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Biomedical subjects

J Jain

Publications and source records attributed to J Jain.

At least 19 recordsLinked to original sources
PubMed2006

Can dose reduction to one parotid gland prevent xerostomia?--A feasibility study for locally advanced head and neck cancer patients treated with intensity-modulated radiotherapy.

AIMS: Dryness of the mouth is one of the most distressing chronic toxicities of radiation therapy in head and neck cancers. In this study, parotid function was assessed in patients with locally advanced head and neck cancers undergoing intensity-modulated radiotherapy (IMRT) with or without chemotherapy. Parotid function was assessed with the help of a questionnaire and parotid scintigraphy, especially with regards to unilateral sparing of the parotid gland. MATERIALS AND METHODS: In total, 19 patients were treated with compensator-based IMRT between February 2003 and March 2004. The dose to the clinical target volume ranged between 66 and 70 Gy in 30-35 fractions to 95% of the isodose volume. Ipsilateral high-risk neck nodes received an average dose of 60 Gy and the contralateral low-risk neck received a dose of 54-56 Gy. Eight of 19 patients also received concomitant chemotherapy. RESULTS: Subjective toxicity to the parotid glands was assessed with the help of a questionnaire at 0, 3 and 6 months and objective toxicity was assessed with parotid scintigraphy at 0 and 3 months. The mean dose to the ipsilateral parotid gland ranged from 19.5 to 52.8 Gy (mean 33.14 Gy) and the mean dose to the contralateral gland was 11.1-46.6 Gy (mean 26.85 Gy). At a median follow-up of 13 months, 9/19 patients had no symptoms of dryness of the mouth (grade I), 8/19 had mild dryness of the mouth (grade II) and only 2/19 had grade III xerostomia, although the parotid gland could only be spared on one side in most of the patients. CONCLUSIONS: Minimising the radiation dose to one of the parotid glands with the help of IMRT in patients with advanced head and neck cancers can prevent xerostomia in most patients and parotid scintigraphy is a useful method of documenting xerostomia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Right atrial trans-septal approach for left atrial myxomas--nine-year experience.

OBJECTIVE: In this single-center study we reviewed our experience with left atrial myxomas occurring over the past 9 years. METHODS: Sixty-three patients underwent excision of cardiac myxomas between 1995 and 2004. Of these, 56 patients (32 females and 24 males) had left atrial (LA) myxoma. The mean age was 37.80+12.97 years (range 3.5-67 years). Echocardiography was the only diagnostic evaluation done. The preferred approach for resection was right atrial trans-septal. Annual echocardiographic evaluation was undertaken following surgery. Follow-up is current and available in all the survivors (range 4 months-9 years). RESULTS: Clinically 75% of the LA myxomas simulated mitral stenosis. The symptoms were present for 2-6 months before operation. Most (86%) LA myxomas were attached to the fossa ovalis. Few (14%) originated from the LA wall, mitral valve annulus and anterior mitral leaflet. One patient succumbed to low cardiac output and another died of massive embolic stroke following surgery. There were no late deaths. Two patients (3.7%) developed left hemiparesis after operation but recovered completely. There was one (1.9%) recurrence 3 years after surgery. Atrial fibrillation occurred in one patient. Mitral insufficiency which was seen in two (3.7%) patients prior to surgery subsided following excision of the tumor. Postoperatively 94% patients remained without symptoms. CONCLUSION: Owing to the risk of valvular obstruction or embolization early surgery is indicated. Right atrial trans-septal approach is safe and easy. Most patients are asymptomatic following surgery. A yearly follow-up is essential.

Adolescent↗
PubMed2005

Cadmium accumulation and antioxidative responses in the Sesbania drummondii callus.

The effect of cadmium (Cd) on growth, accumulation, and antioxidative response was studied in Sesbania drummondii callus, cultivated on different concentrations of Cd (0-250 microM) for four weeks. Callus growth was comparable to that of the control for concentrations up to 50 microM Cd; however, concentrations higher than 50 microM affected growth. A concentration of 100 microM Cd inhibited growth by 16%, with respect to control. Cd concentration in callus increased with increasing Cd concentrations in the growth medium. Callus accumulated 530 mg Cd kg(-1) of their dry weight at 100 microM Cd concentration. Sesbania callus responded to Cd-induced oxidative stress by modulating antioxidants (glutathione and other non-protein thiols) level and antioxidative enzymes: superoxide dismutase (SOD), ascorbate peroxidase (APX), and glutathione reductase (GR). The content of the glutathione (GSH) and GSH/GSSG ratio first increased up to a concentration of 50 microM Cd and then decreased. The content of other non-protein thiols significantly increased with increasing Cd concentrations in the growth medium. The activities of antioxidative enzymes, SOD, APX, and GR, followed the same trends as antioxidants first increasing up to a concentration of 50 microM Cd and then decreasing. These results suggest that antioxidative defense mechanisms play a significant role in Cd detoxification and accumulation in Sesbania drummondii.

Antioxidants↗
PubMed2005

Thorium uptake by wheat at different stages of plant growth.

Data on biogeochemistry of thorium are rather limited. So far little is known about toxic effects of small amounts of the radionuclide on higher plants. In this study the uptake of thorium by wheat seedlings was measured by greenhouse experiments. Germination of wheat seeds for 6 days in the presence of thorium resulted in accumulation of the metal in all parts of the seedlings. When the Th-rich seedlings were transferred to normal soil and were grown there further for 7 days, Th concentrations in roots and leaves decreased significantly (in leaves the Th content decreased up to the level of Th in the control plants). In seeds, however, Th content remained unchanged. An increase of Th content in roots and seeds was also observed as a result of addition of thorium to soil but in this case the concentration of Th in leaves did not change. The accumulation of Th in plants affected the uptake of other elements including essential macro-nutrients. The most strongly affected part of the plants was leaf.

Germination↗
PubMed2005

TEM/AFM investigation of size and surface properties of nanocrystalline ceria.

A series of ceria nanoparticles were synthesized by using a microemulsion method. The effect of relative concentration of surfactant/water on the size and the surface roughness of ceria nanoparticles was examined using transmission electron microscopy (TEM) and atomic force microscopy (AFM) respectively. The investigation confirmed a relationship between the size and the roughness properties of the nanoceria as a function of the water to surfactant ratio. With increasing dilution of the surfactant, the size distribution became narrow such that average particle size decreased linearly as the ratio increased without affecting lower size threshold of particles (approximately 10 nm). The surface roughness, on the other hand was found to increase with increasing water to surfactant ratio implying diluted surfactant would provide rougher surface of ceria nanoparticles. The information can be used to tailor the adhesion properties of nanoceria by optimizing the size distribution as well as surface roughness as a function of water to surfactant ratio.

Ceramics↗
PubMed2004

Contraceptive efficacy and safety of DMPA-SC.

DMPA-SC 104 mg/0.65 mL is a new, low-dose subcutaneous (SC) formulation of Depo-Provera contraceptive injection (150 mg/mL medroxyprogesterone acetate injectable suspension) that provides efficacy, safety and immediacy of onset equivalent to Depo-Provera intramuscular (IM) injection. Two large, open-label, Phase 3 studies assessed the 1-year contraceptive efficacy, safety and patient satisfaction with DMPA-SC administered every 3 months (12-13 weeks). Zero pregnancies were reported in both studies, which included a total of 16,023 woman-cycles of exposure to DMPA-SC and substantial numbers of overweight or obese women. DMPA-SC was well-tolerated and adverse events were similar to those reported previously with Depo-Provera IM. Thus, DMPA-SC offers women a new, highly effective and convenient long-acting contraceptive option.

Adult↗
PubMed2001

VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent.

Inosine monophosphate dehydrogenase (IMPDH) is an essential rate-limiting enzyme in the purine metabolic pathway, catalyzing the de novo synthesis of guanine nucleotides required for lymphocyte proliferation. IMPDH has therefore been an attractive target for developing immunosuppressive drugs (e.g., CellCept and mizoribine). Here we describe the immunosuppressive activity of VX-497, a novel noncompetitive inhibitor of IMPDH. VX-497 (MW 452.5) is orally bioavailable and inhibits the proliferation of primary human, mouse, rat, and dog lymphocytes at concentrations of approximately 100 nM. The inhibitory effect of VX-497 on lymphocytes is reversed in the presence of exogenous guanosine, but not in the presence of adenosine or uridine, confirming that the antilymphocytic activity of VX-497 is specifically due to inhibition of IMPDH. The antiproliferative effect of VX-497 in cells is also reversed within 48 h of its removal. Based on evaluation of VX-497 in several lymphoid and nonlymphoid cells, the antiproliferative effect of VX-497 is observed to be most pronounced on lymphoid and keratinocyte cells as compared with fibroblasts. In vivo, oral administration of VX-497 inhibits the primary IgM antibody response in a dose-dependent manner, with an ED(50) value of approximately 30-35 mg/kg in mice. Single daily dosing of VX-497 is observed to be as effective as twice-daily dosing in this model of immune activation. These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation.

Animals↗
PubMed2001

Structure of GSK3beta reveals a primed phosphorylation mechanism.

GSK3beta was identified as the kinase that phosphorylates glycogen synthase but is now known to be involved in multiple signaling pathways. GSK3beta prefers prior phosphorylation of its substrates. We present the structure of unphosphorylated GSK3beta at 2.7 A. The orientation of the two domains and positioning of the activation loop of GSK3beta are similar to those observed in activated kinases. A phosphate ion held by Arg 96, Arg 180 and Lys 205 occupies the same position as the phosphate group of the phosphothreonine in activated p38gamma, CDK2 or ERK2. A loop from a neighboring molecule in the crystal occupies a portion of the substrate binding groove. The structure explains the unique primed phosphorylation mechanism of GSK3beta and how GSK3beta relies on a phosphoserine in the substrate for the alignment of the beta- and alpha-helical domains.

Amino Acid Motifs↗
PubMed2000

Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon.

The enzyme IMP dehydrogenase (IMPDH) catalyzes an essential step in the de novo biosynthesis of guanine nucleotides, namely, the conversion of IMP to XMP. The major event occurring in cells exposed to competitive IMPDH inhibitors such as ribavirin or uncompetitive inhibitors such as mycophenolic acid (MPA) is a depletion of the intracellular GTP and dGTP pools. Ribavirin is approved as an inhaled antiviral agent for treatment of respiratory syncytial virus (RSV) infection and orally, in combination with alpha interferon (IFN-alpha), for the treatment of chronic hepatitis C virus (HCV) infection. VX-497 is a potent, reversible uncompetitive IMPDH inhibitor which is structurally unrelated to other known IMPDH inhibitors. Studies were performed to compare VX-497 and ribavirin in terms of their cytotoxicities and their efficacies against a variety of viruses. They included DNA viruses (hepatitis B virus [HBV], human cytomegalovirus [HCMV], and herpes simplex virus type 1 [HSV-1]) and RNA viruses (respiratory syncytial virus [RSV], parainfluenza-3 virus, bovine viral diarrhea virus, Venezuelan equine encephalomyelitis virus [VEEV], dengue virus, yellow fever virus, coxsackie B3 virus, encephalomyocarditis virus [EMCV], and influenza A virus). VX-497 was 17- to 186-fold more potent than ribavirin against HBV, HCMV, RSV, HSV-1, parainfluenza-3 virus, EMCV, and VEEV infections in cultured cells. The therapeutic index of VX-497 was significantly better than that of ribavirin for HBV and HCMV (14- and 39-fold, respectively). Finally, the antiviral effect of VX-497 in combination with IFN-alpha was compared to that of ribavirin with IFN-alpha in the EMCV replication system. Both VX-497 and ribavirin demonstrated additivity when coapplied with IFN-alpha, with VX-497 again being the more potent in this combination. These data are supportive of the hypothesis that VX-497, like ribavirin, is a broad-spectrum antiviral agent.

Animals↗
PubMed1996

Tumor necrosis factor alpha gene regulation in activated T cells involves ATF-2/Jun and NFATp.

The human tumor necrosis factor alpha (TNF-alpha) gene is one of the earliest genes expressed upon the activation of a T or B cell through its antigen receptor. Previous experiments have demonstrated that in stimulated T cells, a TNF-alpha promoter element, kappa 3, which binds NFATp, is required for the cyclosporin A-sensitive transcriptional activation of the gene. Here, we demonstrate that a cyclic AMP response element (CRE), which lies immediately upstream of the kappa 3 site, is also required for induction of TNF-alpha gene transcription in T cells stimulated by calcium ionophore or T-cell receptor ligands. The CRE binds ATF-2 and Jun proteins in association with NFATp bound to kappa 3. These proteins bind noncooperatively in vitro; however, the transcriptional activity of the CRE/kappa 3 composite site is dramatically higher than the activity of the kappa 3 site alone, indicating that the two sites cooperate in vivo. This study is the first demonstration of a role for ATF-2 in TNF-alpha gene transcription and of a functional interaction between ATF-2/Jun and NFATp. This novel pairing of NFATp with ATF-2/Jun may account for the specific and immediate pattern of TNF-alpha gene transcription in stimulated T cells.

Activating Transcription Factor 2↗
PubMed1995

Immunosuppressive drugs prevent a rapid dephosphorylation of transcription factor NFAT1 in stimulated immune cells.

The immunosuppressive drugs cyclosporin A and FK506 interfere with the inducible transcription of cytokine genes in T cells and in other immune cells, in part by preventing the activation of NF-AT (nuclear factor of activated T cells). We show that transcription factor NFAT1 in T cells is rapidly dephosphorylated on stimulation, that dephosphorylation occurs before translocation of NFAT1 into the cell nucleus, and that dephosphorylation increases the affinity of NFAT1 for its specific sites in DNA. Cyclosporin A prevents the dephosphorylation and the nuclear translocation of NFAT1 in T cells, B cells, macrophages, and mast cells, delineating at least one mechanism that contributes to the profound immunosuppressive effects of this compound.

Animals↗
PubMed1995

Only one of the two DNA-bound orientations of AP-1 found in solution cooperates with NFATp.

BACKGROUND: The transcription factor AP-1 activates the expression of numerous genes in response to mitogenic stimuli. AP-1 regulates gene expression both through solitary binding to independent recognition sites and, in cooperation with various heterologous transcription factors, through targeting to composite response elements. The two subunits that make up the AP-1 heterodimer, Fos and Jun, possess identical residues at positions that make sequence-specific contacts to DNA. This degeneracy leaves the protein with no apparent way of orienting itself uniquely on DNA by differentially recognizing its two non-identical half-sites. Here, we have analyzed the orientation of the AP-1 basic-leucine-zipper (bZip) domain on a cognate site, both alone and in the cooperative complex formed together with the 'nuclear factor of activated T cells' (NFATp). RESULTS: The results of affinity cleaving experiments demonstrate that, in solution, the AP-1 bZip binds DNA as a mixture of two orientational isomers. However, in the cooperative complex formed with NFATp on a composite response element, the AP-1 bZip adopts a single orientation, with Jun and Fos bound to the NFATp-proximal and NFATp-distal half-sites, respectively. Protein cross-linking experiments demonstrate that protein-protein contacts are responsible for this 'orientational locking'. CONCLUSIONS: Our results demonstrate that, through protein-protein interactions, one protein can force another to adopt a single DNA-bound orientation. Thus, cooperative interactions between adjacent regulatory proteins can influence not only the energetics of their interactions with DNA, but also their precise geometric and stereochemical arrangement. Because orientational isomers present markedly different structures to the transcriptional apparatus, it seems likely that orientation will exert an effect on the ability to activate transcription.

Amino Acid Sequence↗
PubMed1995

A similar DNA-binding motif in NFAT family proteins and the Rel homology region.

The cyclosporin-sensitive factor NFATp cooperates with Fos and Jun family proteins to regulate transcription of the interleukin 2 gene in activated T cells. We have defined a 187-amino-acid fragment of NFATp, located centrally within the protein sequence, as the minimal region required for DNA binding and for complex formation with Fos and Jun. The sequence of this region of NFATp shows a low degree of similarity to the Rel homology region. One specific short sequence in NFATp (RAHYETEG), located near the NH2 terminus of the DNA-binding domain, resembles a highly conserved sequence (RFRYxCEG) that is located near the NH2 terminus of the Rel homology region and that has been implicated in DNA binding by Rel family proteins. Mutational analysis demonstrates that the residues in this sequence that are identical in NFATp and Rel family proteins contribute to DNA binding by NFATp. Further, mutation of the threonine residue in this sequence to cysteine, as in Rel proteins, confers on NFATp a sensitivity to sulfhydryl modification similar to that of Rel family proteins. The results suggest that NFATp and Rel family proteins bind to DNA using similar structural motifs.

Amino Acid Sequence↗
PubMed1995

Transcriptional regulation of the IL-2 gene.

The past two years have seen significant advances in our understanding of IL-2 gene transcription. Many of the relevant transcription factors have been identified, the intracellular mechanisms regulating their functions are being elucidated, and the multiple roles of calcineurin are beginning to be appreciated.

Base Sequence↗
PubMed1994

Expression of the transcription factor NFATp in a neuronal cell line and in the murine nervous system.

The transcription factor NFATp, which has a central role in cytokine gene induction in T cells, was previously thought to be expressed only in T cells and other immune cells. Here we report that NFATp is also expressed in the rat PC12 pheochromocytoma cell line and in the murine nervous system. Antisera against T cell NFATp recognize proteins of similar apparent molecular weight in T cells, PC12 cells, and murine olfactory bulb. The immunoreactive proteins from PC12 cells and from olfactory bulb bind to an NFAT site of the murine interleukin-2 promoter with the same specificity as T cell NFATp. Immunohistochemical staining localizes NFATp to neurons, specifically to olfactory receptor neurons and to their terminals in the olfactory bulb. The presence of NFATp in the nervous system suggests that it has a role in the transcription of specific neuronal genes in response to increases in cytosolic calcium.

Adrenal Gland Neoplasms↗
PubMed1994

Normal peripheral T-cell function in c-Fos-deficient mice.

The ubiquitous transcription factors Fos and Jun are rapidly induced in T cells stimulated through the T-cell antigen receptor and regulate transcription of cytokines, including interleukin 2, in activated T cells. Since positive and negative selection of thymocytes during T-cell development also depends on activation through the T-cell receptor, Fos and Jun may play a role in thymocyte development as well. Fos and Jun act at several regulatory elements in the interleukin 2 promoter, including the AP-1 and NFAT sites. Using antisera specific to individual Fos and Jun family members, we show that c-Fos as well as other Fos family members are present in the inducible AP-1 and NFAT complexes of activated murine T cells. Nevertheless, c-Fos is not absolutely required for the development or function of peripheral T cells, as shown by using mice in which both copies of the c-fos gene were disrupted by targeted mutagenesis. c-Fos-deficient mice were comparable to wild-type mice in their patterns of thymocyte development and in the ability of their peripheral T cells to proliferate and produce several cytokines in response to T-cell receptor stimulation. Our results suggest that other Fos family members may be capable of substituting functionally for c-Fos during T-cell development and cytokine gene transcription in activated T cells.

Animals↗
PubMed1993

Isolation of the cyclosporin-sensitive T cell transcription factor NFATp.

Nuclear factor of activated T cells (NFAT) is a transcription factor that regulates expression of the cytokine interleukin-2 (IL-2) in activated T cells. The DNA-binding specificity of NFAT is conferred by NFATp, a phosphoprotein that is a target for the immunosuppressive compounds cyclosporin A and FK506. Here, the purification of NFATp from murine T cells and the isolation of a complementary DNA clone encoding NFATp are reported. A truncated form of NFATp, expressed as a recombinant protein in bacteria, binds specifically to the NFAT site of the murine IL-2 promoter and forms a transcriptionally active complex with recombinant protein fragment react with T cell NFATp. The molecular cloning of NFATp should allow detailed analysis of a T cell transcription factor that is central to initiation of the immune response.

Amino Acid Sequence↗