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Biomedical subjects

Y G Meng

Publications and source records attributed to Y G Meng.

30 records · Page 2Linked to original sources
PubMed1997

Is inadequate thrombopoietin production a major cause of thrombocytopenia in cirrhosis of the liver?

BACKGROUND/AIMS: Thrombocytopenia secondary to cirrhosis of the liver and portal hypertension is a well-known complication of advanced stage liver disease, but theories about the underlying pathogenetic mechanisms, mostly centering on splenic sequestration and destruction of platelets, have failed to solve the problem so far. METHODS: Peripheral platelet count and thrombopoietin levels in human plasma were measured in 28 patients with cirrhosis of the liver. Seven of those patients underwent orthotopic liver transplantation and five patients portal decompression by transjugular intrahepatic portosystemic shunt. Thrombopoietin plasma levels were followed for 14 days after the interventions. RESULTS: No measurable thrombopoietin was detectable in the plasma of 28 thrombocytopenic patients with cirrhosis of the liver, in contrast to thrombocytopenic patients without liver disease. Seven of these patients with cirrhosis underwent orthotopic liver transplantation, resulting in a rise of thrombopoietin levels within 2 days after transplantation. The rise in platelet number followed with a mean lag of 6 days, and shortly thereafter, thrombopoietin levels returned to levels below the limit of detection. Five patients with thrombocytopenia, who underwent only decompression of portal hypertension, showed no rise in either thrombopoietin levels or platelet count. CONCLUSIONS: Thrombocytopenia associated with liver disease may at least in part be attributable to inadequate thrombopoietin production in the failing liver.

Humans↗
PubMed1996

Thyroid-stimulating hormone promotes the secretion of vascular endothelial growth factor in thyroid cancer cell lines.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a vascular endothelial cell-specific mitogen secreted by some cancer cells and is a major regulator of angiogenesis. Because thyroid-stimulating hormone (TSH) promotes growth and progression of thyroid cancers, we postulated that TSH may increase the production and secretion of VEGF by thyroid cancer cells. METHODS: We examined primary cultures of normal human thyroid (NT 1.0), medullary thyroid cancer (MTC 1.1), and cell lines derived from the papillary (TPC-1), follicular (FTC-133), and Hürthle cell (XTC-1) thyroid cancer. We quantified the concentration of VEGF in conditioned medium by means of enzyme-linked immunosorbent assay. RESULTS: Cell lines derived from thyroid secrete VEGF. Basal VEGF secretion was similar in normal and thyroid cancer cells, except XTC-1, which has high basal secretion (p < 0.01). All thyroid cancer cells secrete significantly more VEGF than normal thyroid cells after TSH (10 mIU/ml) stimulation (p < 0.05). TSH stimulated secretion of VEGF in FTC-133 (8.2 ng/dl versus 18.8 ng/dl), TPC-1 (5.5 ng/dl versus 26.9 ng/dl), and MTC 1.1 (5.9 ng/dl versus 13.4 ng/dl) cell lines (p < 0.01), but not in NT 1.0 (8.4 ng/dl versus 9.9 ng/dl) and XTC-1 (25.4 ng/dl versus 31.2 ng/dl) cells. CONCLUSIONS: These results suggest that VEGF secretion is constitutively activated in some thyroid cancers and that VEGF secretion is stimulated by TSH; thus TSH may promote growth in some thyroid cancers by stimulating VEGF secretion and angiogenesis.

Endothelial Growth Factors↗
PubMed1996

Circulating thrombopoietin concentrations in thrombocytopenic patients, including cancer patients following chemotherapy, with or without peripheral blood progenitor cell transplantation.

Thrombopoietin, the ligand for the c-mpl receptor, promotes proliferation and maturation of megakaryocytes. An ELISA using a chimaeric receptor, mpl-IgG, for capture, and rabbit antibody to thrombopoietin for detection was developed for the quantitation of thrombopoietin in human serum or plasma. This ELISA preferentially detects full-length thrombopoietin compared to the bioactive N-terminal half of the molecule which has homology to erythropoietin. Thrombopoietin was not detected (< 0.16 ng/ml) in 88/89 healthy individuals. However, elevated thrombopoietin concentrations of up to 3 ng/ml were detected in 59/63 thrombocytopenic patients, including cancer patients following chemotherapy. In cancer patients receiving chemotherapy with (n = 12) or without (n = 6) peripheral blood progenitor cell transplantation, thrombopoietin concentrations varied inversely with platelet counts throughout the treatment period. In general, patients who received myeloablative chemotherapy on days -7 to -2 and peripheral blood progenitor cell transplantation on day 0 had high thrombopoietin levels (0.6-2.9 ng/ml) around day 5. Low platelet counts (< 20 x 10(9)/l) occurred between days 4 and 9. Patients who received high-dose chemotherapy on day 1 (equivalent to day -7 for transplantation patients) to day 6 without transplantation had high thrombopoietin concentrations (1.4-2.3 ng/ml) around day 13 and low platelet counts occurred between days 7 and 17.

Adult↗
PubMed1996

Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis.

The human endometrium undergoes a complex process of vascular and glandular proliferation, differentiation, and regeneration with each menstrual cycle in preparation for implantation. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific angiogenic protein that appears to play an important role in both physiological and pathological neovascularization. To investigate whether VEGF may regulate human endometrial angiogenesis, we examined VEGF messenger ribonucleic acid (mRNA) and protein throughout the menstrual cycle and studied the regulation of VEGF by reproductive steroids in isolated human endometrial cells. By ribonuclease protection analysis, VEGF mRNA increased relative to early proliferative phase expression by 1.6-,2.0-, and 3.6-fold in midproliferative, late proliferative, and secretory endometrium, respectively. In histological sections, VEGF mRNA and protein were localized focally in glandular epithelial cells and more diffusely in surrounding stroma, with greatest VEGF expression in secretory endometrium. Consistent with these in vivo results, the treatment of isolated human endometrial cells with estradiol (E2), medroxyprogesterone acetate (MPA), or E2 plus MPA significantly increased VEGF mRNA expression over the control value by 3.1-, 2.8-, and 4.7-fold, respectively. The VEGF response to E2 was rapid, with steady state levels of VEGF mRNA reaching 85% maximum 1 h after the addition of steroid. E2 also caused a 46% increase in secreted VEGF protein, and the combination of E2 and MPA caused an 18% increase. VEGF expression in endometriosis, an angiogenesis-dependent, estrogen-sensitive disease was similar to that seen in eutopic endometrium. Peritoneal fluid concentrations of VEGF were significantly higher in women with moderate to severe endometriosis than in women with minimal to mild endometriosis or no disease. VEGF, therefore, may be important in both physiological and pathological angiogenesis of human endometrium, as it is an estrogen-responsive angiogenic factor that varies throughout the menstrual cycle and is elevated in women with endometriosis.

Cells, Cultured↗
PubMed1994

Transfection of murine myeloma cells to produce a chimeric antibody to the interleukin-2 receptor.

Murine myeloma X63Ag8.653 cells were transfected with heavy and light-chain expression vectors for a chimeric antibody (Ab) to the human interleukin-2 receptor. A cell line producing low quantities of the chimeric Ab was obtained and was transfected with either the cytomegalovirus (CMV) immediate-early gene ie1 or Epstein-Barr virus (EBV) BMLF1 DNA, together with the hygromycin B resistance (HyR) encoding gene for selection to improve productivity. Two cell lines with a four to eightfold increase in productivity were obtained. They showed higher levels of heavy- and light-chain mRNA expression. CMV ie1 or EBV BMLF1 DNA was not detected and no integration pattern changes for the heavy- and light-chain DNA were seen. The long-term productivity of one of the cell lines showed hygromycin B (Hy) requirement. Transfection with the HyR DNA alone also resulted in cells with increased productivity. The expression vectors contained the immunoglobulin light-chain enhancer kappa B DNA sequences (kappa B site). Nuclear extracts from parent myeloma cells showed one kappa B-binding protein band on a polyacrylamide gel, but nuclear extracts from transfected cells showed two additional slower-migrating bands. Increased Ab production correlated with an increased ratio of the medium-mobility kappa B-binding protein band to the high-mobility band. The possibility that Hy used for selection activated kappa B-binding proteins and increased Ab expression is discussed.

Animals↗
PubMed1994

[The characteristic of lymphokine-activated killer cells induced from tumor draining lymph-node cell].

A short time lymphocyte culture for lymphokine activated killer (LAK) cells was presented, the lymphocytes being collected from the tumor draining regional lymph nodes in seven patients with gynecologic malignant tumors. The results showed different cytotoxic activities of LAK cells against Lewis pulmonary cancer cells, CAOV, cells and the new separated ovarian cancer cells. And the cytotoxic activity of the LAK cells increased with the rise of the effecter cell-target cell ratio and maintained at a certain level when the rise of the latter's increase reached a certain extent. The cytotoxic activity of the LAK cells against autologous tumor cells (as from ovarian cancer) were shown to be much stronger than against the others. As the culture days lengthened, the cytotoxicities of the LAK cells from interleukin-2/OKT 3 culture became stronger than from interloukin-2 alone. Large quantities of lymphocytes could be collected from tumor-draining lymphe nodes. This is a preliminary investigation on the inducing of LAK cells from lymphocytes of the draining regional lymph nodes of malignant gynecologic tumors. The quantitative increase of LAK cells and the effect of their cytotoxic activities are to be further explored.

Cytotoxicity, Immunologic↗
PubMed1990

J chain deficiency in human IgM monoclonal antibodies produced by Epstein-Barr virus-transformed B lymphocytes.

Six human IgM monoclonal antibodies against Pseudomonas aeruginosa were purified and characterized. On agarose-acrylamide sodium dodecyl sulfate (SDS) gels run under nonreducing conditions, IgM monoclonal antibodies showed variable amounts of a slower migrating form of IgM in addition to the one co-migrating with plasma IgM. Protein blotting with anti-J chain antibody showed that the slower migrating form did not contain J chain. Analysis of one of the monoclonal antibodies by sucrose gradient centrifugation showed that the J chain-deficient form sedimented faster than the complete IgM. It is known that IgM preparations lacking J chain sediment faster by sucrose gradient centrifugation analysis and tend to form hexamers. The slower migrating form of IgM we observed on SDS gels under nonreducing conditions could be hexameric IgM. Further evaluation of this monoclonal antibody demonstrated that both forms of IgM had the same antigen-binding activity. Glycosylation of the light chain was demonstrated in two of the monoclonal antibodies.

Antibodies, Monoclonal↗
PubMedDate not supplied

Binding of cynomolgus monkey IgE to a humanized anti-human IgE antibody and human high affinity IgE receptor.

Antibodies which block IgE binding to its high affinity receptor have the therapeutic potential for treating allergic diseases. A humanized anti-human IgE antibody (E25) was developed for this purpose. Cynomolgus monkeys were used for preclinical studies of E25. We studied the binding of purified human IgE and cynomolgus monkey IgE to E25 and the human high affinity IgE receptor alpha-chain-IgG fusion molecule (Fc epsilon RI-IgG) by surface plasmon resonance. Human IgE and cynomolgus monkey IgE bound to immobilized E25 with similar affinity (apparent Kd = 0.06 and 0.19 nM, respectively). Human IgE and cynomolgus monkey IgE also bound to immobilized Fc epsilon RI-IgG with similar affinity (apparent Kd = 0.28 and 0.30 nM, respectively). These data suggest that the cynomolgus monkey is a valid model for preclinical studies of the E25 antibody and probably for other antibodies which block IgE binding to its receptor. An enzyme-linked immunosorbent assay (ELISA) for measuring cynomolgus monkey IgE was developed to support preclinical studies. This ELISA used FcERI-IgG for capture and peroxidase labelled goat polyclonal antibody to human IgE for detection. Using purified cynomolgus monkey IgE as the standard, the serum IgE levels in six cynomolgus monkeys measured were 4-23 micrograms/ml.

Animals↗
PubMedDate not supplied

Efficacy and concentration-response of murine anti-VEGF monoclonal antibody in tumor-bearing mice and extrapolation to humans.

The development of a neovascular supply (angiogenesis) is a major aspect of tumorigenesis. Recent work has indicated that vascular endothelial growth factor (VEGF) is a major regulator of angiogenesis. In vitro and in vivo studies have demonstrated that an anti-VEGF antibody is capable of suppressing the growth of human tumor cell lines. The following study was conducted in tumor-bearing nude mice to evaluate the concentration-response relationship of murine anti-VEGF monoclonal antibody (muMAb VEGF) so that an efficacious plasma concentration of the recombinant humanized form (rhuMAb VEGF) in cancer patients could be estimated. (This study was included in our Investigational New Drug application to support the clinical dosing regimen and projected human safety factors for the toxicology program.) Additionally, the growth dynamics of the tumors were evaluated as a function of dose to explore whether a mechanismic interpretation of tumor growth inhibition by muMAb VEGF is possible. On day 1, A673 human rhabdomyosarcoma cells (2 x 10(6) cells/mouse) were injected subcutaneously in 188 beige nude mice (16-24 g). Treatment with muMAb VEGF (0.05-5.0 mg/kg; n = 24/group), phosphate-buffered saline (n = 10), or anti-gp120 isotype-matched control antibody (5.0 mg/kg; n = 10) began 24 hr later. Each animal received intraperitoneal injections of test material twice weekly for 4 wk. Immediately prior to each dose, 2 mice from each muMAb VEGF group were selected randomly, and plasma was collected for pharmacokinetic evaluation; at the end of the study, samples were collected from all animals for pharmacokinetic evaluation. Tumor dimensions were recorded weekly, and at the end of the study, tumor weight and dimensions were recorded. Satisfactory tumor suppression in nude mice was achieved at muMAb VEGF doses of > or =2.5 mg/kg, where the average trough muMAb VEGF plasma concentration was 30 microg/ml (concentrations in individual animals >10 microg/ml). Assuming the pharmacokinetics of rhuMAb VEGF in patients will resemble the pharmacokinetics of a similar humanized anticancer monoclonal antibodies, a clinical dosing regimen was designed to maintain the rhuMAb VEGF plasma concentration in this efficacious range. This study shows an approach that can be used to estimate a human dosing regimen from preclinical pharmacokinetic/pharmacodynamic data. Because we have just initiated clinical trials with rhuMAb VEGF we cannot judge clinical outcome in relation to these preclinical predictions; nonetheless, it is hoped that by sharing our approach and thought processes with other investigators we can assist the discovery and development of anticancer therapeutics.

Animals↗
PubMedDate not supplied

Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration.

Access of recombinant proteins to the retina following intravitreal administration is poorly understood. A study was conducted in male Rhesus monkeys (15 to 28 mo of age; 2.8-3.3 kg) in order to compare the intraocular tissue distribution, pharmacokinetics, and safety of 125Iodine (I)-labeled full-length humanized rhuMAb HER2 antibody (148 kD) and of 125I-labeled humanized rhuMAb vascular endothelial growth factor Fab antibody (48.3 kD) following bilateral bolus intravitreal injection on day 0 (5 animals/group). The dose administered to each eye was 25 microg (9-10 microCi) in 50 microl. Animals were euthanatized on day 0 (1 hr postdose) and on days 1, 4, 7, and 14. Safety assessment included direct ophthalmoscopy, intraocular pressure measurements, clinical observations, body weight, and hematology and clinical chemistry panels. Blood and vitreous samples were collected daily (blood only) and at necropsy for pharmacokinetics and analysis for antibodies to the test materials; the ocular tissue distribution of the test material was evaluated by microautoradiography. All animals completed the study. Microautoradiography demonstrated that the full-length antibody did not penetrate the inner limiting membrane of the retina at any of the time points examined. In contrast, the Fab antibody fragment diffused through the neural retina to the retinal pigment epithelial layer at the 1-hr time point and persisted in this location for up to 7 days. Systemic exposure to test material was low but variable: the highest plasma concentration of the full-length antibody was 20.3 ng/ml, whereas plasma concentrations for the Fab antibody remained below the limit of quantitation (i.e., <7.8 ng/ml). An immune response to the test material was not evident in either treatment group. The half-life in vitreous was 5.6 days for the full-length antibody and 3.2 days for the Fab antibody. The shorter intravitreal half-life of the Fab antibody is related to its smaller size and its significant diffusion through the retinal layers. The differences in pharmacokinetics and tissue distribution that are noted between the full-length and Fab antibodies in this study identify potential therapeutic approaches that may be exploited in specific disease conditions.

Animals↗