD38. Recently we reported that all-trans-retinoic acid (ATRA) is a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells. Here we report that ATRA-induced expression of CD38 antigen in myeloid cells is mediated through retinoic acid-alpha receptor (RAR alpha). ATRA failed to induce CD38 expression in a mutant subclone of the HL-60 myeloid leukemia cell line (designated HL-60R) that is relatively resistant to ATRA-induced granulocytic differentiation. Retroviral vector-mediated transduction of RA receptor (RAR alpha) into this HL-60R subclone completely restored the sensitivity of these cells to ATRA in terms of their ability to express CD38. In contrast, CD38 expression was not inducible by ATRA in HL-60R cells, transfected with a functional RAR beta, RAR gamma, or RXR alpha receptor. Induction of CD38 in acute promyelocytic and acute myeloblastic leukemia cells was independent of ATRA-induced cytodifferentiation. Following culture with ATRA, increased CD38 protein levels were also observed in normal CD34+ bone marrow cells, but not on normal circulating granulocytes. From these results, we conclude that CD38 is ATRA inducible in myeloid leukemia cells and normal CD34+ bone marrow cells. This effect is independent of differentiation and is mediated by RAR alpha in HL-60 cells, suggesting a similar role for RAR alpha in CD38 expression in other hematopoietic cells.

ADP-ribosyl Cyclase↗
PubMed1994

Inhibition by all-trans-retinoic acid of tumor necrosis factor and nitric oxide production by peritoneal macrophages.

Besides their growth-inhibiting and differentiation-inducing properties, retinoids have been shown to exert immunomodulatory and anti-inflammatory functions by mechanisms that are not well understood. Tumor necrosis factor-alpha (TNF), a cytokine produced by mononuclear phagocytes, has been shown to be an important mediator of endotoxin-induced septic shock, cachexia, bone resorption, and inflammation. Nitric oxide may also have a role in septic shock, hypotension, and vasodilatation. In this study, we examined the effects of retinoids on the production of TNF and nitric oxide by murine peritoneal macrophages. Of the various retinoids studied, all-trans-retinoic acid (RA) was most potent; it almost completely inhibited the production of TNF by macrophages activated with endotoxin and interferon-gamma. The inhibitory effect was dependent on the dose and duration of RA exposure to macrophages. RA also blocked phorbol ester-induced TNF production in a macrophage cell line (RAW 264.7). Besides TNF, the retinoid suppressed the production of nitric oxide from activated peritoneal macrophages. The importance of these results in relation to controlling various harmful effects of cytokines released by activated macrophages is discussed.

Animals↗
PubMed1994

Interaction of liposome-associated all-trans-retinoic acid with squamous carcinoma cells.

Because of their antiproliferative and differentiation-inducing properties, retinoids have been used clinically as therapeutic and chemopreventive agents against squamous-cell carcinomas (SCC). As is the case for many therapeutic agents, however, the administration of retinoids is associated with toxic effects. Because encapsulation of certain drugs in lipid vesicles (liposomes) has been shown to result in reduced toxic effects, we studied the in vitro interaction of liposome-encapsulated all-trans-retinoic acid (L-ATRA) with a SCC line (MDA 886Ln) and its multicellular tumor spheroid (MTS) model. Various L-ATRA formulations were tested for incorporation of retinoic acid, toxic effects against human red blood cells, uptake and retention by tumor cells, and antiproliferative effects against SCC. Of the different formulations tested, L-ATRA containing diphosphatidyl palmitoylcholine (DPPC) and stearylamine (SA; 9:1, w/w) showed optimal drug incorporation, high stability, and minimal toxicity toward red blood cells and was highly efficacious in delivering ATRA and, thus, in inhibiting the growth of MDA 886Ln and its MTS model. DPPC: SA L-ATRA inhibited the expression of the enzyme keratinocyte transglutaminase in epidermal cells as effectively as did the free drug. These results suggest that liposomes can serve as an effective carrier system for the delivery of retinoids to SCC.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Liposome encapsulation circumvents the hepatic clearance mechanisms of all-trans-retinoic acid.

All-trans-retinoic acid (ATRA) has been proven active against a range of malignancies in isolated tissue culture systems and in human clinical trials, but the duration of its effects has been transient. Recent evidence indicates that the basis for the limited duration of ATRA's activity, at least in one form of leukemia, is a pharmacological adaptation that results in reduced serum concentration after prolonged treatment. This finding suggests that an i.v. formulation of ATRA may significantly improve the potency and duration of ATRA's activity in leukemia and, potentially, other malignancies as well. Liposomal ATRA (L-ATRA) was developed to provide a formulation of this retinoic acid isomer that can be administered intravenously to provide potential pharmacological advantages over the oral formulation. When L-ATRA was administered to rats over a prolonged period, the blood levels of the drug did not change over time. In vitro studies of isolated liver microsomes revealed that catabolism of the drug was not altered in rats that were repeatedly administered the L-ATRA formulation. Whereas microsomes isolated from animals that were orally administered free ATRA the same number of times with the same doses showed a significant increase in metabolism of the drug. These results suggest that an i.v. formulation of ATRA such as L-ATRA could be extremely useful in inducing long-term remissions in patients with APL.

Animals↗
PubMed1994

Human CD38: a glycoprotein in search of a function.

The human CD38 molecule appears to mediate several diverse activities, including signal transduction, cell adhesion and cyclic ADP-ribose synthesis. In this article, the authors consolidate the information available on this highly interesting, multifunctional protein.

ADP-ribosyl Cyclase↗
PubMed1994

Urinary red cell morphology to detect site of hematuria.

We studied the urinary RBC morphology in 87 consecutive cases of significant hematuria by 3 commonly used methods: (a) light microscopy of the unstained urinary sediment; (b) phase contrast microscopy of the unstained urinary sediment; and (c) Wright's staining of the urinary sediment, in order to compare the sensitivity of these methods in detecting dysmorphic RBCs and thus predicting the site of hematuria. The clinical data and the relevant investigations were made available after the morphology of RBCs in the urine was identified. Out of the 87 patients, 45 had a glomerular and 42 had a nonglomerular cause o hematuria. Phase contrast microscopy showed a sensitivity of 91.1%, Wright's stain of 82.2% and light microscopy of 66.7% in detecting a glomerular source of hematuria. Nonglomerular hematuria could be detected in 92.9% cases by each of the 3 methods. It is concluded that phase contrast microscopy is most sensitive for the detection of dysmorphic RBCs in the urine, Wright's stain nearly as sensitive whilst light microscopy of the unstained sediment is least sensitive. Urinary RBC morphology is a useful adjunct in the diagnosis of hematuria and saves the patients from unnecessary investigations.

Adolescent↗
PubMed1993

Rapid induction of CD38 antigen on myeloid leukemia cells by all trans-retinoic acid.

The CD38 or T10 molecule is one of the least understood differentiation antigens. Virtually no information is available on the regulation and functions of CD38 antigen in hematopoietic cells. Using human promyelocytic leukemia cells, we demonstrate that all trans-retinoic acid is a potent and specific inducer of CD38 expression in myeloid lineage. At physiological doses, all trans-retinoic acid induces significant levels (8 to 10-fold) of CD38. Similarly, in patients with promyelocytic leukemia, a significant increase (3 to 6-fold) in CD38 expression was observed in vivo following single oral dose administration of all trans-retinoic acid. The induction of CD38 is a specific response of myeloid cells to retinoic acid and is not seen with other agents that induce differentiation. We believe that the induction of CD38 antigen is an early event in retinoid-regulated gene expression in normal and transformed myeloid cells.

ADP-ribosyl Cyclase↗
PubMed1993

Induction of differentiation in myeloid leukemia cell lines and acute promyelocytic leukemia cells by liposomal all-trans-retinoic acid.

All-trans-retinoic acid (ATRA) induces complete remissions in the majority of patients with acute promyelocytic leukemia. Despite continuous p.o. ATRA administration, many patients relapse after a short remission duration. In these patients, ATRA plasma concentrations were found to be very low, which was related to induction of retinoic acid-binding protein and increased drug catabolism by cytochrome P-450-mediated reactions. An i.v. ATRA formulation, which can be achieved by encapsulating ATRA into liposomes, may have the potential to overcome these unwanted effects. We investigated the ability of liposomal ATRA (L-ATRA) to induce differentiation of human myeloid leukemia cell lines (HL-60, KG-1, and THP-1). Cellular differentiation, as assessed by morphological criteria and by the expression of a mature myeloid cell surface antigen (CD11b on HL-60 and KG-1 cells), was induced by culture in the presence of L-ATRA. The ability of L-ATRA-treated HL-60 cells to reduce nitroblue tetrazolium demonstrated that they were functionally differentiated cells. Cell cycle analysis revealed significant growth inhibition of the cells after L-ATRA treatment. Following culture with L-ATRA, cells from five patients with acute promyelocytic leukemia were found to be morphologically and immunophenotypically mature myeloid cells. L-ATRA was as effective as free ATRA in inducing differentiation of the cell lines and of the cells from patients with acute promyelocytic leukemia. We conclude that L-ATRA effectively induces differentiation and may be a useful parenteral ATRA formulation for overcoming the pharmacological mechanisms that lead to "retinoid resistance."

Cell Cycle↗
PubMed1993

Calculation of volume flow rate by the proximal isovelocity surface area method: simplified approach using color Doppler zero baseline shift.

OBJECTIVES: The goal of this study was to develop an accurate, simplified proximal isovelocity surface area (PISA) method for calculating volume flow rate using lower blue-red interface velocity produced by a color Doppler zero baseline shift technique. BACKGROUND: The Doppler color proximal isovelocity surface area method has been shown to be accurate for calculating the volume flow rate (Q) across a narrowed orifice by the formula Q = PISA x Blue-red interface velocity. A hemispheric model is generally used to calculate proximal isovelocity surface area (PISA = 2 pi a2, where a = the radius corresponding to the blue-red interface velocity). Although a hemispheric model is simple, requiring measurement of one radius, it may underestimate the actual volume flow rate because, in the general case, the shape of a proximal isovelocity surface area is hemielliptic. Although a hemielliptic model is generally more accurate for calculating proximal isovelocity surface area, it is more complex, requiring measurement of two orthogonal radii. METHODS: Sixteen in vitro constant flow model studies were performed using planar circular orifices (diameter range 6 to 16 mm). The blue-red interface velocity was changed from 3 to 54 cm/s using color Doppler zero baseline shift. RESULTS: 1) With decreasing blue-red interface velocity, the size of the proximal isovelocity surface area was increased, and its shape changed from hemielliptic to hemispheric. 2) With the blue-red interface velocity in the range 11 to 15 cm/s, the proximal isovelocity surface area became nearly hemispheric; however, it was difficult to determine the blue-red interface radius at a blue-red interface velocity < 10 cm/s because of interface fluctuations. 3) Calculated volume flow rate using the hemispheric proximal isovelocity surface area model with a single radius was relatively accurate at a blue-red interface velocity of 11 to 15 cm/s (mean percent difference from actual volume flow rate was -3.6%). CONCLUSIONS: Because the shape of the proximal isovelocity surface area is nearly hemispheric at a blue-red interface velocity of 11 to 15 cm/s, volume flow rate can be accurately calculated in this proximal isovelocity surface area interface velocity range (produced by zero baseline shift) by measuring a single-interface radius. This approach should be clinically useful for calculating the volume flow rate across stenotic and regurgitant valves and across shunt defects.

Blood Flow Velocity↗
PubMed1993

Significance of increased proportion of CD10-positive cells in nonmalignant bone marrows of children.

An immunophenotypic pattern characterized by increased proportions of CD10, CD19, and HLA-DR+ cells is observed in the bone marrow of some children with nonmalignant hematologic diagnoses. The purpose of this study was to ascertain the clinical and pathologic significance of this immunophenotype. The morphologic and immunophenotypic results of bone marrow specimens from 23 children with nonmalignant hematologic conditions are presented. In 11 children, an increased percentage of immature B-cell precursors was observed, suggesting the presence of B-lineage malignancy. None of the children have developed malignant lymphoproliferative disease in as long as 4 years of follow-up, despite the demonstration of a clonal lymphocyte proliferation in one patient. Although the biologic significance of the bone marrow immunophenotype is not yet understood, it is important to recognize that this lymphocyte pattern occurs commonly in children with nonmalignant hematologic conditions, and may reflect an increase in normally occurring lymphoid precursor cells.

Antigens, CD↗
PubMed1993

Dosimetry for quality assurance in electron-beam sterilization of medical devices.

During recent years, electron-beamed sterilization has quickly moved towards being able to compete with gamma-radiation sterilization, particularly now that several companies are offering high-power accelerators that can deliver electron beams with energies of 10 MeV; these beams are powerful enough to penetrate most medical devices. This article describes the role of dosimetry and the procedures used in the quality assurance and documentation required for electron-beam sterilization.

Electrons↗
PubMed1993

FPGA implementation of VXIbus interface hardware.

The HP E1399A development card is a B-size, register based device that can be used to simplify the development of simple, custom VXIbus instruments. The E1399A provides interface logic that buffers a 16-bit bidirectional data bus and performs other functions required by the VXIbus standard. However, the amount of interface logic required is high enough to substantially reduce the breadboard area that is available to the user. This paper reports on evaluation of field programmable gate array (FPGA) technology to the implementation of the VXIbus interface circuitry. Using FPGAs (Xilinx), all the logic of the E1399A can be fit into at most two low cost gate array packages with an attendant savings in board space. This results in a reliable design that provides the interface between the VXIbus and the user's custom circuitry.

Computers↗
PubMed1992

The NZB mouse as a model for chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and the only leukemia for which a possible genetic component has been described. Analysis of this genetic component has been hindered by the fact that disease onset normally occurs after age 50. We report here the aged NZB mouse as an animal model for CLL. NZB mice have a genetically regulated, age-dependent onset of clonal, aneuploid cells which are IgM+ and Ly1+ (CD5+ B-cells). Peripheral blood smears from old NZB mice show an increase in circulating lymphocytes and "smudged" or ruptured cells, often seen in human CLL. Electron microscopic examination of these cells shows them to be mature lymphocytes. Light microscopy of the spleen shows infiltration of small lymphocytes and is consistent with CLL pathology. These long-lived, CLL-like cells can be serially passaged into recipient animals. This continued passage occasionally results in the development of a large cell lymphoma detectable in the spleen, lymph nodes, and liver. The histology of this lymphoma is quite distinct from that of the CLL-like cells, but the phenotype is that of an aneuploid CD5+, IgM+ cells. This apparently represents a continued transformation of the CLL-like clone similar to the development of Richter's syndrome in human CLL. Therefore, the NZB mouse can be a valuable tool for the determination of the genetic basis of CLL ontogeny and the conversion of CLL into Richter's syndrome.

Age Factors↗
PubMed1992

Antiproliferative effects of free and liposome-encapsulated retinoic acid in a squamous carcinoma model: monolayer cells and multicellular tumor spheroids.

Antiproliferative effects of free retinoic acid (RA) and liposome-encapsulated RA (RAlp) were compared in a squamous carcinoma system using both monolayer cells and multicellular tumor spheroids (MTS), an in-vivo-like model with three-dimensional histological structure. Initial studies examined the effect of lipid composition on the efficiency of RA encapsulation and on the subsequent toxicity of RAlp to red blood cells. In 5-day growth assays for monolayer cells, RA and RAlp (1 microM-0.1 nM) produced similar growth inhibition. In 6-day growth assays for MTS, RAlp was shown to have increased effectiveness. Liposomal uptake by the squamous carcinoma cells was examined by culturing monolayers and MTS with fluorescence-tagged liposomes and examining them under fluorescence microscopy between days 1 and 6. Phagocytosed liposomes were present, but their low levels suggested that other mechanisms of drug delivery such as adsorption, fusion or direct lipid transfer probably occurred for RAlp. Histological examination of MTS showed that RA and RAlp produced similar alterations. In this squamous carcinoma system, liposomes are effective in delivering retinoic acid and in producing biological effects in monolayer cells and within the three-dimensional structure of MTS.

Carcinoma, Squamous Cell↗
PubMed1992

Identification of a novel transglutaminase from the filarial parasite Brugia malayi and its role in growth and development.

Recently, we reported the presence of a putative transglutaminase in adult female worms of Brugia malayi [1]. The enzyme activity was shown to be essential for in utero growth and development of microfilariae. Here, we demonstrate that adult worms of B. malayi have a large amount of epsilon-(gamma-glutamyl)lysine isopeptide bonds, a product of physiologically active transglutaminase. A 25-kDa immunoreactive band detected in female worm extracts by a monospecific monoclonal antibody (CUB 7401) against guinea pig liver transglutaminase was associated with the enzymatic activity. Unlike the mammalian enzyme, the parasite enzyme did not require Ca2+ for its catalytic activity. Furthermore, in utero developing embryos, especially during early stages of development, contained very high amounts of this enzyme. Adult female worms contained several proteins that could serve as suitable substrates for the enzyme. Inhibition of the enzyme activity by an enzyme-specific pseudosubstrate, monodansylcadaverine, led to a time- and dose-dependent inhibition of microfilariae production and release by gravid female worms. The inhibition of microfilariae production was due to the inhibition of transglutaminase-catalyzed crosslinking of parasite proteins that in turn seemed to be essential for in utero growth and development of the embryos. The results suggest that transglutaminase-catalyzed reactions may play an important role during early development of embryos to mature microfilariae inside the adult female worms of filarial parasites.

Animals↗
PubMed1992

Regurgitant volume estimation in patients with mitral regurgitation: initial studies using color Doppler "proximal isovelocity surface area" method.

Doppler color flow mapping of a proximal isovelocity surface area (PISA), calculated from a blue-red aliasing radius, has been shown in vitro to be accurate for estimating volume flow rate across a narrowed orifice. Volume flow rate (in cm 3/sec) can be calculated as PISA (in cm 2) x aliasing velocity (in cm/sec). This method has advantages over other color Doppler approaches in that PISA-derived volume flow rate calculations appear to be independent of machine parameter settings and orifice shape. We evaluated the clinical applicability of the PISA method in 49 patients with native valve mitral regurgitation (MR). Color Doppler flow mapping was performed at color aliasing velocities of 54-72 cm/sec. Twenty-four patients were excluded because a color aliasing radius was not clearly seen: 20 of these 24 patients had mild MR. In the remaining 25 patients, the ratio of maximum regurgitant jet area-to-left atrial area, as well as the regurgitant stroke volume estimated using the time-velocity integral method, were compared to regurgitant stroke volume calculated from the PISA method. Maximum PISA was calculated using a formula derived from previous in vitro studies: PISA = 8.05 x r 2, where r is the maximum color Doppler aliasing radius in the apical four-chamber view.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Flow Velocity↗