Search PubMed⌕ Search

Biomedical subjects

J Chang

Publications and source records attributed to J Chang.

At least 325 records · Page 18Linked to original sources
PubMed1995

A phase I trial of bryostatin 1 in patients with advanced malignancy using a 24 hour intravenous infusion.

Bryostatin 1 is a macrocyclic lactone derived from the marine invertebrate Bugula neritina. In vitro, bryostatin 1 activates protein kinase C (PKC), induces the differentiation of a number of cancer cell lineages, exhibits anti-tumour activity and augments the response of haemopoietic cells to certain growth factors. In vivo, bryostatin 1 is also immunomodulatory, but the range of tumours which respond to bryostatin 1 in xenograft tumour models is mostly the same as the in vitro tumour types, suggesting a direct mode of action. Nineteen patients with advanced malignancy were entered into a phase I study in which bryostatin 1 was given as a 24 h intravenous infusion, weekly, for 8 weeks. Myalgia was the dose-limiting toxicity and the maximum tolerated dose was 25 micrograms m-2 per week. The myalgia was cumulative and dose related, and chiefly affected the thighs, calves and muscles of extraocular movement. The mechanism of the myalgia is unknown. CTC grade 1 phlebitis affected every patient for at least one cycle and was caused by the diluent, PET, which contains polyethylene glycol, ethanol and Tween 80. Most patients experienced a 1 g dl-1 decrease in haemoglobin within 1 h of commencing the infusion which was associated with a decrease in haematocrit. Radiolabelled red cell studies were performed in one patient to investigate the anaemia. The survival of radiolabelled red cells during the week following treatment was the same as that seen in the week before treatment. However, there was a temporary accumulation of radiolabelled red cells in the liver during the first hour of treatment, suggesting that pooling of erythrocytes in the liver might account for the decrease in haematocrit. Total or activated PKC concentrations were measured in the peripheral blood mononuclear cells (PBMCs) of three patients for the first 4 h of treatment and during the last hour of the infusion. This showed that PKC activity was significantly modulated during the infusion. Bryostatin 1 is immunomodulatory in vitro, and we have confirmed this activity in vivo. An investigation of the first three cycles of treatment in seven patients showed an increased IL-2-induced proliferative response in peripheral blood lymphocytes and enhanced lymphokine-activated killer (LAK) activity. A previously reported rise in serum levels of interleukin 6 (IL-6) and tumour necrosis factor alpha (TNF 1) was not confirmed in our study; of nine patients in this study, including patients at all dose levels, none showed an increase in these cytokines.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1995

Differential correlation between translocation and down-regulation of conventional and new protein kinase C isozymes in C6 glioma cells.

Correlation between translocation and down-regulation of conventional protein kinase C alpha (cPKC alpha) and new PKC delta (nPKC delta) induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) at different time courses (5 min, 30 min, 1 h, 3 h, 6 h, 10 h, 17 h, and 24 h) was studied in C6 glioma cells. From the dose-dependent translocations of these two isoforms by 10-min treatment with TPA (1, 3, 10, 30, 100, 300, and 1,000 nM), we found that cPKC alpha was translocated by 3-1,000 nM and nPKC delta was translocated by 10-1,000 nM TPA. Both isoforms were maximally translocated by 100-1,000 nM TPA, whereas 1 nM did not translocate these two isoforms. When the cells were treated with 1,000 nM TPA for 5 min to 17 h, the translocation of these two isoforms occurred rapidly after 5-min treatment and could be sustained for 1 h, whereas down-regulation occurred after 3-h treatment and almost complete down-regulation was observed after 17-h treatment. However, the extent of down-regulation of nPKC delta was greater than that of cPKC alpha at 3-, 6-, and 10-h treatment. Further studies by using different doses of TPA (100, 10, 3, and 1 nM) and extending the time to 24 h showed that cPKC alpha was more resistant to down-regulation. This conventional isoform was maintained at a translocation state even after long-term treatment with 3-100 nM TPA, and complete down-regulation was only shown after 1,000 nM treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Neoplasms↗
PubMed1995

Potentiation of 2,6-dinitrotoluene genotoxicity in Fischer 344 rats by pretreatment with coal tar creosote.

Pretreatment of male Fischer 344 rats for 5 wk with coal tar creosote, a coal distillation product that is widely used as a wood preservative, potentiated the excretion of urinary mutagens in 2,6-dinitrotoluene (DNT) treated rats. Creosote increased the bioactivation of DNT to significantly greater levels of urinary genotoxic metabolites and/or formed DNA adducts in the liver. A significant increase in the excretion of mutagenic DNT metabolites was observed after the first week of creosote treatment, peaked at wk 3, and then decreased by 33% after 5 wk of treatment. Nevertheless, there was a significant increase (66%) in the formation of DNT-derived DNA adducts in the livers of rats treated with DNT plus creosote at wk 5. Increased cecal beta-glucuronidase activity and reduced small intestinal nitroreductase activity may play roles in the bioactivation of DNT. The excretion of mutagenic DNT metabolites supplies useful information about the bioactivation of DNT; it does not provide a useful index of DNT-derived hepatic DNA adduct formation. Such interactions could be important to predictive risk assessment because the overall cancer risk of such chemical mixtures may exceed the sum of the component risks.

Analysis of Variance↗
PubMed1995

Sequestration of acetylated LDL and cholesterol crystals by human monocyte-derived macrophages.

Monocyte-derived macrophages accumulate and process cholesterol in atherosclerotic lesions. Because of the importance of this process, we examined the interaction of cholesterol crystals and acetylated low density lipoprotein (AcLDL) with human monocyte-macrophages in a combined chemical and morphological study. These two forms of cholesterol induced extensive compartmentalization of the macrophage cytoplasm. Unexpectedly, the compartments maintained a physical connection to the extracellular space as demonstrated with ruthenium red staining. The compartments formed through invagination of the top surface of the macrophage plasma membrane. Some cholesterol crystals and AcLDL were sequestered within these surface-connected compartments for up to five days in the case of the crystals and for one day in the case of AcLDL. Pulse-chase studies of fractionated macrophages indicated that [3H]cholesterol redistributed from the surface-connected compartments into lysosomes (where the cholesterol remained unesterified) and into lipid droplets (where the cholesterol was stored as cholesteryl ester). Intracellular uptake and esterification of cholesterol was blocked by cytochalasin D. However, once cholesterol was sequestered in the surface-connected compartments, subsequent esterification of the cholesterol could not be inhibited by cytochalasin D. Apolipoprotein E was localized within the surface-connected compartments by immunogold labeling suggesting a possible function for this protein in the processing of lipid taken up through the sequestration pathway. Removal of microcrystalline cholesterol from the medium resulted in release of most of the accumulated cholesterol microcrystals from the macrophages, as well as disappearance of the surface-connected compartments. Thus, sequestration is a novel endocytic mechanism in which endocytic compartments remain connected to the extracellular space. This differs from phagocytosis where endocytic vacuoles rapidly pinch off from the plasma membrane. Sequestration provides a means for macrophages to remove substances from the extracellular space and later release them.

Apolipoproteins E↗
PubMed1995

Effects of prolonged (1 year) choline deficiency and subsequent re-feeding of choline on 1,2-sn-diradylglycerol, fatty acids and protein kinase C in rat liver.

Rats fed a choline-deficient diet develop foci of enzyme-altered hepatocytes with subsequent formation of hepatic tumors. They also develop fatty livers, because choline is needed for hepatic secretion of lipoproteins. We have previously reported that 1,2-sn-diradylglycerol accumulates in the livers of rats fed a choline-deficient diet for 1-27 weeks, and that protein kinase C activity in the hepatic plasma membrane is elevated during that time (da Costa et al., J. Biol. Chem., 268, 2100-2105, 1993). In the present study, we examined the changes that occur in rat liver at 52 weeks of choline deficiency and determined whether these changes were reversible when choline was returned to the diet of the deficient animals for 1 or 16 weeks. At 52 weeks, non-tumor liver samples from the experimental animals had increased 1,2-sn-diradylglycerol concentrations in the lipid droplets compared with control animals. Plasma membrane 1,2-sn-diradylglycerol levels in the liver did not differ between the two groups, but an age-related increase in membrane 1,2-sn-diradylglycerol concentrations was observed. Unsaturated free fatty acids, another activator of protein kinase C, accumulated in the deficient livers. Protein kinase C activity associated with the plasma membrane remained significantly elevated at 52 weeks in deficient livers. Hepatic foci expressing gamma-glutamyltranspeptidase were detected only in the deficient rats (0.83% of liver volume) and 15% of these rats had hepatocellular carcinoma at 1 year on the diet. At 53 weeks (1 week after choline was returned to the deficient group), 1,2-sn-diradylglycerol concentrations in the lipid droplets and hepatic free fatty acids had dropped to control levels. By 68 weeks (16 weeks of re-feeding choline), the membrane protein kinase C activity had returned to normal. At this time, 14% of the experimental animals had hepatocellular carcinoma. We suggest that choline deficiency altered the protein kinase C-mediated signal transduction within liver and this contributed to hepatic carcinogenesis in these animals.

Aging↗
PubMed1995

Listeriosis in bone marrow transplant recipients: incidence, clinical features, and treatment.

Cultures of blood and/or cerebrospinal fluid from four of 1,013 bone marrow transplant recipients treated at our center between January 1972 and April 1994 were positive for Listeria monocytogenes. The overall occurrence of listeriosis was 0.39 case per 100 transplantations. Allograft recipients had received prior treatment with parenteral methylprednisolone, thus supporting an association between listeriosis and corticosteroids. Treatment with parenteral ampicillin (200 mg/[kg.d]) and gentamicin is recommended for a minimum of 3 weeks before oral therapy. Two patients with penicillin allergies in this study failed to respond to chloramphenicol-based therapeutic regimens. Recurrent meningitis occurred in two patients, and the therapeutic use of intrathecal gentamicin/vancomycin did not confer a survival advantage (i.e., the patients did not survive).

Adolescent↗
PubMed1995

A matched control study of familial epithelial ovarian cancer: patient characteristics, response to chemotherapy and outcome.

BACKGROUND: Many of the characteristics of patients with familial epithelial ovarian cancer (EOC) are not yet well defined. This report describes some of the characteristics of patients with EOC in particular response rates to chemotherapy and 5-year survival, and compares them with matched controls with sporadic EOC. PATIENTS AND METHODS: There were 28 cases of familial epithelial ovarian cancer (EOC) presenting to the Royal Marsden Hospital from January 1983 to September 1993. The incidence of familial EOC over this time period was 2.2% (28/1268). For each case of familial EOC, 3 controls were selected and matched for age, FIGO stage, volume of residual disease after initial surgery and type of chemotherapy; the matched controls were compared to the familial EOC cases for differences in histological subtype, response to chemotherapy and 5-year survival. There was a statistically significant difference in histological subtype, 83% of patients with familial EOC had serous cystadenocarcinoma compared to 49% in the matched control group (p = 0.0025) providing evidence that familial EOC has a genetic basis. However there were no differences in median age or FIGO stage between patients with familial EOC and the sporadic cases and no difference in overall response to chemotherapy or 5-year survival. CONCLUSIONS: Our results imply that familial and sporadic EOC are biologically very similar and therefore molecular studies on the pathogenesis of and cellular mechanisms involved in EOC may have an important impact on therapeutic strategies for the much commoner sporadic form of the disease. In addition, our data suggest that all patients should be closely questioned with regard to family history not just those who present at a young age.

Adolescent↗
PubMed1995

Carcinosarcoma of the ovary: incidence, prognosis, treatment and survival of patients.

BACKGROUND: Carcinosarcomas (also known as malignant mixed mullerian tumours) are rare malignant neoplasms that histologically contain both epithelial and stromal components. METHODS AND MATERIALS: All cases of carcinosarcoma of the ovary presenting to the Royal Marsden Hospital from January 1975 to August 1993 were retrospectively analysed and the histological sections reviewed. RESULTS: There were 37 cases of carcinosarcoma of the ovary representing 1.12% of the ovarian neoplasms seen at this institution. The median age of presentation was 65 years (range 26-85 years) and 70% of patients had advanced disease (FIGO stage III and IV). Clinical features at presentation were similar to those encountered in patients with epithelial ovarian cancer. The overall median survival was 247 days with 40% 1-year survival and 6% 5-year survival for all stages. Early FIGO stage was the only independent prognostic factor for survival. Histology (homologous/heterologous subtypes; grade, type or percentage of the epithelial component) had no significant impact on survival. Adjuvant radiotherapy may have a role and single agent platinum compounds are active, giving a response rate of 35%. CONCLUSIONS: The management of this tumour is difficult and randomised trials are needed to accrue sufficient patient numbers to demonstrate optimal therapy.

Adult↗
PubMed1995

Chronic ethanol intake and burn injury: evidence for synergistic alteration in gut and immune integrity.

OBJECTIVE: Chronic ethanol (EtOH) intake and injury are both associated with increased susceptibility to infection in the host. This study examined the immune and gastrointestinal alterations induced by chronic EtOH intake and injury, and compared the effects of enteral and intravenous administration of EtOH. DESIGN: Rats received 20% EtOH daily for 14 days by gavage [oral (PO)] or superior vena cava [intravenous (i.v.)] infusion. Mean blood EtOH concentrations at 90 minutes after administration were 95.3 mg/dL (PO) and 94.4 mg/dL (i.v.). An additional group of animals underwent a 30% total body surface area full-thickness burn injury 4 hours after the final dose of EtOH or normal saline on experimental day 14. All animals were killed 4 days after burn injury. MATERIALS AND METHODS: Nonadherent splenic lymphocytes were tested for mitogenic responses to the T-cell mitogens concanavalin A (ConA) and phytohemagglutinin (PHA), and the B-cell mitogens lipopolysaccharide (LPS) and pokeweed. Quantitative bacterial cultures of mesenteric lymph nodes and liver were also performed. Alterations of intestinal mucosa were determined by measurement of ileal mucosal weight, DNA, protein, and diamine oxidase content. Circulating plasma endotoxin concentrations were also measured. MEASUREMENTS AND MAIN RESULTS: Chronic PO-EtOH intake induced a significant impairment in mitogenic response to T-cell mitogens, with a fourfold reduction in ConA and a twofold reduction in PHA response (p < 0.05 by analysis of variance) and increased bacterial translocation (70% vs. 10%). Chronic EtOH administered by the i.v. route did not reduce mitogenic response to any of the mitogens studied. Histologic examination of ileal segments demonstrated that chronic PO-EtOH administration was associated with significant mucosal disruption and exfoliation. Chronic administration of PO-EtOH prior to burn injury induced a significant impairment in spleen mitogenic response to ConA, PHA, and LPS when compared with all other burn injury groups. Chronic administration of EtOH by the i.v. route prior to burn injury did not alter splenic mitogenesis. In addition, chronic PO-EtOH prior to burn injury increased bacterial translocation rates (80% vs. 33%) and prevented the normal intestinal reparative response to burn injury (demonstrated by a significant reduction in ileal mucosal weight, DNA, and diamine oxidase content). CONCLUSIONS: Enteral but not i.v. administration of EtOH induced significant immunologic dysfunction (demonstrated by altered spleen mitogenic response) and gastrointestinal dysfunction (demonstrated by depressed ileal mucosal weight, DNA, and diamine oxidase content, and increased bacterial translocation rates). In addition, the administration of chronic enteral EtOH prior to injury resulted in significant immune suppression and impaired the host's ability for normal intestinal repair. These results suggest that this EtOH-induced reduction in immunocompetence may be gut-mediated and that the administration of alcohol prior to injury may result in a synergistic alteration of gut and immune integrity.

Alcoholism↗
PubMed1995

Burn injury induces a biphasic immunoglobulin M response to bacterial antigen.

We studied 75 BALB/c mice to examine the role of impaired immunoglobulin M (IgM) synthesis in the increased risk of bacterial infection after burn injury by investigating the kinetics of IgM synthesis to peptidoglycan polysaccharide (PGPS), a ubiquitous bacterial antigen. Splenocytes were isolated 1, 5, and 8 days postburn (PBD) and cultured with lipopolysaccharide for 5 days. Culture supernatant was collected and anti-PGPS IgM and total IgM levels were measured by ELISA. Total IgM-secreting cells were measured by ELISPOT assay. Total IgM and anti-PGPS IgM per IgM-secreting cell were calculated. On PBD 1, anti-PGPS IgM synthesis but not total IgM synthesis is increased in burned animals. By PBD 5, total IgM and anti-PGPS IgM synthesis in the burn group start to fall and by PBD 8, both are significantly decreased. The early increase in anti-PGPS IgM synthesis represents a positive response to bacterial challenge. However, the late nonspecific decrease in total IgM and anti-PGPS IgM synthesis suggests a potential mechanism for increased susceptibility to bacterial infection 5 to 10 days after burn injury.

Animals↗
PubMed1995

Expression of phosphatidylserine-dependent antigens on the surface of differentiating BeWo human choriocarcinoma cells.

PROBLEM: Antiphospholipid antibodies (aPLs) are associated with pregnancy loss, pregnancy-induced hypertension, and intrauterine growth retardation. We have previously reported that phosphatidylserine (PS)-dependent antigens are expressed in formalin-fixed cells concurrent with differentiation in a choriocarcinoma model (BeWo) of cytotrophoblast. That study, however, could not differentiate between cytoplasmic or surface antigen expression. METHOD: Three monoclonal aPLs that differentiate between PS- and cardiolipin (CL)-dependent antigens were reacted with BeWo, with or without forskolin activation, before fixation, and antibody binding was evaluated by immunoperoxidase techniques. RESULTS: Activation with forskolin induced a PS-dependent antigenic determinant on the surface on BeWo cells. CL-reactive monoclonal antibodies did not react with the cell surface, whether forskolin treated or not. CONCLUSION: These observations demonstrate that a PS-dependent antigen is expressed on the surface of a model of differentiating cytotrophoblastic cells and should be accessible in vivo to circulating aPLs.

Antibodies, Antiphospholipid↗
PubMed1995

Human foamy virus Bel1 transactivator contains a bipartite nuclear localization determinant which is sensitive to protein context and triple multimerization domains.

The Bel1 protein of human foamy virus is a 300-amino-acid nuclear regulatory protein which transactivates the gene expression directed by the homologous long terminal repeat and the human immunodeficiency virus type 1 long terminal repeat. While previous reports suggested that the single basic domain of Bel1 from residues 211 to 222 and/or 209 to 226 is necessary and sufficient for efficient nuclear localization (L. K. Venkatesh, C. Yang, P. A. Theodorakis, and G. Chinnandurai, J. Virol. 67:161-169, 1993; F. He, J. D. Sun, E. D. Garrett, and B. R. Cullen, J. Virol. 67:1896-1904, 1993), our recent data showed that another basic domain, from amino acid residues 199 to 200, is also required for nuclear localization of Bel1 (C. W. Lee, C. Jun, K. J. Lee, and Y. C. Sung, J. Virol. 68:2708-2719, 1994). To clarify this discrepancy, we constructed various bel1-lacZ chimeric constructs and several linker insertion mutants and determined their subcellular localization. When the region of Bel1 containing basic domains was placed at an internal site of the lacZ gene, the nuclear localization signal (NLS) of Bel1 consisted of two discontinuous basic regions separated by an intervening sequence. Moreover, insertion of specific amino acids between two basic regions disrupted the activity of the Bel1 NLS. On the other hand, Bel1 residues 199 and 200 were not required to direct the Bel1-beta-galactosidase chimeric protein to the nucleus when the Bel1 NLS was appended to the amino terminus of beta-galactosidase. These results indicate that the function of the Bel1 NLS is sensitive to the protein context within which the sequence is present. In addition, we demonstrated that the Bel1 protein forms a multimeric complex in the nuclei of mammalian cells by using a sensitive in vivo protein-protein interaction assay. Mutational analyses revealed that the regions which mediate multimer formation map to three domains of Bel1, i.e., residues 1 to 31, 42 to 82, and 82 to 111. Furthermore, our results show that the region of Bel1 from residues 202 to 226 prevents Bel1 from forming a multimeric complex.

Amino Acid Sequence↗
PubMed1995

Clostridium difficile infection in hamsters fed an atherogenic diet.

Diarrhea and unexpected death were encountered in a group of young Syrian hamsters (Mesocricetus auratus) used for hyperlipoproteinemia and atherosclerosis research. The animals were fed an atherogenic diet containing 18% saturated fat and 0.366% cholesterol. Mortality began 45 days after hamsters were placed on this atherogenic diet. The atherogenic studies were aborted at 74 days because of high mortality. Toxigenic Clostridium difficile was isolated from animals found dead or euthanatized because of illness. Signs observed were unexpected death and acute liquid diarrhea. Characteristic pathologic changes were necrosis and hemorrhage of the intestinal mucosa with acute inflammation. Hepatic lipidosis was a consistent finding presumed to be associated with the consumption of the atherogenic diet. The study was repeated by placing 23 hamsters on the atherogenic diet and 10 hamsters on the control diet. In animals fed the atherogenic diet, the average time to mortality differed between studies, but clinical signs, gross and histologic lesions, culture findings, and toxin results in both atherogenic diet groups were similar. C. difficile was not isolated from the feeds. No antibiotics were found in the atherogenic diet. The results from these studies suggest that hamsters fed an atherogenic diet have increased susceptibility to disease caused by C. difficile as compared with hamsters fed a normal fat and cholesterol diet.

Animals↗
PubMed1995

Sarcoidosis with cardiac involvement.

Patients with significant cardiac sarcoidosis are at increased risk of sudden death from ventricular dysrhythmias or conduction disturbances. We report a patient in whom there was radiographic and histologic evidence of systemic sarcoidosis; though histologic confirmation of involvement of heart by sarcoidosis is lacking, the clinical manifestations, radionuclide image findings, rhythm disturbances, and the response to steroid therapy are strong evidence in favor of myocardial involvement by the granulomatous process.

Cardiomyopathies↗
PubMed1995

Establishment and characterization of two cell lines derived from human transitional cell carcinoma.

Two continuous cell lines derived from the neoplastic urothelium had been maintained in culture for more than two years. The first cell line derived from the urothelium of a fusion papillocarcinoma on the left lateral wall of the bladder was designated as TBC-1 and grown in vitro for more than 150 generations. The second cell line derived from the urothelium of a papillocarcinoma in the left renal pelvis was designated as TPC-1 and grown in vitro for more than 100 generations. Characterization studies made on both cell lines showed that the cells had a rapid doubling time, exhibited multilayering and produced tumors in sc of BALB/c. Tumor nodules that produced sc of BALB/c kept similar cellular and pathological features to those of the primary biopsy specimens under light and electron microscopes. TPC-1 cell line exhibited a three-dimensional structure of transitional epithelium on the nylon-mesh disk which was coated with a layer of rat tail collagen. Both TBC-1 and TPC-1 cell lines formed colonies in soft agar. Their forming rates were 35% and 28%, respectively. The chromosome number of TBC-1 cells ranged from 17 to 84, with a modal number of 54; whereas that of TPC-1 cells ranged from 28 to 139, with a modal number of 49. The TBC-1 cells showed mutant p53 and ras p21 protein expression and expressed weakly ABH blood group isoantigens. Analysis of lactic dehydrogenase (LDH) isozymes showed the highest levels of LDH isozyme 4 sonicated cell lysates of TBC-1 and TPC-1 respectively.

Adult↗
PubMed1995

[Impact of placental hormone withdrawal on postpartum depression].

Prenatal and postpartum measurements of serum beta-hCG, estradiol (E2) and progesterone (P) concentration were done by radioimmunoassay in 20 cases of postpartum depression (PD) and 20 cases without postpartum depression (NPD). The results showed significantly higher serum levels of P and beta-hCG (at 36-37 gestational week) in PD, but no difference in the serum P and beta-hCG concentration between the PD and NPD after childbirth. The falling of the two hormones was faster in PD than in NPD. In neither prenatal nor postpartum test was any difference seen in serum E2 concentration between PD and NPD. These results suggest that supposely, the endogenous risk factor, the rapid withdrawal of the placental hormones (P and beta-hCG) after delivery, leads to PD.

Chorionic Gonadotropin↗