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Biomedical subjects

S Shen

Publications and source records attributed to S Shen.

At least 127 records · Page 7Linked to original sources
PubMed1998

[Frequency dependence of somatostatin and calcitonin gene related peptide release induced by electroacupuncture in rat spinal cord].

Radioimmunoassay (RIA) was used to determine the changes of the immunoreactivity (ir) of somatostatin (SOM) and calcitonin gene-related peptide (CGRP) in the spinal perfusate of rat induced by electroacupuncture (EA) of different frequencies. The frequency of EA was chosen to be 2, 15 and 100 Hz and the spinal perfusate was collected in three periods of 30 min before, during and after EA. The results indicate: (1) low frequency EA (2 Hz) increased the spinal SOM-ir level by 39% (P < 0.05) but decreased that of CGRP-ir by 47% (P < 0.05); (2) conversely, 15 Hz EA decreased spinal fluid SOM-ir level by 37% (P < 0.05) but increased that of CGRP-ir by 92% (P < 0.05); (3) 100 Hz EA behaved like 15 Hz in inhibiting SOM-ir level (P < 0.01), but without effect on CGRP-ir. The above results show that specific frequency is required for peripheral electrical stimulation to activate or suppress the release of spinal neuropeptides SOM and CGRP, a fact that may have clinical implications.

Animals↗
PubMed1998

[Clinical and experimental research of Epimedium brevicornum in relieving neuroendocrino-immunological effect inhibited by exogenous glucocorticoid].

OBJECTIVE: To study protective effect of Epimedium brevicornum (EB) on hypothalamus-pituitary-adrenal-thymus (HPAT) axis inhibited by exogenous glucocorticoid. METHODS: In clinical research, variation of cortisol, adrenocorticotrophin (ACTH), lymphocyte proliferative reaction were observed before and after medication in 65 patients took prednisone, and were randomly divided into Fufang prednisone group (mixture of prednisone and EB) and prednisone group. An experimental model of HPAT axis inhibited by corticosterone (CORT) was established to observe the effect of EB on relevant indices of HPAT axis. RESULTS: The level of ACTH and CORT in plasma decreased and lymphocyte proliferative reaction reduced in patients (P < 0.05). In experimental study, monoaminic transmitters activated in hypothalamus; weight of pituitary, adrenal and thymus decreased; number of CRH positive neurons in hypothalamic paraventricular nucleus, CRH positive neurofibrilin median eminence and anterior pituitary ACTH positive secretory cells decreased; adrenal fasciculate zone and thymus cortex atrophies; NK cell cytotoxicity and the level of IL-2 and gamma-IFN which were produced by lymphocytes reduced in CORT-rats (P < 0.05). There were significant difference between Fufang prednisone group (clinical research) or EB group (experimental research) and CORT control groups, P < 0.05. CONCLUSION: EB could relieve neuroendocrino-immunological effect inhibited by exogenous glucocorticoid.

Adult↗
PubMed1998

[Study on the NIR-Raman spectra and NIR-SERS spectra of amsacrine].

The near infrared surface-enhanced Raman spectra (NIR-SERS) of amsacrine,an anticancer agent, on silver collids were recored with high quality. The NIR-SERS enhancement factor is up to 10(4) magnitude. In comparison with the near infrared Raman (NIR-Raman) spectra of solid amsacrine, more information of vibrational structures of amsacrine molecules at low concentration and almost in its practical application envi ronment, can be given by the NIR-SERS. The enhancement mechanism is associated with the adsorption of acridyl ring and sulfonyl on silver surface.

Amsacrine↗
PubMed1998

Yttrium-90-DOTA-peptide-chimeric L6 radioimmunoconjugate: efficacy and toxicity in mice bearing p53 mutant human breast cancer xenografts.

UNLABELLED: The novel radioimmunoconjugate, 90Y-DOTA-peptide-chimeric L6 (ChL6), was designed to reduce radiation to critical normal tissues with an exceptionally stable 90Y chelate moiety and a biodegradable linker. Human breast cancer tumors (HBT 3477) in mice were treated with 90Y-DOTA-peptide-ChL6 to examine the effects of increasing dose on the therapeutic efficacy and toxicity of this new agent. METHODS: Groups of athymic mice bearing HBT 3477 xenografts received 4.1- to 14.1-MBq doses of 90Y-DOTA-peptide-ChL6 intravenously. The lethal dose (LD)(50/30), general well-being (weight loss), hematotoxicity and therapeutic efficacy were studied. RESULTS: The LD(50/30) was 12.8 MBq, which corresponded to doses of 17.9 and 50.9 Gy to the total body and tumor (200 mm3), respectively. Deaths were associated with hematotoxicity; no deaths occurred at doses of 9.6 MBq or less. At sublethal doses, the rate of tumor response (cures +/- complete responses + partial responses) increased with increasing dose: 4.1 MBq, 27%; 5.9 MBq, 41%; 8.5 MBq, 69%; and 9.6 MBq, 79% (maximum tolerated dose, MTD). In mice receiving doses of 4.1-9.6 MBq, 6 of 74 (8%) of tumors were cured. Increasing the 90Y dose led to smaller tumor size at nadir and longer tumor regrowth delay but no increase in cure. Although the HBT 3477 p53 gene was found to be mutant resulting in p53 protein not binding DNA breaks, tumors at MTD demonstrated evidence of apoptosis. CONCLUSION: In the human breast cancer athymic mouse model, 90Y-DOTA-peptide-ChL6 had a high therapeutic index and LD(50/30) leading to a 79% response rate at the MTD. The evidence of apoptosis as a mechanism for this tumor response in p53 mutant breast cancer warrants further studies because these observations are relevant to the treatment of lethal breast cancer.

Adenocarcinoma↗
PubMed1998

A preliminary cell kinetics model of thrombocytopenia after radioimmunotherapy.

UNLABELLED: Thrombocytopenia is often the dose-limiting toxicity for radionuclide therapy. Prediction of platelet counts after therapy is important for treatment planning. Simple prediction methods based on linear correlation between radiation dose and blood count nadir have been insufficient because they have not considered time, because of the complicated hierarchical structure of the hematopoietic system in which platelets are not directly injured by low dose rate radiation and because of changing radiation dose rates to marrow with time. This study addresses these problems using a cell kinetics model. METHODS: The model consists of compartments for progenitor cells, megakaryocytes, platelets and stromal cells. A linear quadratic formula was used for progenitor cell survival. Stromal cells were described by a model based on a maximum likelihood estimate for cellular damage, repair and proliferation. Reported values for murine cellular turnover rates and radiosensitivity of progenitor cells were used in the model calculations. Experimental mice received 4 Gy of external beam radiation for tumor implantation and 12.4-23.3 MBq 67Cu-2-iminothiolane-BAT-Lym-1 (BAT = 6-[p-(bromoacetamido) benzyl]-1,4,8,11-tetra-azacyclotetradecane-N,N',N'',N'''-tetraacet ic acid) 19-30 days later. Blood counts were measured three times each week. RESULTS: The model predicted the severity of thrombocytopenia, and the time of the nadir corresponded to measured values in mice. For a dose of 14.2 MBq 67Cu-2-iminothiolane-BAT-Lym-1 that induced a platelet nadir of 20% of baseline (Grade II), the model predicted that at least 20 days were needed before a second 14.2-MBq injection if a subsequent nadir of <10% of baseline (Grade IV) was to be avoided. CONCLUSION: The nadir and duration of thrombocytopenia predicted by the model were similar to those observed in the mice. Predicted information could be useful for planning the dose and timing of fractionated radionuclide therapy. This model provides a stepping stone for future development of a predictive model for patients.

Animals↗
PubMed1998

Characterization of soybean lipoxygenase immobilized in cross-linked phyllosilicates.

Lipoxygenase (LOX) is an enzyme that regioselectively introduces the hydroperoxide functionality into polyunsaturated fatty acids, such as linoleic acid (LA). Hydroperoxide derivatives of polyunsaturated fatty acids are of interest because they can serve as important intermediates in the synthesis of chemical and pharmaceutical compounds. In this study, LOX was immobilized in dispersed phyllosilicate layers that were cross-linked with silicate polymers formed by the hydrolysis of tetramethyl orthosilicates. The effects of substrate concentration, reaction temperature and solvent participation were studied on the oxidation of LA by LOX. The temperature optimum for the oxidation of LA by immobilized LOX was 25 degrees C and values of Km and Vmax for this reaction were 1.7 mM and 0.023 micromol/min respectively. Enzymic activity was stimulated by the addition of 10% (v/v) iso-octane to the reaction mixture. The immobilized LOX preparation showed a degree of substrate preference that demonstrated that 1,3-dilinolein was a better substrate than LA in the oxidation reaction, followed in order by 1-monolinolein, methyl oleate and trilinolein. In general, LOX immobilized in cross-linked phyllosilicates retained the physical and chemical characteristics of free LOX.

Diglycerides↗
PubMed1998

Comparison of 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-peptide-ChL6, a novel immunoconjugate with catabolizable linker, to 2-iminothiolane-2-[p-(bromoacetamido)benzyl]-DOTA-ChL6 in breast cancer xenografts.

Radioimmunotherapy using 131I-ChL6 antibody has shown promise in patients with breast cancer. To enhance this potential, a novel ChL6 immunoconjugate that is catabolizable and tightly binds 90Y and (111)In was developed. The immunoconjugate, 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-peptide-ChL6, consists of the macrocyclic chelator DOTA linked to ChL6 by a peptide that is preferentially catabolized in the liver. The pharmacokinetic and dosimetric properties of the radioimmunoconjugates (RICs) (111)In- and 90Y-DOTA-peptide-ChL6 and (111)In- and 90Y-2-iminothiolane (2-IT)-2-[p-(bromoacetamido)benzyl]-DOTA-ChL6 were compared in athymic mice bearing HBT3477 human breast cancer xenografts. Each of the RICs was stable in vivo and concentrated well in the xenografts. Liver concentration, cumulative radioactivity (activity over time), and radiation dose of the DOTA-peptide-ChL6 RICs were one-third to one-half of those of the corresponding 2-IT-2-[p(bromoacetamido)benzyl]-DOTA-ChL6 RICs. Indium-111 RICs were imperfect tracers for corresponding 90Y RICs, although their pharmacokinetics and radiation dosimetries were similar. The results of this study were consistent with previously published in vitro data, which indicated that the peptide linker of DOTA-peptide-ChL6 was catabolized by cathepsin B. The cumulative activities and radiation doses to the liver of DOTA-peptide-ChL6 RICs were one-half of those of corresponding RICs with the 2-IT linker. Preliminary data from pilot studies in patients with breast cancer are in accord with these observations. These novel DOTA-peptide RICs seem to have excellent clinical potential for radioimmunotherapy associated with marrow transplantation, for which liver radiation is likely to be dose limiting for 90Y.

Animals↗
PubMed1997

Impact of splenomegaly on therapeutic response and I-131-LYM-1 dosimetry in patients with B-lymphocytic malignancies.

BACKGROUND: Patients with B-cell non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) frequently have splenomegaly, which has been reported to cause poor tumor targeting of radiolabeled antibodies. Consequently, patients with splenomegaly have been ineligible for some trials of radioimmunotherapy because of the assumption that they would not benefit. METHODS: Forty-nine patients with NHL and five with CLL received an initial dose of 131I-Lym-1 ranging from 740-8140 MBq. Six patients had prior splenectomy. The remaining 48 patients had spleen volumes ranging from 140-2830 ml determined using x-ray computed tomography. Medical Internal Radiation Dose Committee formalism was used to determine dosimetry, and spleen volume was used to adjust the S value for the spleen of each patient. RESULTS: Spleen radiation dose decreased as spleen volume increased, although there was a positive correlation (r = 0.75) between spleen volume and spleen cumulated activity. There was no clear relationship between spleen volume and tumor radiation dose, although tumor radiation doses were low in five patients whose spleen volumes were greater than or equal to 970 ml. There was no apparent relationship between spleen volume and therapeutic response to 131I-Lym-1. Two of five patients whose spleen volumes were greater than or equal to 970 ml responded despite low tumor radiation doses, whereas two of six patients with prior splenectomy did not respond. CONCLUSIONS: The results of this study provide no clear evidence that patients with splenomegaly should be excluded from radioimmunotherapy trials because of the assumption that they will not benefit. Splenomegaly was associated with decreased radiation dose to the spleen, and to tumors only for extraordinarily large spleens.

Humans↗
PubMed1997

Imaging for improved prediction of myelotoxicity after radioimmunotherapy.

BACKGROUND: The severity of myelotoxicity after radioimmunotherapy has been predicted from body and blood radiation doses to marrow. However, marrow radiation can be increased substantially if the marrow or skeleton contains the malignancy targeted by the radiolabeled monoclonal antibodies. A study of 29 patients treated with iodine-131 (131I)-Lym-1 showed that radiation doses to marrow from body and blood had little correlation with myelotoxicity. The purpose of the present study was to assess the significance of marrow targeting and other factors for prediction of myelotoxicity. METHODS: Injected radioactivity and nontargeted radiation doses to marrow were compared with peripheral blood cell counts after the first therapy dose of 131I-Lym-1 in 16 heavily pretreated patients with non-Hodgkin's lymphoma (NHL). Bone marrow biopsy, targeted marrow radiation doses, marrow image uptake scores, age, Karnofsky performance score (KPS), previous chemotherapy, and tumor burden were also compared with blood counts. RESULTS: Myelotoxicity was not predicted well by injected radioactivity, total body radiation, or body and blood radiation doses contributed to marrow (P > 0.1). Biopsy-proven bone marrow lymphoma also failed to predict myelotoxicity (P > 0.1). Thrombocytopenia and leukopenia were predicted well by targeted radiation dose to marrow (P < 0.05) obtained by 131I imaging. Similarly, marrow image scores predicted decreases in platelets and white blood cells (WBCs; P < 0.05). Prediction of myelotoxicity using marrow radiation dose methods was slightly improved when serum lactic dehydrogenase (LDH), age, KPS, and prior chemotherapy were included in the analysis (P < or = 0.01). CONCLUSIONS: Prediction of myelotoxicity was improved in this group of patients by assessment of the targeting component of marrow radiation and was better predicted and obtained more easily by semiquantitative marrow image scores. Further improvement in prediction was slight when other factors were considered.

Bone Marrow↗
PubMed1997

Enhancement of 67Cu-2IT-BAT-LYM-1 therapy in mice with human Burkitt's lymphoma (Raji) using interleukin-2.

BACKGROUND: Lymphomas have been shown to be responsive to 131I immunoconjugates in studies conducted in mice and patients. We have observed that copper 67 (67Cu)-labeled Lym-1 remains in lymphomatous tissue longer than 131I-Lym-1 and, consequently, results in higher absorbed radiation doses to tumors. In addition, recombinant interleukin-2 (rIL-2) has been reported to increase tumor uptake of radiolabeled antibody. Therefore, we examined the efficacy of 67Cu-labeled Lym-1 and the ability of rIL-2 to enhance this efficacy in athymic mice implanted with Raji xenografts. METHODS: 6[p-(bromoacetamido) benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N', N'',N'''-tetraacetic acid (BAT) was conjugated to Lym-1 via 2-iminothiolane (2IT) to prepare 2IT-BAT-Lym-1, which was labeled with 67Cu. Mice with Raji xenografts were treated with 335-500 microCi (12.4-18.0 MBq) of 67Cu-2IT-BAT-Lym-1 with or without 48,000-144,000 IU of rIL-2 once or were treated b.i.d. for 5 days beginning simultaneously with 67Cu-2IT-BAT-Lym-1. Mouse weight, blood counts, and mortality were monitored to assess toxicity, and tumor size was measured to assess efficacy. In addition, groups of mice were sacrificed to assess the biodistribution of 67Cu-2IT-BAT-Lym-1 with and without rIL-2. RESULTS: In mice treated with 335 microCi of 67Cu-2IT-BAT-Lym-1 alone, 28% of tumors were cured. When 48,000 IU of rIL-2 were added, 50% were cured. The overall response-rate was 50% for both regimens. In mice treated with 400 microCi of 67Cu-2IT-BAT-Lym-1 alone, 42% responded, all of which were cured. When 48,000 IU of rIL-2 were added, 77% of tumors responded, and 38% were cured. Larger or multiple doses of rIL-2 did not result in additional therapeutic enhancement. The tumor uptake and radiation dose after 67Cu-2IT-BAT-Lym-1 were about two times greater when a single dose of rIL-2 was added: This may be the basis for enhanced therapeutic efficacy. Mortality was not altered for 335 microCi or 400 microCi doses of 67Cu-2IT-BAT-Lym-1 by rIL-2 nor were other toxicity parameters. Mortality was increased at 500 microCi by the addition of rIL-2. CONCLUSIONS: 67Cu-2IT-BAT-Lym-1 provided a therapeutic and frequently curative dose of radiation to tumored mice at tolerated doses. The therapeutic effectiveness of 67Cu-2IT-BAT-Lym-1 may have been enhanced by rIL-2.

Animals↗
PubMed1997

Atomic structure of a thermostable subdomain of HIV-1 gp41.

Infection by HIV-1 involves the fusion of viral and cellular membranes with subsequent transfer of viral genetic material into the cell. The HIV-1 envelope glycoprotein that mediates fusion consists of the surface subunit gp120 and the transmembrane subunit gp41. gp120 directs virion attachment to the cell-surface receptors, and gp41 then promotes viral-cell membrane fusion. A soluble, alpha-helical, trimeric complex within gp41 composed of N-terminal and C-terminal extraviral segments has been proposed to represent the core of the fusion-active conformation of the HIV-1 envelope. A thermostable subdomain denoted N34(L6)C28 can be formed by the N-34 and C-28 peptides connected by a flexible linker in place of the disulfide-bonded loop region. Three-dimensional structure of N34(L6)C28 reveals that three molecules fold into a six-stranded helical bundle. Three N-terminal helices within the bundle form a central, parallel, trimeric coiled coil, whereas three C-terminal helices pack in the reverse direction into three hydrophobic grooves on the surface of the N-terminal trimer. This thermostable subdomain displays the salient features of the core structure of the isolated gp41 subunit and thus provides a possible target for therapeutics designed selectively to block HIV-1 entry.

Amino Acid Sequence↗
PubMed1997

Wip1, a novel human protein phosphatase that is induced in response to ionizing radiation in a p53-dependent manner.

Exposure of mammalian cells to ionizing radiation (IR) induces a complex array of cellular responses including cell cycle arrest and/or apoptosis. IR-induced G1 arrest has been shown to depend on the presence of the tumor suppressor p53, which acts as a transcriptional activator of several genes. p53 also plays a role in the induction of apoptosis in response to DNA damage, and this pathway can be activated by both transcription-dependent and -independent mechanisms. Here we report the identification of a novel transcript whose expression is induced in response to IR in a p53-dependent manner, and that shows homology to the type 2C protein phosphatases. We have named this novel gene, wip1. In vitro, recombinant Wip1 displayed characteristics of a type 2C phosphatase, including Mg2+ dependence and relative insensitivity to okadaic acid. Studies performed in several cell lines revealed that wip1 accumulation following IR correlates with the presence of wild-type p53. The accumulation of wip1 mRNA following IR was rapid and transient, and the protein was localized to the nucleus. Similar to waf1, ectopic expression of wip1 in human cells suppressed colony formation. These results suggest that Wip1 might contribute to growth inhibitory pathways activated in response to DNA damage in a p53-dependent manner.

Amino Acid Sequence↗
PubMed1997

Three-dimensional quantitative structure-activity relationship of melatonin receptor ligands: a comparative molecular field analysis study.

A three-dimensional quantitative structure-activity relationship using the comparative molecular field analysis (CoMFA) paradigm applied to 57 melatonin receptor ligands belonging to diverse structural families was performed. The compounds studied which have been synthesized previously and reported to be active at chicken brain melatonin receptors were divided into a training set of 48 molecules and a test set of 9 molecules. As most of these compounds have a highly flexible ethylamido side chain, the alignments were based on the most sterically constrained molecule which contains a tricyclic phenalene structure. This tricyclic compound can adopt an axial and an equatorial conformation. Two different molecular superpositions representing possible positioning within the receptor site have been suggested previously. CoMFA was tentatively used to discriminate between alternate hypothetical biologically active conformation and between possible positionings. The best 3D quantitative structure-activity relationship model found yields significant cross-validated, conventional, and predictive r2 values equal to 0.798, 0.967, and 0.76, respectively, along with an average absolute error of prediction of 0.25 log units. These results suggest that the active conformation of the most flexible molecules including melatonin is in a folded form if we consider the spatial position of the ethylamido side chain relative to the aromatic ring.

Animals↗
PubMed1997

The development of an antigen capture polymerase chain reaction assay to detect and type human enteroviruses.

Antigen capture polymerase chain reaction (AC-PCR) is a technique that combines the advantages of PCR with those of antibody mediated methods, to detect and type human enteroviruses. Virus particles are captured by specific antisera and RNA is released by heat denaturation to generate the substrate for reverse transcription and PCR. Use of this technique results in purification of human enteroviruses from tissue culture and 10% faecal samples in a serotype-specific manner allowing both rapid detection and a direct correlation between serological and genetic typing methods. The sensitivity of AC-PCR was comparable with that of PCR protocols employing a conventional organic solvent based extraction procedure.

Animals↗
PubMed1997

Reproducibility of operator processing for radiation dosimetry.

Reproducibility of operator processing for radiation dose and biological half-life was assessed for radioimmunotherapy. Mean coefficient of variation for intra-operator consecutive processing and for inter-operator processing was less than 15% for all tissues. The mean coefficient of variation for intraoperator processing over 2 wk or inter-operator processing comparing an experienced and less experienced operator was generally greater, and particularly so for tumors. Satisfactory reproducibility was achievable using visual determination of regions of interests after 80 h of training.

Breast Neoplasms↗
PubMed1997

Practical determination of organ S values for individual patients for therapy.

Radiation dose calculations using S values of a reference man can introduce substantial errors for individuals patients. We found that all non target sources can be included in the remainder of the body estimate for therapeutic radionuclides. A practical method to derive organ S values based on MIRD data and the mass of the organ and total body of individual patients is proposed.

Humans↗
PubMed1997

Cytochrome P4502C11 is a target of diclofenac covalent binding in rats.

Diclofenac antiserum was previously developed and used to detect protein adducts of metabolites of dichlofenac in livers of mice and rats. In this study, the antibody has been used to facilitate the purification of a major 51 kDa microsomal adduct of diclofenac from the liver microsomes of male rats that were treated with diclofenac. The adduct was identified as male-specific cytochrome P4502C11 based on its N-terminal amino acid sequence, reaction with a cytochrome P4502C11 antibody, and by its absence from liver microsomes of diclofenac-treated female rats. When diclofenac was incubated with liver microsomes of control rats in the presence of NADPH, only the 51 kDa adduct was produced. The formation of the adduct was inhibited by a cytochrome P4502C11 monoclonal antibody, but not by reduced glutathione or N-alpha-acetyl-L-lysine. No adduct was detected when diclofenac was incubated with liver microsomes from female rats. Moreover, adduct formation in vivo appeared to lead to a 72% decrease in the activity of cytochrome P4502C11. The results indicate that cytochrome P4502C11 metabolizes diclofenac into a highly reactive product that covalently binds to this enzyme before it can diffuse away and react with other proteins.

Animals↗