PubMed Health⌕ Search

Biomedical subjects

A Khanna

Publications and source records attributed to A Khanna.

At least 19 recordsLinked to original sources
PubMed2026

Genomic basis of developmental defects of enamel and sex-specific effects.

We conducted a multi-ancestry genome-wide association study (GWAS) of developmental defects of enamel (DDE) in the primary dentition among 6,061 U.S. preschool-aged children (3-5 years). We investigated four DDE phenotypes (demarcated opacities, diffuse opacities, hypoplastic defects, and a combined DDE trait) leveraging main-effect models, joint gene-sex interaction testing (2df), and sex-stratified analyses. SNP-based heritability for the combined DDE trait was estimated at 20%, with concordance analyses robustly supporting a genetic etiology. We identified 39 unique genome-wide significant loci (P<5&#xd7;10 ), with five surpassing a study-wide Bonferroni-corrected statistical significance criterion (P<1.25&#xd7;10 9), including Y RNA and ALDH1A1. The main-effect GWAS identified 20 loci, including HBS1L and MYB, genes regulating hematopoiesis with plausible roles in amelogenesis. Joint test and sex-stratified analyses revealed 19 additional loci, including ALDH1A1, TENM2, and DLGAP2, demonstrating sex-specific heterogeneity. Nineteen loci exhibited sex-specific differences after Bonferroni correction (P<2x10-3), including genes involved in retinoic acid signaling (ALDH1A1), odontogenesis (TENM2), and neurodevelopment (DLGAP2, CDH10). Pathway enrichment highlighted ectodermal and synapse organization networks, suggesting shared etiological mechanisms between DDE and systemic conditions like neurofibromatosis and autism spectrum disorder. Notably, no locus generalized in an external GWAS of permanent dentition DDE, underscoring fundamental biological differences in the genetic architectures governing primary versus permanent enamel formation. Crucially, a comprehensive cross-trait pleiotropy lookup against early childhood caries (ECC) revealed no shared genetic architecture, supporting the notion that the established clinical and epidemiological association between DDE and ECC is likely driven by structural defects increasing caries lesion susceptibility rather than genetic pleiotropy. By integrating gene-sex interaction testing, this study offers novel insights into the complex, sexually dimorphic genetic etiology of DDE and augments the biological evidence base that can support the development of precision pediatric dentistry.

developmental defects of enamel↗
PubMed1997

Striking augmentation of hematopoietic cell chimerism in noncytoablated allogeneic bone marrow recipients by FLT3 ligand and tacrolimus.

The influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and the recently identified hematopoietic stem-progenitor cell mobilizing factor flt3 ligand (FL) on donor leukocyte microchimerism in noncytodepleted recipients of allogeneic bone marrow (BM) was compared. B10 mice (H2b) given 50x10(6) allogeneic (B10.BR [H2k]) BM cells also received either GM-CSF (4 microg/day s.c.), FL (10 microg/day i.p.), or no cytokine, with or without concomitant tacrolimus (formerly FK506; 2 mg/kg) from day 0. Chimerism was quantitated in the spleen 7 days after transplantation by both polymerase chain reaction (donor DNA [major histocompatibility complex class II; I-E(k)]) and immunohistochemical (donor [I-E(k)+] cell) analyses. Whereas GM-CSF alone significantly augmented (fivefold) the level of donor DNA in recipients' spleens, FL alone caused a significant (60%) reduction. Donor DNA was increased 10-fold by tacrolimus alone, whereas coadministration of GM-CSF and tacrolimus resulted in a greater than additive effect (28-fold increase). A much more striking effect was observed with FL + tacrolimus (>125-fold increase in donor DNA compared with BM alone). These findings were reflected in the relative numbers of donor major histocompatibility complex class II+ cells (many resembling dendritic cells) detected in spleens, although quantitative differences among the groups were less pronounced. Evaluation of cytotoxic T lymphocyte generation by BM recipients' spleen cells revealed that FL alone augmented antidonor immunity and that this was reversed by tacrolimus. Thus, although FL may potentiate antidonor reactivity in nonimmunosuppressed, allogeneic BM recipients, it exhibits potent chimerism-enhancing activity when coadministered with recipient immunosuppressive therapy.

Animals↗
PubMed1997

In vivo hyperexpression of transforming growth factor-beta1 in mice: stimulation by cyclosporine.

BACKGROUND: We have demonstrated that cyclosporine (CsA) stimulates transforming growth factor (TGF) beta1 expression in vitro and that growth of mammalian cells can be arrested by CsA via a TGF-beta1-dependent mechanism. Herein, we have explored whether CsA stimulates TGF-beta1 hyperexpression in vivo. METHODS: Four groups of B6AF1 mice were studied: group 1, control; group 2, CsA pretreatment; group 3, anti-CD3 monoclonal antibody pretreatment; and group 4, CsA plus anti-CD3 pretreatment. RESULTS: CsA pretreatment augmented TGF-beta1 protein expression and increased intrarenal display of TGF-beta1 mRNA. This heightened TGF-beta1 expression was associated with an impaired T cell proliferative response. CONCLUSIONS: Our observations, together, advance the hypothesis that CsA might function in vivo as an immunosuppressant not only by inhibiting the expression of proinflammatory cytokines (e.g., interleukin 2), but also by stimulating the expression of TGF-beta1, a potent immunosuppressive cytokine. Moreover, prevention of TGF-beta1 hyperexpression might prevent CsA-associated renal fibrosis, as TGF-beta1 is a fibrogenic cytokine.

Animals↗
PubMed1997

Intracellular Ca2+ elevation and cyclosporin A synergistically induce TGF-beta 1-mediated apoptosis in lymphocytes.

Apoptosis plays an essential role in the development and homeostasis of the immune system. During lymphocyte development, potentially autoreactive cells are eliminated via the activation of a tightly regulated cell death program(s). Similar processes operate in mature lymphocytes, to control the magnitude of the normal immune response by eliminating activated lymphocytes. However, differences in susceptibility to signal-induced apoptosis between immature and mature lymphocytes are numerous. One well-characterized example occurs in response to Ca2+ elevation: peripheral T lymphocytes are resistant, while immature thymocytes are highly susceptible, to Ca2+-mediated cell death (CMCD). In this study, we show that the immunosuppressant cyclosporin A (CsA) primes splenic lymphocytes to undergo CMCD upon ionomycin stimulation. This CsA-induced CMCD affected both T and B lymphocytes. CsA-plug Ca2+-mediated apoptosis was dissected into a two-step process: first, CsA and Ca2+ synergized to induce TGF-beta 1 secretion by B cells; and then TGF-beta 1 and Ca2+ synergistically triggered T and B lymphocyte apoptosis. Together, our results suggest that lymphocyte apoptosis may play a role in CsA-induced immunosuppression via a TGF-beta-dependent mechanism.

Animals↗
PubMed1997

Internal hernia and volvulus of the small bowel following liver transplantation.

Internal herniation with volvulus of the small intestine is an uncommon, but potentially fatal, complication after liver transplantation. We present here four cases in which the herniation occurred around the Roux-en-Y loop used for the biliary reconstruction. One patient died due to intestinal and liver allograft necrosis; another lost almost the entire small intestine and has since undergone successful intestinal transplantation. Two patients survived following surgery that involved reduction of the hernia and closure of the mesenteric defect. Clinical diagnostic implications emphasize early diagnosis and appropriate operative intervention.

Adolescent↗
PubMed1997

Immunostimulatory therapy with anti-CD3 monoclonal antibodies and recombinant interleukin-2: heightened in vivo expression of mRNA encoding cytotoxic attack molecules and immunoregulatory cytokines and regression of murine renal cell carcinoma.

The response rate to IL-2 immunotherapy, currently used in the treatment of metastatic renal cell cancer, is limited. Based on our earlier demonstration that a combined regimen of monoclonal antibodies directed at the T cell surface protein CD3 (anti-CD3 mAbs) and IL-2 is synergistic in constraining tumor progression in a murine fibrosarcoma hepatic metastasis model, we have explored the efficacy of an anti-CD3 mAbs plus IL-2 regimen in a murine renal cell cancer model. Our studies demonstrate that a regimen of anti-CD3 mAbs plus IL-2 is superior to treatment with anti-CD3 mAbs alone or IL-2 alone in reducing the number of pulmonary metastases and in prolonging survival. Moreover, the efficacious regimen is associated with heightened intrapulmonary expression of mRNA encoding cytotoxic attack molecules (perforin, granzyme B) and immunoregulatory cytokines (IL-4, IL-10 and IFN- gamma).

Animals↗
PubMed1997

Vaccinia virus serpin B13R (SPI-2) inhibits interleukin-1beta-converting enzyme and protects virus-infected cells from TNF- and Fas-mediated apoptosis, but does not prevent IL-1beta-induced fever.

The vaccinia virus (VV) strain Western Reserve B13R gene encodes a 38.5 kDa intracellular polypeptide that is non-essential for virus replication in vitro and does not affect virus virulence in a murine intranasal model. The protein has 92% amino acid identity with the cowpox virus cytokine response modifier A (crmA) protein which inhibits the interleukin (IL)-1beta converting enzyme (ICE). Here, we show that extracts from THP-1 cells infected with VV strains expressing B13R prevent the cleavage of in vitro transcribed and translated pro-IL-1beta into mature IL-1beta. Similarly, THP-1 cells infected with VVs expressing B13R process pro-IL-1beta into mature IL-1beta inefficiently in situ. Despite its inhibition of ICE, B13R does not prevent fever in infected mice, a systemic effect mediated by IL-1beta. Instead, fever is controlled by the VV IL-1beta receptor, encoded by gene B15R, and deletion of both the B13R and B15R genes did not increase the febrile response compared to deletion of B15R alone. The B13R protein does, however, block apoptosis mediated by anti-Fas antibodies or by tumour necrosis factor (TNF) and cycloheximide. Using DNA fragmentation, chromium release and microscopic analyses it was shown that cells infected with wild-type VV strain WR, or a revertant virus in which the B13R gene had been re-inserted into the B13R deletion mutant, are more resistant than uninfected cells or deletion mutant-infected cells to apoptosis mediated by anti-Fas and TNF.

Animals↗
PubMed1997

Mapping of 10 novel microsatellites in the MHC class III region: application to the study of autoimmune disease.

The MHC class III region contains many genes that are good candidates for involvement in autoimmune disease. We report the mapping and characterization of 10 novel (CA)n microsatellites spanning the region, which are highly informative and suitable for linkage and association studies. We used these markers to identify haplotypes of MHC class III microsatellite alleles in DNA from cell lines homozygous for MHC class II and class I alleles.

Autoimmune Diseases↗
PubMed1996

The gene G13 in the class III region of the human MHC encodes a potential DNA-binding protein.

G13 is a single-copy gene lying approx. 75 kb centromeric of the complement gene cluster in the class III region of the human MHC. The gene spans approx. 17 kb of DNA and has been shown to encode mRNA of approx. 2.7 kb that is present in cell lines representing lymphoid and non-lymphoid tissues, indicating that it is ubiquitously expressed. The complete nucleotide sequence of the 2.7 kb mRNA has been derived from cDNA and genomic clones. The longest open reading frame obtained for G13 codes for a 703 amino acid protein of approx. 77 kDa in molecular mass. Comparison of the putative G13 amino acid sequence with the protein databases revealed significant similarities with DNA-binding proteins of the leucine zipper class, including a human cAMP response element binding protein. G13 contains a bZIP motif, a region rich in basic amino acids adjacent to a coiled-coil leucine zipper domain, common to this class of proteins that is known to be involved in dimerization and DNA binding. Antibodies raised against a fragment encoding the C-terminal half of the putative G13 protein recognized a major polypeptide of approx. 86 kDa and a minor polypeptide of approx. 78 kDa on immunoblotting of U937 cell extracts; this has been confirmed by immunoprecipitation experiments. Even though it contained at least one potential bipartite nuclear localization signal, the G13 protein was present both in the cytoplasm and the nucleus of the fibroblast cells. Thus G13 might be a novel DNA-binding protein that is perhaps translocated to the nucleus in a regulated manner.

Amino Acid Sequence↗
PubMed1996

CD2 antigen targeting reduces intragraft expression of mRNA-encoding granzyme B and IL-10 and induces tolerance.

We explored the hypothesis that CD2 antigen-specific therapy would reduce intragraft gene expression and facilitate the emergence of transplantation tolerance. This postulate was tested in a murine pancreatic islet cell allograft model in which a novel mAb directed at the CD2 antigen, RM2-2 anti-CD2 mAb (RM2-2 mAb), was used to regulate CD2 antigen-dependent antiallograft response. Peritransplant administration (day -1, 0, and day + 1 with respect to transplantation) of RM2-2 mAb resulted in significantly longer survival of DBA/2 pancreatic islet cell allografts in the B6AFl recipient compared with untreated recipients. RM2-2 mAb therapy facilitated the induction of antigen-specific tolerance: whereas retransplantation with the original donor strain (DBA/2) islet cell allograft was successful, retransplantation with a third-party donor (SJL) islet cell allograft was not. In vivo administration of RM2-2 mAb therapy resulted in a decrease in the percentage of T cells that coexpressed the CD2 antigen (demonstrated by two-color flow cytometry) and in a decrease in intragraft expression of cytotoxic cell specific granzyme B mRNA and IL-10 mRNA (detected by RT-PCR). Our data, in addition to demonstrating for the first time the efficacy of RM2-2 anti-CD2 mAb, suggest that CD2 antigen is a suitable target for the induction of transplantation tolerance.

Animals↗
PubMed1996

Transforming growth factor-beta 1: regulation with a TGF-beta 1 antisense oligomer.

Transforming growth factor-beta 1 (TGF-beta 1) is a member of a family of polypeptides important in embroygenesis, tissue repair and cell growth. On the other hand, TGF-beta 1 is considered to be a causative factor in organ dysfunction and in immune deregulation of AIDS. The proteoglycan decorin and anti-TGF-beta antibodies have been used to mitigate the adverse consequences of TGF-beta 1 overexpression. We describe here a novel TGF-beta 1 complementary DNA (antisense oligomer) that is specific for TGF-beta 1 genomic DNA. The TGF-beta 1 antisense oligomer, complementary to the nucleotides flanking the first transcription start site of the human TGF-beta 1 gene and phosphorothioate modified, was efficacious in: (a) constraining TGF-beta 1 promoter activity; (b) reducing TGF-beta 1 secretion; (c) preventing TGF-beta 1 dependent inhibition of DNA synthesis; and (d) inhibiting phenotypic alterations in TGF-beta sensitive A-549 human adenocarcinoma cells. Our findings, in addition to demonstrating the efficacy of the TGF-beta 1 antisense oligomer, suggest that the oligomer might be of value for the treatment of diseases in which TGF-beta 1 overexpression might play a pathogenetic role.

Adenocarcinoma↗
PubMed1996

Delta F 508 molecular mutation in Indian children with cystic fibrosis.

A preliminary report of 13 Indian children with cystic fibrosis who were screened for the commonest mutation (delta F 508) is presented. Six (46%) patients were homozygous for delta F 508, while two patients were compound heterozygotes. Thus 14 (53.8%) of 26 mutant chromosomes had delta F 508 mutation. These findings confirm that cystic fibrosis occurs in India and all children with persistent respiratory problems and/or malabsorption should be screened for this disease.

Child↗
PubMed1995

Hepatitis C virus core protein: synthesis, affinity purification and immunoreactivity with infected human sera.

The genomic region encoding the core (C) protein (amino acids 1-162) of hepatitis C virus (HCV) was expressed in Escherichia coli as a recombinant (re-) protein with the maltose-binding protein (MBP) using the prokaryotic expression vector pMAL-CR1. The fusion protein (C::MBP) was identified as a approx. 62-kDa polypeptide by immunoblot analysis using antiserum to MBP and HCV-infected human sera. The size of C::MBP corresponded to the calculated combined molecular mass of the approx. 20-kDa HCV C protein and the approx. 42-kDa MBP. The approx. 62-kDa C::MBP was purified using amylose resin as a matrix in affinity chromatography, and showed specific reactivity with HCV-infected human sera. These results suggest that C::MBP may serve as a source of the core antigen for immunological studies on HCV infection.

ATP-Binding Cassette Transporters↗
PubMed1995

Stimulation of transforming growth factor-beta 1 transcription by cyclosporine.

In searching for a candidate mechanism for the immunosuppressive as well as fibrogenic consequences of cyclosporine usage, we have explored the hypothesis that cyclosporine stimulates transcription of transforming growth factor-beta 1 (TGF-beta 1), a multifunctional cytokine endowed with immunosuppressive and fibrogenic properties. Our results demonstrate that cyclosporine (i) stimulates TGF-beta 1 promoter-dependent transcription of chloramphenicol acetyl transferase gene in transiently transfected human A-549 cells, (ii) stimulates the synthesis of TGF-beta 1 RNA transcripts in human T cells, and (iii) permits the expression/emergence of DNA regulatory proteins (retinoblastoma control factor-1 (RCF-1) and RCF-2) that bind and regulate TGF-beta 1 promoter activity. Our studies demonstrate for the first time that cyclosporine stimulates TGF-beta 1 gene transcription and suggest a novel mechanism of action of cyclosporine.

Base Sequence↗
PubMed1995

Physiological and pharmacological inhibitors of luteinizing hormone-dependent steroidogenesis induce heat shock protein-70 in rat luteal cells.

Heat shock protein (HSP) synthesis increases in cells with a broad range of stress conditions. We recently showed that induction of HSP-70 is associated with inhibition of hormone-sensitive steroidogenesis, but not hormone-sensitive cAMP accumulation, in rat luteal cells by a mechanism associated with interruption of cholesterol translocation in mitochondria. As HSP induction may be an early mediator of luteal regression, we investigated whether physiological and pharmacological inhibitors of luteal function would induce HSP-70 in rat luteal cells. Both [35S]methionine labeling and Western blotting with antibodies against the inducible form of HSP-70 revealed HSP induction in rat luteal cells by 1 microM prostaglandin F2 alpha (PGF2 alpha) coincident with inhibition of progesterone synthesis. In contrast, PGE2 (1 microM) failed to increase HSP-70 synthesis. Phorbol 12-myristate 13 acetate (3 microM), tumor necrosis factor-alpha (100 ng/ml), and ionomycin (1 microM) also induced HSP synthesis. Induction of HSP-70 was preceded by the rapid activation of heat shock transcription factor, which binds to the heat shock transcriptional control element. Gel retardation assays demonstrated heat shock transcription factor activation within 15 min of PGF2 alpha treatment. Northern analysis with an oligonucleotide probe specific for inducible HSP-70 showed induction at the transcriptional level by the above agents within 30 min. As functional luteal regression is known to display elements of a stress response, the finding that a number of factors that inhibit hormone-sensitive progesterone synthesis rapidly activate the heat shock response further implicates HSPs as possible mediators of luteolysis.

Animals↗