Biomedical subjects
Sanjay Kumar
Publications and source records attributed to Sanjay Kumar.
Delays in legislation slow the progress of CME in India.
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Adeno-associated virus 2-mediated antiangiogenic cancer gene therapy: long-term efficacy of a vector encoding angiostatin and endostatin over vectors encoding a single factor.
Angiogenesis is characteristic of solid tumor growth and a surrogate marker for metastasis in many human cancers. Inhibition of tumor angiogenesis using antiangiogenic drugs and gene transfer approaches has suggested the potential of this form of therapy in controlling tumor growth. However, for long-term tumor-free survival by antiangiogenic therapy, the factors controlling tumor neovasculature need to be systemically maintained at stable therapeutic levels. Here we show sustained expression of the antiangiogenic factors angiostatin and endostatin as secretory proteins by recombinant adeno-associated virus 2 (rAAV)-mediated gene transfer. Both vectors provided significant protective efficacy in a mouse tumor xenograft model. Stable transgene persistence and systemic levels of both angiostatin and endostatin were confirmed by in situ hybridization of the vector-injected tissues and by serum ELISA measurements, respectively. Whereas treatment with rAAV containing either endostatin or angiostatin alone resulted in moderate to significant protection, the combination of endostatin and angiostatin gene transfer from a single vector resulted in a complete protection. These data suggest that AAV-mediated long-term expression of both endostatin and angiostatin may have clinical utility against recurrence of cancers after primary therapies and may represent rational adjuvant therapies in combination with radiation or chemotherapy.
India s treatment programme for AIDS is premature.
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Report highlights shortcomings in private medical schools in India.
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Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage injury.
OBJECTIVE: Acute joint injury leads to increased risk for osteoarthritis (OA). Although the mechanisms underlying this progression are unclear, early structural, metabolic, and compositional indicators of OA have been reproduced using in vitro models of cartilage injury. This study was undertaken to determine whether glycosaminoglycan (GAG) loss following in vitro cartilage injury is mediated by cellular biosynthesis, activation of enzymatic activity, or mechanical disruption of the cartilage extracellular matrix. METHODS: Immature bovine cartilage was cultured for up to 10 days. After 3 days, groups of samples were subjected to injurious mechanical compression (single uniaxial unconfined compression to 50% thickness, strain rate 100% per second). GAG release to the medium was measured, and levels were compared with those in location-matched, uninjured controls. The effects of medium supplementation with inhibitors of biosynthesis (cycloheximide), of matrix metalloproteinase (MMP) activity (CGS 27023A or GM 6001), and of aggrecanase activity (SB 703704) on GAG release after injury were assessed. RESULTS: GAG release from injured cartilage was highest during the first 4 hours after injury, but remained higher than that in controls during the first 24 hours postinjury, and was not affected by inhibitors of biosynthesis or degradative enzymes. GAG release during the period 24-72 hours postinjury was similar to that in uninjured controls, but the MMP inhibitor CGS 27023A reduced cumulative GAG loss from injured samples between 1 day and 7 days postinjury. Other inhibitors of enzymatic degradation or biosynthesis had no significant effect on GAG release. CONCLUSION: Injurious compression of articular cartilage induces an initially high rate of GAG release from the tissue, which could not be inhibited, consistent with mechanical damage. However, the finding that MMP inhibition reduced GAG loss in the days following injury suggests a potential therapeutic intervention.
Molecular mechanisms for organizing the neuronal cytoskeleton.
Neurofilaments and microtubules are important components of the neuronal cytoskeleton. In axons or dendrites, these filaments are aligned in parallel arrays, and separated from one another by nonrandom distances. This distinctive organization has been attributed to cross bridges formed by NF side arms or microtubule-associated proteins. We recently proposed a polymer-brush-based mechanism for regulating interactions between neurofilaments and between microtubules. In this model, the side arms of neurofilaments and the projection domains of microtubule-associated proteins are highly unstructured and exert long-range repulsive forces that are largely entropic in origin; these forces then act to organize the cytoskeleton in axons and dendrites. Here, we review the biochemical, biophysical, genetic and cell biological data for the polymer-brush and cross-bridging models. We explore how the data traditionally used to support cross bridging may be reconciled with a polymer-brush mechanism and compare the implications of recent experimental insights into axonal transport and physiology for each model.
Tamoxifen improves endothelial function and reduces carotid intima-media thickness in postmenopausal women.
BACKGROUND: Tamoxifen is a selective estrogen-receptor modulator shown to improve several cardiovascular risk factors in postmenopausal women with breast cancer. In animal studies tamoxifen inhibits the progression of atherosclerosis. Although the presence of a history with tamoxifen treatment is related to a lower intima-media thickness (IMT) of the common carotid artery, data from controlled follow-up studies are lacking to support this observation. METHODS: We examined 14 postmenopausal women with early stage breast cancer with indication for tamoxifen treatment (20 mg/d) and 13 healthy postmenopausal women. Flow-mediated dilatation (FMD) of the brachial artery, combined carotid IMT, and aortic pulse wave were measured before and 6 months after treatment in the tamoxifen group and at the same times in the control group. RESULTS: FMD and IMT were significantly increased and decreased, respectively, in the treatment group compared to the control group (FMD: +2.2% +/- 0.9% vs +0.085% +/- 1%, P =.012; IMT: -0.088 +/- 0.03 mm vs +0.04 +/- 0.03 mm, P =.018, mean +/- standard error of the mean, treatment vs control group). These differences remained significant even when adjusted for age, duration of menopause, and cardiovascular risk factors. Low-density lipoprotein cholesterol was also significantly reduced after tamoxifen treatment. CONCLUSIONS: Tamoxifen treatment slows the progression of atherosclerosis in postmenopausal women with breast cancer as assessed by changes in carotid IMT. An improvement in endothelial function and blood lipid profile may be the reason for this beneficial effect.
Delayed localised subcutaneous emphysema following sternal repair.
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Construction of bacterial artificial chromosome libraries from the parasitic nematode Brugia malayi and physical mapping of the genome of its Wolbachia endosymbiont.
The parasitic nematode, Brugia malayi, causes lymphatic filariasis in humans, which in severe cases leads to the condition known as elephantiasis. The parasite contains an endosymbiotic alpha-proteobacterium of the genus Wolbachia that is required for normal worm development and fecundity and is also implicated in the pathology associated with infections by these filarial nematodes. Bacterial artificial chromosome libraries were constructed from B. malayi DNA and provide over 11-fold coverage of the nematode genome. Wolbachia genomic fragments were simultaneously cloned into the libraries giving over 5-fold coverage of the 1.1 Mb bacterial genome. A physical framework for the Wolbachia genome was developed by construction of a plasmid library enriched for Wolbachia DNA as a source of sequences to hybridise to high-density bacterial artificial chromosome colony filters. Bacterial artificial chromosome end sequencing provided additional Wolbachia probe sequences to facilitate assembly of a contig that spanned the entire genome. The Wolbachia sequences provided a marker approximately every 10 kb. Four rare-cutting restriction endonucleases were used to restriction map the genome to a resolution of approximately 60 kb and demonstrate concordance between the bacterial artificial chromosome clones and native Wolbachia genomic DNA. Comparison of Wolbachia sequences to public databases using BLAST algorithms under stringent conditions allowed confident prediction of 69 Wolbachia peptide functions and two rRNA genes. Comparison to closely related complete genomes revealed that while most sequences had orthologs in the genome of the Wolbachia endosymbiont from Drosophila melanogaster, there was no evidence for long-range synteny. Rather, there were a few cases of short-range conservation of gene order extending over regions of less than 10 kb. The molecular scaffold produced for the genome of the Wolbachia from B. malayi forms the basis of a genomic sequencing effort for this bacterium, circumventing the difficult challenge of purifying sufficient endosymbiont DNA from a tropical parasite for a whole genome shotgun sequencing strategy.
Metastatic left atrial synovial sarcoma mimicking a myxoma.
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Expression of Babesia equi EMA-1 and EMA-2 during merozoite developmental stages in erythrocyte and their interaction with erythrocytic membrane skeleton.
In the present study, we investigated the cellular localizations and expression patterns of equi merozoite antigens (EMA) -1 and -2 of Babesia equi during its asexual erythrocytic-developmental cycle using anti-EMA-1t or -2t mono-specific mouse serum. Indirect fluorescent antibody tests demonstrated that EMA-1 and EMA-2 were not expressed in all the erythrocytic-developmental stages of the merozoites and that these two antigens were co-expressed during the early developmental stages. Additionally, it was shown that EMA-1 and EMA-2 were mutually expressed on the surface of extra-erythrocytic merozoites and also that the intra-erythrocytic merozoites shed only EMA-2 antigen in the infected erythrocytic cytoplasm or inside the membrane surface. The specific binding of EMA-2 to a Triton X-100-insoluble horse erythrocyte membrane fraction was also demonstrated. These findings facilitate our understanding of the biological roles of merozoite surface proteins of B. equi and our investigation for new drug targets.
Identification of a piroplasm protein of Theileria orientalis that binds to bovine erythrocyte band 3.
Theileria orientalis infects cattle and causes various disease symptoms, including anaemia and icterus. The erythrocytic stages are responsible for these symptoms but the molecular events involved in these stages have not yet been fully elucidated. In this study, we identified a T. orientalis cDNA that encodes a polypeptide related to identity to the microneme-rhoptry protein of Theileria parva. Analysis of its recombinant product (ToMRP) by indirect fluorescent-antibody test revealed that it is specifically expressed at the early erythrocytic stage after invasion. This expression disappears during the intermediate stages of intra-erythrocytic development. Its expression then reappears at the late stages after the parasite has divided by binary fission into diad or tetrad forms and before these forms are released from the host erythrocyte. In vitro erythrocyte binding assays showed that ToMRP associates with the Triton X-insoluble fraction of erythrocytes membrane but not with intact erythrocytes. Cosedimentation and Western blot analyses revealed that ToMRP binds to band 3, a membrane component of bovine erythrocytes. These observations suggest that ToMRP may be involved in the parasite's egress from and/or invasion into the host erythrocytes by interacting with a protein in the membrane skeleton of the erythrocyte and thereby modifying the structure and function of the cell.
Replacement of a regurgitant pulmonary valve with a stentless bioprosthesis.
Acquired surgical disease of the pulmonary valve is rare. We report a 72-year-old man who presented with subacute endocarditic pulmonary regurgitation. This lesion was surgically corrected with a stentless bioprosthesis. Previously, homografts and various xenografts have been used for replacement of the pulmonary valve both in the pediatric population and in adult patients with congenital heart disease. Pulmonary regurgitation is a rare lesion, but if it is encountered our case demonstrates that it can be successfully and easily treated with pulmonary valve replacement by using a stentless bioprosthesis.
6. Cathepsin K inhibitors: their potential as anti-osteoporosis agents.
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Re: quantitative evaluation of AgNORs in bone tumours.
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Osteogenic differentiation of recombinant adeno-associated virus 2-transduced murine mesenchymal stem cells and development of an immunocompetent mouse model for ex vivo osteoporosis gene therapy.
Gene therapy for osteopenic conditions including osteoporosis is a potential alternative to pharmacotherapy for cost effectiveness, long-term viability, and the ability to enhance bone mass by anabolic approaches. Increased understanding of mesenchymal stem cell (MSC) lineage differentiation during osteogenesis, and of the molecular pathways involved in bone cell production, provides an opportunity for the advancement of gene therapy approaches for osteopenic conditions. The potential of MSCs in osteoblast differentiation and the relative ease of MSC isolation and culturing offer a promising resource for the development of ex vivo gene therapy for bone defects. In an effort to develop ex vivo gene therapy for osteoporosis, we used gene-modified MSCs in a preclinical mouse model to determine the efficiency of transduction of murine MSCs by recombinant adeno-associated virus 2 (AAV) vectors carrying reporter genes and determined their osteogenic potential after recombinant AAV-mediated expression of bone morphogenic protein 2, known to induce osteoblast differentiation. Although surgical ovariectomy is believed to induce progressive bone loss in mouse models, similar to an osteoporosis-like phenotype in humans, several factors, including hormonal alteration and dietary habits, significantly affect both the onset and progression of the disease. Thus, in the present study, we determined the influence of these factors and developed an immunocompetent mouse model of osteoporosis with degenerative bone loss as in the human pathology.
Augmentation of antitumor activity of a recombinant adeno-associated virus carcinoembryonic antigen vaccine with plasmid adjuvant.
Recombinant adeno-associated virus 2 (rAAV) vectors have been successfully used for sustained expression of therapeutic genes. The potential of using rAAV as a cancer vaccine vector and the impact of a bacterial plasmid adjuvant on this activity were investigated. C57BL/6 mice received a single intramuscular injection of rAAV expressing the human tumor-associated antigen, carcinoembryonic antigen (CEA). Three weeks later, when CEA expression was optimal, a bacterial plasmid containing methylated DNA motifs was injected into the same muscle. Mice were challenged 1 week later with syngeneic MC38 tumor cells stably expressing CEA. Immunization with rAAV-CEA alone resulted in sustained transgene expression and the elicitation of a humoral immune response to CEA. Cellular immune response, however, was weak, and tumor protection was not significant. In contrast, immunization with rAAV-CEA and the plasmid adjuvant resulted in stronger cellular immune response to CEA and tumor protection. The addition of plasmid adjuvant increased both myeloid dendritic cell recruitment in situ and CEA-specific T-helper-1-associated immune response. These data indicate that robust rAAV transgene expression of a tumor antigen followed by transient plasmid delivery to recruit and activate dendritic cells is an effective method of eliciting antitumor cellular immune responses.