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Biomedical subjects

S Agrawal

Publications and source records attributed to S Agrawal.

At least 145 records · Page 8Linked to original sources
PubMed1999

Evaluation of the Yale-Brown Obsessive Compulsive Scale (YBOCS-hd) for heavy drinking with mild to moderately dependent alcohol abusers.

BACKGROUND: Many similarities have been noted between urges and desires to drink heavily and obsessive-compulsive disorders (OCD). Based on such similarities, Modell et al. (1992) developed the Yale-Brown Obsessive Compulsive Scale for heavy drinking (YBOCS-hd), a modified version of YBOCS, to assess obsessions and compulsions related to heavy drinking. Evaluation of the YBOCS-hd has been limited to more severely dependent alcohol abusers. METHODS: The present study used a self-administered version of the YBOCS-hd to evaluate (1) the severity of drinking-related obsessive compulsive symptoms with mild to moderately dependent alcohol abusers (problem drinkers), and (2) whether end-of-treatment changes in YBOCS-hd scores would be related to within-treatment functioning. RESULTS: Results indicated that problem drinkers have lower alcohol-related Obsessive and Compulsive subscale scores than did more severely dependent drinkers, but higher scores than did non-problem drinkers, supporting the construct validity of the YBOCS-hd. In addition, at the end of treatment, the YBOCS-hd scores of alcohol abusers who drank at low-risk levels during treatment were significantly lower than the scores of those who drank at high-risk levels. Lastly, exploratory factor analysis did not provide support for the two purported YBOCS-hd subscales (Obsessive, Compulsive). Instead, the analysis yielded a single general factor and a second factor that contained two questions measuring heavy drinking. CONCLUSIONS: Despite the fact that total YBOCS-hd scores covaried with drinking, neither the total YBOCS-hd pretreatment score nor the two subscale scores predicted functioning at the end of treatment. The present results call into question the utility of the YBOCS-hd, because a single item measuring the heaviness of drinking was as useful as the total YBOCS-hd and its two subscales in relating changes during treatment to end-of-treatment functioning for problem drinkers. However, although the YBOCS-hd does not predict changes in drinking, it may have value as an indirect measure of drinking in situations where direct measurement of alcohol consumption is undesirable (i.e., direct measurement might be reactive). Because the present findings are derived from problem drinkers, further research is needed to confirm the factor structure of the YBOCS-hd with clients who represent a broader range of alcohol problem severity.

Adult↗
PubMed1999

Adjuvant therapy in invasive thymoma: an audit of cases treated over an 8 year period.

Invasive thymomas comprise 0.1%-0.2% of all malignancies in India. This report is an audit of 11 cases (10 males and 1 female) at a mean age of 36.6 years (range 25-52 years) of invasive thymoma accrued over an eight year period treated by combined modality treatment. Nine of these presented with myaesthenia gravis. All patients underwent initial surgery (3 partial and 8 total resections) and postoperative radiotherapy. Two of the three partially resected patients received one course of chemotherapy prior to radiotherapy consisting of cyclophosphamide, vincristine, procarbazine and prednisolone. At a median follow up of 28 months (range 2-87) there have been no local relapses, one distant metastasis and one death due to uncontrolled myaesthenia. The treatment strategies with invasive thymomas would depend upon the extent of resection. Postoperative radiotherapy appears to be indicated in all cases, however the role of chemotherapy may be limited to those with partial resection.

Adult↗
PubMed1998

Sequence-specific RNase H cleavage of gag mRNA from HIV-1 infected cells by an antisense oligonucleotide in vitro.

We have used a ribonuclease protection assay to investigate RNase H cleavage of HIV-1 mRNA mediated by phosphorothioate antisense oligonucleotides complementary to the gag region of the HIV-1 genome in vitro. Cell lysate experiments in H9 and U937 cells chronically infected with HIV-1 IIIB showed RNase H cleavage of unspliced gag message but no cleavage of spliced message which did not contain the target gag region. RNase H cleavage products were detected at oligonucleotide concentrations as low as 0.01 microM and the RNase H activity was seen to be concentration dependent. Similar experiments with 1-, 3- and 5-mismatch oligonucleotides demonstrated sequence specificity at low concentrations, with cleavage of gag mRNA correlating with the predicted activities of the parent and mismatch oligonucleotides based on their hybridization melting temperatures. Experiments in living cells suggested that RNase H-specific antisense activity was largely determined by the amount of oligonucleotide taken up by the different cell lines studied. RNase H cleavage products were detected in antisense oligonucleotide treated MT-4 cells acutely infected with HIV-1 IIIB, but not in infected H9 cells treated with oligonucleotide under the same conditions. The data presented demonstrate potent and specific RNase H cleavage of HIV-1 mRNA mediated by an antisense oligonucleotide targeted to HIV-1 gag mRNA, and are in agreement with previous reports that the major obstacle to demonstrating antisense activity in living cells remains the lack of penetration of these agents into the desired cellular compartment.

Gene Products, gag↗
PubMed1998

Mixed-backbone oligonucleotides as second-generation antisense agents with reduced phosphorothioate-related side effects.

Mixed-backbone oligonucleotides containing alternative phosphorothioate and phosphodiester linkages in the 2'-O-methylribonucleosides segment show increased affinity with complementary targets, increased stability towards nucleases in vitro and in vivo, and reduced phosphorothioate-related prolongation of partial thromboplastin time compared to phosphorothioate oligodeoxynucleotides, thereby providing antisense agents with reduced side effects.

Drug Stability↗
PubMed1998

CD3 hyporesponsiveness and in vitro apoptosis are features of T cells from both malignant and nonmalignant secondary lymphoid organs.

There is a dogma in tumor immunology that tumor-infiltrating lymphocytes (TIL) are defective based on their lack of antitumoral efficacy in vivo and on impaired response to in vitro functional tests. However, TIL have been compared usually with peripheral blood T lymphocytes, raising doubts on the conclusions drawn. Therefore, we compared TIL from B cell non-Hodgkin's lymphomas (NHL) with T cells from nonmalignant secondary lymphoid organs. NHL-TIL were unresponsive to activation by immobilized anti-CD3 mAb, although bypassing T cell receptor (TCR)/CD3 signaling led to proliferation. The poor proliferative responses of NHL-TIL could not be explained by quantitative defects in TCRzeta expression. NHL-TIL underwent marked spontaneous apoptosis in vitro with loss of approximately 50% of cells after 24 h of culture. This was associated with downregulation of the antiapoptotic Bcl-xL and Bcl-2 proteins, whereas viable NHL-TIL maintained their expression. IL-2, anti-CD3/IL-2, and manipulation of the Fas/Fas-ligand death pathway had no effect on NHL-TIL survival. Apoptosis was not due to increased cell cycling, as NHL-TIL were quiescent, nonproliferating cells. T cells from inflammatory, nonmalignant tissues gave similar functional results to NHL-TIL, suggesting the existence of factors common to the microenvironment of these diverse pathologies. Thus, the quiescent, anergic phenotype of NHL-TIL cannot be attributed solely to tumor factors, but rather is a feature of T cells from chronic inflammatory lesions.

Apoptosis↗
PubMed1998

Solid-phase stereoselective synthesis of 2'-O-methyl-oligoribonucleoside phosphorothioates using nucleoside bicyclic oxazaphospholidines.

The use of 2'-OMe-ribonucleoside bicyclic oxazaphospholidines derived from (R)- or (S)-2-pyrrolidinemethanol has enabled the stereoselective synthesis of (Rp)-, and (Sp)-2'-O-methyloligoribonucleoside phosphorothioates. Interestingly, higher stereoselectivity (96-98%) was observed in the synthesis of (Sp)-2'-O-methyl-oligoribonucleoside phosphorothioates compared to that in the case of (Sp)-oligodeoxyribonucleoside phosphorothioates (90%).

Chromatography, High Pressure Liquid↗
PubMed1998

Effects of phosphorothioate oligodeoxyribonucleotide and oligoribonucleotides on human complement and coagulation.

We have synthesized and studied the effects of phosphorothioate (PS) oligodeoxyribonucleotide (DNA) and oligoribonucleotides (RNA, 2'-O-methyl-RNA and 2'-5'-RNA) on complement activation and prolongation of activated partial thromboplastin time (aPTT) in vitro. These results suggest that a PS-DNA prolongs aPTT, and inhibits complement lysis more than do the PS-RNA analogs.

Base Sequence↗
PubMed1998

Cooperative inhibition of renal cancer growth by anti-epidermal growth factor receptor antibody and protein kinase A antisense oligonucleotide.

BACKGROUND: The expression of epidermal growth factor receptor (EGFR) and type I cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKAI) is associated with neoplastic transformation. By use of human renal cancer cell lines (i.e., 769-P, ACHN, A498, and SW839), we investigated the antiproliferative activity and the antitumor activity of an anti-EGFR humanized chimeric mouse monoclonal antibody, MAb C225, and a novel mixed backbone 18-mer antisense oligonucleotide, HYB 190, that targets expression of the RIalpha regulatory subunit of PKAI. METHODS: The antiproliferative activity of MAb C225 and oligonucleotide HYB 190, alone or in combination, on different renal cancer cell lines was determined by monitoring cell growth in soft agar. In addition, the induction of apoptosis by treatment with the anti-EGFR antibody and/or antisense PKAI oligonucleotides was evaluated by flow cytometric analysis of fragmented DNA. The antitumor activity of MAb C225 and oligonucleotide HYB 190 was determined in athymic mice bearing established ACHN tumor xenografts. Cell proliferation and tumor growth data were evaluated for statistical significance using Student's t test; reported P values are two-sided. RESULTS: MAb C225 and oligonucleotide HYB 190 inhibited colony formation in soft agar in a dose-dependent manner for all renal cancer cell lines tested. We observed a potentiation of growth inhibition and induction of apoptosis when 769-P cells and ACHN cells were treated with both agents. Combination treatment with MAb C225 and oligonucleotide HYB 190 caused regression of ACHN tumor xenografts, whereas single-agent treatment only delayed tumor growth. CONCLUSION: The combination of anti-EGFR MAb C225 and ited cooperative antiproliferative effects and cooperative antitumor effects on EGFR and PKAI-expressing human renal cancer cell lines.

Animals↗
PubMed1998

Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage.

The MDM2 oncogene encodes an inhibitor of the p53 tumor suppressor protein that regulates p53 in a negative feedback loop. MDM2 gene amplification and overexpression occur in several types of tumors and are often associated with poor prognosis. An MDM2 antisense phosphorothioate oligodeoxynucleotide has been identified that effectively inhibits MDM2 expression in tumor cells containing MDM2 gene amplifications. Antisense inhibition of MDM2 is associated with a decrease in MDM2-p53 complex formation, increase in p53-inducible gene expression, increase in p53 transcriptional activity, and apoptosis. Significantly, inhibition of MDM2 expression enhances the activation of p53 by a DNA-damaging cancer chemotherapy agent in a synergistic fashion. Therefore, the MDM2 negative feedback pathway is an important limiting factor in DNA damage-induced p53 activation. MDM2 antisense oligonucleotides may be useful as antitumor agents alone or as enhancers of other conventional DNA-damaging drugs.

Apoptosis↗
PubMed1998

Synergistic inhibition of HIV-1 by an antisense oligonucleotide and nucleoside analog reverse transcriptase inhibitors.

We have studied the effects of the gag antisense phosphorothioate oligonucleotide GEM 91 and mismatch antisense controls on the antiviral activities of ddC and other nucleoside analogs in HIV-infected MT-4 cells using a cytoprotection based assay. Under standard assay conditions, i.e. simultaneous incubation of drugs, HIV-1 IIIB and MT-4 cells, both GEM 91 and mismatch controls interacted synergistically with ddC resulting in an approximate 40-fold decrease in the IC50 value of ddC; this suggests a potent but sequence non-specific effect of GEM 91. Under post-adsorption assay conditions, i.e. pre-incubation of virus and cells and removal of excess HIV before drug addition, GEM 91 exhibited synergism with ddC, with an approximate 5-fold decrease in ddC IC50 value. This favorable interaction was not seen with any of the mismatch oligonucleotides, suggesting the involvement of a sequence-specific mechanism of action. Similar results were seen with the thymidine analogs AZT and d4T in combination with GEM 91. These data suggest a potential role for GEM 91 and future sequence-specific antisense drugs in combination with nucleoside analogs for the treatment of HIV infection. It is essential that potential interactions between new and existing classes of anti-HIV drugs are studied extensively as antiretroviral drug combinations become increasingly more complex.

Adsorption↗
PubMed1998

Impact of mixed-backbone oligonucleotides on target binding affinity and target cleaving specificity and selectivity by Escherichia coli RNase H.

All phosphorothioate mixed-backbone oligonucleotides (MBOs) composed of deoxyribonucleotide and 2'-O-methylribonucleotide segments were studied for their target binding affinity, specificity, and RNase H activation properties. The 2'-O-methylribonucleotide segment, which does not activate RNase H, serves as a high affinity target-binding domain and the deoxyribonucleotide (DNA) segment, which binds to the target with a lower affinity than the former domain, serves as an RNase H-activation or target-cleaving domain. In order to understand the influence of the size and position of the DNA segment of MBOs on RNase H-mediated cleavage of the RNA target, we designed and synthesized a series of 18-mer MBOs with the DNA segment varying from a stretch of two to eight deoxyribonucleotides in the middle, at the 5'-end, or at the 3'-end, of the MBOs. UV absorbance melting experiments of the duplexes of the MBOs with the complementary and singly mismatched RNA targets suggest that the target binding affinity of the MBOs increases as the number of 2'-O-methylribonucleotides increases, and that the binding specificity is influenced by the size and position of the DNA segment. Analysis of RNase H assay results indicates that the minimum substrate cleavage site and cleavage efficiency of RNase H are influenced by the position of the DNA segment in the MBO sequence. RNA cleavage efficiency decreases as the position of the DNA segment of the MBO.RNA heteroduplex is changed from the 3'-end to the middle and to the 5'-end of the target strand. Studies with singly mismatched targets indicate that the RNase H-dependent point mutation selectivity of the MBOs is affected by both the position and size of the DNA segment in the MBO sequence.

Binding Sites↗