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Biomedical subjects

J Chang

Publications and source records attributed to J Chang.

At least 253 records · Page 14Linked to original sources
PubMed1997

Expression of transforming growth factor beta type II receptor reduces tumorigenicity in human gastric cancer cells.

Expression of transforming growth factor beta (TGF-beta) receptor type II (RII) is required for the growth-inhibitory effects of TGF-beta on proliferating epithelial cells. TGF-beta RII mutations have been identified in a broad spectrum of human epithelial malignancies, including colon and gastric cancers, and are highly correlated with development of TGF-beta resistance in cell lines derived from these tumors. In this study, the role of TGF-beta RII in regulating the tumorigenic potential of the SNU-638 human gastric cancer cell line was investigated by infecting these cells with retroviral construct (MFG) expressing TGF-beta RII. The SNU-638 cell line displays the DNA replication error phenotype and encodes a truncated, inactive TGF-beta RII protein. Infection of these cells with retroviral constructs expressing wild-type TGF-beta RII led to significant increases in TGF-beta RII mRNA and protein expression. These cells responded to exogenous TGF-beta with reduced proliferation compared to that of control cells infected with retroviral vector expressing chloramphenicol acetyltranferase. Addition of TGF-beta-neutralizing antibodies led to increased proliferation of wild-type TGF-beta RII-expressing SNU-638 cells but had no effect on control cells. The latter finding suggests that TGF-beta acts in an autocrine fashion to inhibit cell proliferation in SNU-638 cells. When transplanted into athymic nude mice, wild-type TGF-beta RII-expressing SNU-638 cells showed decreased and delayed tumorigenicity compared with control cells. This study suggests a strong association between the expression of wild-type TGF-beta RII and the degree of malignancy in human gastric cancer cells.

Animals↗
PubMed1997

Structural and functional complementation of an inactive Bcl-2 mutant by Bax truncation.

Interactions among proteins in the Bcl-2 family regulate the onset of programmed cell death. Previous work has shown that the death-inhibiting family members Bcl-2 and Bcl-xL form heterodimers with the death-promoting homologue Bax and that certain site-directed mutants of Bcl-2 and Bcl-xL lose both biological activity and the ability to bind Bax. To better understand the structural basis of heterodimer formation, we have used a yeast two-hybrid assay to screen for mutants of Bax that regain the ability to bind to these inactive Bcl-2(G145A) and Bcl-xL(G138A) mutants. This screen identified a series of C-terminally truncated Bax molecules that contain complete BH3 (Bcl-2 homology domain 3) domains but that have lost BH1 and BH2 sequences. These results indicate that while the Bcl-2 and Bcl-xL mutants fail to bind full-length Bax, they still retain a binding site for the critical BH3 domain. This suggests that conformational constraints in full-length Bax regulate its ability to bind to other Bcl-2 family members. Furthermore, we demonstrate that the normally inert Bcl-2(G145A) mutant effectively blocks apoptosis induced by a C-terminally truncated Bax molecule, but does not block apoptosis induced by wild-type Bax. This demonstrates that cell protection can be effected by directly binding pro-apoptotic members of the Bcl-2 family.

Amino Acid Sequence↗
PubMed1997

Comparative absorption of bismuth in Sprague-Dawley rats following oral administration of preparations containing bismuth sucrose octasulfate, bismuth subsalicylate, and bismuth subcitrate.

The absorption of bismuth from De-Nol (bismuth subcitrate, DN), Pepto-Bismol (bismuth subsalicylate, PB) and bismuth sucrose octasulfate (BISOS) was examined in male Sprague-Dawley rats after a single oral dose of each compound (60mg bismuth). Bismuth was analysed in blood, urine, kidney, brain, liver, and lung using graphite furnace atomic absorption spectrophotometry. Bismuth Cmax averaged 18.4 +/- 11.6 ng mL(-1) for BISOS, 292 +/- 130 ng mL(-1) for DN, and 21.5 +/- 9.63 ng mL(-1 ) for PB. Cmax was significantly lower for BISOS compared to DN (p<0.05) but not significantly different for BISOS compared to PB (p > 0.05). Bismuth AUC was 1356 +/- 474 ng h(-1) mL (-1) for BISOS, 2129 +/- 452 ng h(-l) mL(-1) for DN, and 1824 +/- 919 ng h(-1) for PB, which indicated a lower extent of absorption from BISOS compared to DN. Kidney, liver, and lung levels of bismuth were also significantly lower for BISOS compared to DN (p < 0.05). Bismuth urinary excretion was significantly lower for BISOS (0.04 +/- 0.02%) compared to DN (0.27 +/- 0.15%) but not significantly different compared to PB (0.07 +/- 0.03%). These data suggest that the absorption of bismuth following oral administration of bismuth sucrose octasulfate is significantly lower than that from De-Nol and similar to that from Pepto-Bismo.

Administration, Oral↗
PubMed1997

Mass balance of 14C-bismuth sucrose octasulfate in Sprague-Dawley rats: evidence for dissociation of bismuth from sucrose octasulfate.

The mass balance of 14C bismuth sucrose octasulfate (BISOS) was investigated in eight male Sprague-Dawley rats after single oral doses of 1.0 g kg-1. Bismuth and radioactivity were monitored in blood, urine, and feces for up to 144 h post-dose, while kidneys, brain, liver, and lungs were assayed for bismuth at 144 h post-dose. In a separate experiment, bismuth was monitored in bile of bile-duct-cannulated animals for 48 h post-dose. Fecal excretion of bismuth averaged 95.8 +/- 5.30% bismuth dose, while 99.2 +/- 3.63% of the radiolabel was excreted in feces. Urinary excretion of bismuth averaged 0.051 +/- 0.028% bismuth dose, and 1.83 +/- 1.08% radioactive dose. Biliary excretion of bismuth averaged 0.0003 +/- 0.0006% bismuth dose, and 0.026 +/- 0.030% radiolabeled dose. An average 0.005 +/- 0.002% of the bismuth dose was present in kidney, liver, and lung. Bismuth levels in brain were below quantifiable limits. Though BISOS contains 57.3% by weight of bismuth, peak blood concentrations of bismuth were three orders of magnitude lower than for BISOS equivalents (Cmax for BISOS averaged 110 +/- 55.4 micrograms eq mL-1, while for bismuth it was 26.1 +/- 10.3 ng mL-1). This data indicates that bismuth dissociates from sucrose octasulfate, probably during the absorption phase, and exhibits differential pharmacokinetic characteristics from sucrose octasulfate. The low biliary and urinary excretion of both bismuth and BISOS equivalents is indicative of low systemic absorption. Greater than 96% recovery in feces, bile, and urine indicates that mass balance was achieved following oral administration.

Absorption↗
PubMed1997

HIV infection of macrophages and pathogenesis of AIDS dementia complex: interaction of the host cell and viral genotype.

AIDS dementia complex (ADC) develops in only a third of HIV-infected patients who progress to AIDS. Macrophages and microglial cells are the major cellular sites of productive HIV replication in brain. Using 11 blood isolates of HIV from asymptomatic patients there was marked variation in tropism and the level of productive infection in recently adherent monocytes and monocyte-derived macrophages cultured in vitro. However, less variation was seen with 19 blood isolates from advanced HIV infection and 11 postmortem tissue isolates from brain, cerebrospinal fluid, spleen, and lung. Newly adherent monocytes expressed CCR5 in all seven patients tested, consistent with their susceptibility to infection but not explaining the above variability. There is, also marked regional variability in neuropathology in the brain of patients with ADC. We have demonstrated that there was marked variation in the V3 sequences of HIV clones from different regions of the cortex of a patient with ADC, suggesting independent evolution of HIV replication in brain. Furthermore, production of the neurotoxin quinolinic acid from HIV-infected macrophages varied, depending on the host and source of HIV isolate. Hence variations in viral genotype, production by infected macrophages, and subsequent toxin production may contribute to the variability in neuropathology between individuals and between different regions of the brain in the same individual.

AIDS Dementia Complex↗
PubMed1997

Laparoscopic fundoplication to enhance pulmonary function in children with severe reactive airway disease and gastroesophageal reflux disease.

BACKGROUND: The relationship between severe reactive airway disease (RAD) and gastroesophageal reflux disease (GERD) has been noted but the relationship is poorly understood. This study reports our experience with laparoscopic fundoplication and its effect on the pulmonary status of children with severe steroid-dependent reactive airway disease. METHODS: Fifty-six patients with severe steroid-dependent RAD and medically refractory GERD underwent laparoscopic Nissen fundoplications. Mean age was 7 years and mean weight was 20 kg. All patients had the procedure completed successfully laparoscopically with an average operative time of 62 min. Average hospital stay was 1.6 days. RESULTS: Forty-eight of 56 patients noted significant improvement in their respiratory symptoms in the first week. Fifty of 56 patients have been weaned off their oral steroids and four others have had a greater than 50% decrease in their dose. Sixteen patients had a documented increase in their FEV1 in the initial postoperative period (avg. 26%). CONCLUSION: Patients with steroid-dependent RAD and GERD refractory to medical management show improvement in their respiratory status following fundoplication and the majority can be weaned off of their oral steroids. Laparoscopic techniques allow this procedure to be performed safely even in this high-risk group of patients.

Adolescent↗
PubMed1997

Moyamoya disease in the United States.

The epidemiology and radiological features of Moyamoya disease (MMD) in the US were investigated. This study encompassed 98 cases; 26 were newly collected from eight US institutions and 72 were previously reported in the US literature. The patients ranged in age from 6 months to 67 years with age peaks in the first, third and fourth decades. MMD was seen in various ethnic groups and females were more commonly involved (71%) than males. A specific etiology could not be determined in most cases but arteriosclerosis and use of oral contraceptives were occasional associations. On angiography and/or magnetic resonance angiography (MRA), carotid arterial stenosis or occlusion was seen bilaterally in 95 cases (97%) and unilaterally in three. On MR or MRA, internal carotid steno-occlusive lesions were well demonstrated in all cases but Moyamoya collateral vessels (MMVs) were visualized in only 65% of the patients. MMVs in the basal ganglia and thalami were best demonstrated on T1 weighted images. Parenchymal lesions were seen in all patients and were often bilateral. With advances in MR techniques and increasing awareness of diagnostic guidelines, MMD will be diagnosed more frequently than before in the US.

Adolescent↗
PubMed1997

Tibialis anterior turnover flap coverage of exposed tibia in a severely burned patient.

A case report of a longitudinally split tibialis anterior turnover flap reconstruction of an exposed tibia in a burn patient is presented here. The patient had sustained deep partial- and full-thickness burns to 70 per cent of his total body surface area (TBSA), resulting in an exposed left patella and upper two-thirds of the left tibia. Although full thickness loss of skin occurred on the left lower leg, no muscle trauma was sustained. Reconstruction was therefore deemed possible using local muscle tissue to provide transposed flap coverage. A gastrocnemius muscle flap was used to cover the exposed patella and superior aspect of the tibia. A portion of the tibialis anterior muscle was split longitudinally and turned over medially to cover the remaining exposed tibia. The advantages offered by this infrequently used flap include technical simplicity, reliability, minimal donor site dysfunction and the allowance of future use of the soleus flap. The tibialis anterior turnover flap may therefore have wide applicability for reconstruction of the severely burned lower extremity.

Accidents, Traffic↗
PubMed1997

Phase II trial of rhIL-6 (interleukin-6) prior to and concurrently with VAD (vincristine, doxorubicin and dexamethasone) chemotherapy for patients with multiple myeloma.

We examined the tolerability and safety of interleukin-6 (rhIL-6) when administered prior to and concurrent with vincristine, doxorubicin and dexamethasone (VAD) in patients with progressive multiple myeloma previously treated with VAD alone. Typical rhIL-6-related effects such as fever, chills, acute phase reactions and reversible abnormalities in liver function tests were observed. The study examined whether rhIL-6 predictably modulated indices of myeloma activity. No consistent, predictable change in myeloma-related parameters was documented upon rhIL-6 administration for either 8 days or 11 days prior to and concurrent with VAD. Two patients showed improved sensitivity to VAD chemotherapy when this was administered with rhIL-6. The overall response rate to rhIL-6 and VAD therapy in this study of relapsed and refractory patients was 50%, comparable to our previous experience with VAD alone in this cohort of patients.

Aged↗
PubMed1997

Differential responses to chemoimmunotherapy in patients with metastatic malignant melanoma.

An open, multicentre non-randomised study was performed to evaluate the activity and toxicity of combination chemoimmunotherapy, consisting of cisplatin, interleukin-2 and interferon-alpha, in metastatic malignant melanoma. Between March 1992 and September 1993, 28 patients with pathologically proven metastatic malignant melanoma, bidimensionally measurable disease and an Eastern Co-operative Oncology Group score < or = 1 were treated with the combination chemoimmunotherapy. The regimen consisted of cisplatin (100 mg/m2 on day 0), interleukin-2 (Proleukin, Chiron, Middlesex, U.K.) 18 x 10(6)IU/m2/d continuous intravenous infusion on days 3-7 and 17-22, with interferon-alpha (Roferon-A, Roche, Hertfordshire, U.K.) 9 x 10(6) U/d subcutaneously on days 3, 5, 7, 17, 19, 21 during the interleukin-2 infusions. The treatment cycle lasted 28 days. Among 27 assessable patients, 5 patients achieved partial responses, for an overall response rate of 18% (95% CI 6-37%). Median progression-free survival was 44 days (range 8-279) and median overall survival was 264 days (range 41-1432). Differential responses were noted in 41% of patients and responses were more frequent in non-visceral disease (skin, lymph node and soft tissue disease) (P = 0.04). These results indicate that differential responses to chemoimmunotherapy are common in patients with metastatic melanoma. This may account for the broad range of response rates reported in the literature.

Adult↗
PubMed1997

Isolated chondrons: a viable alternative for studies of chondrocyte metabolism in vitro.

OBJECTIVE: To develop and test a simple enzymatic procedure for isolating chondrons, which consist of the chondrocytes and their surrounding pericellular microenvironment. DESIGN: Chondrons were obtained by digesting adult human articular cartilage with a mixture of dispase and collagenase. Chondrons and chondrocytes were cultured in alginate beads, immunofluorescence labeled and examined by confocal microscopy. RESULTS: Comparison of freshly isolated chondrons with cryostat sections of cartilage revealed that type VI collagen, type II collagen and aggrecan were retained, but fibronectin and a unique chondroitin sulfate epitope recognized by the antibody, 7D4, were lost. Comparison of enzymatic and mechanical homogenization methods revealed subtle changes in chondron morphology and retention of fibronectin in mechanically isolated chondrons. Average yield of enzyme-isolated chondrons was slightly lower than that of chondrocytes isolated by pronase and collagenase digestion, but was much greater than that reported for mechanically isolated chondrons. Enzyme-isolated chondron viability was greater than 80% 1 day after isolation, and continued to be above 80% through 7 weeks of alginate bead culture. Viability of isolated chondrocytes was initially greater than 80% but fell to 60-80% with time in culture. Chondrons and isolated chondrocytes had a similar division rate except osteoarthritic chondrons were significantly slower after 2 weeks in culture. Cell division was more rapid for nonosteoarthritic chondrons than for osteoarthritic ones. CONCLUSIONS: Enzymatic isolation of chondrons is relatively simple, gives better yield and viability than mechanical isolation, but comparable yield and viability of traditional chondrocyte isolation. Enzymatic chondron isolation allows the effect of the in vivo-formed pericellular matrix on chondrocyte metabolism to be studied in vitro.

Adolescent↗
PubMed1997

Promoting community-based maternal and child health services: a university-health department partnership.

OBJECTIVES: Funded by the Federal Maternal and Child Health Bureau, a partnership between the Johns Hopkins University School of Public Health, Department of Maternal and Child Health (JHU), and the Baltimore City Health Department (BCHD) identifies maternal and child health problems, and develops appropriate interventions. This paper presents the organization and activities of the JHU/BCHD Maternal and Child Community Health Science Consortium as a result of overcoming traditional barriers to collaborative efforts, and discusses what role the Consortium has had in its own collaborative success. METHOD: A review of the literature uncovered a number of barriers to productive interaction. A number of factors contributing to overcoming the barriers was also revealed. The organization and activities of the work of the JHU/BCHD Maternal and Child Community Health Science Consortium has been applied to these barriers and associated factors, and discussed in context of implications for future collaborative efforts. RESULTS: The Consortium has developed a fully integrated administrative structure bridging both the BCHD and JHU. The mission of the Consortium has been translated into four categories of work, each one designed to complement, extend, and augment the other. The infrastructure established in Baltimore, as a direct result of this partnership, has served to overcome traditional barriers to productive academic/agency collaboration, while promoting organizational productivity. This outcome is a result of overcoming the recognized barriers to collaboration. CONCLUSIONS: Health agencies and university public health programs must link resources and collaborate to address public health issues. Commitment to a collaborative approach to the public's health will determine its future.

Child↗
PubMed1997

Confocal analysis of the molecular heterogeneity in the pericellular microenvironment produced by adult canine chondrocytes cultured in agarose gel.

Adult articular chondrocytes are each surrounded by a heterogeneous microenvironment and together form the chondron. Since little is known of chondron development, agarose gel culture, confocal immunohistochemistry and image analysis have been used to characterize the molecular anatomy and temporal development of the chondrocyte pericellular microenvironment in vitro. Two structurally distinct domains were identified during the 12-week culture period. The first comprised a narrow glycocalyx, 1-3 microns in width, which consolidated over time and was rich in collagen types II, VI, IX and XI, fibronectin, decorin and the aggrecan epitopes, 5D4 and HABR. The second region emerged after 4-6 weeks in culture and progressively developed a broad territorial region up to 12 microns wide around the chondrocyte and pericellular glycocalyx. Co-localization studies confirmed the dominance of aggrecan epitopes 2B6, EFG-4, 5D4 and HABR in the territorial domain, whereas surface density mapping with NIH image revealed two patterns of staining, one punctate and stippled, the other more uniform in distribution. The pericellular differentiation identified appeared analogous to the chondrons of adult articular cartilage, and provides an appropriate in vitro model for further studies of cell surface receptor function in the orchestration of pericellular matrix assembly.

Agar↗
PubMed1997

A phase I/II study of leucovorin, carboplatin and 5-fluorouracil (LCF) in patients with carcinoma of unknown primary site or advanced oesophagogastric/pancreatic adenocarcinomas.

Carcinoma of unknown primary site (CUPS) accounts for 5-10% of all malignancies. Forty patients with metastatic CUPS or advanced oesophagogastric/pancreatic adenocarcinomas were recruited. Eligibility included ECOG performance status 0-2, minimum life expectancy of 3 months and measurable disease. The regimen consisted of bolus intravenous 5 fluorouracil (5-FU) and leucovorin (20 mg m-2) days 1-5 and carboplatin (AUC5) on day 3. The leucovorin/carboplatin/5-FU (LCF) was repeated every 4 weeks. The starting dose of 5-FU was 350 mg m-2 day-1 with escalation to 370 and then 400 mg m-2 day -1 after the toxicity at the previous level had been assessed. The maximum tolerated dose (MTD) was defined as the dosage of 5-FU that achieved 60% grade 3/4 toxicity. In addition, objective and symptomatic responses, quality of life and survival were assessed. The MTD of 5-FU in the LCF regimen was 370 mg m-2. The predominant toxicity was asymptomatic marrow toxicity. The 350 mg m-2 level was then expanded. There were two toxic deaths due to neutropenic sepsis, one at 370 mg m-2 after one course and one at 350 mg m-2 after four courses. The objective response rate was 25% with one complete response (CR) and nine partial responses (PRs). The median duration of response was 3.4 months (range 1-10). The CR and eight of the nine PRs were in CUPS patients. Twelve patients developed progressive disease on LCF. Median survival for all 40 patients was 7.8 months (10 months median survival for those treated at 350 mg m-2). The majority of patients described a symptomatic improvement with LCF chemotherapy. The recommended dose of 5-FU for future studies is 350 mg m-2 combined with leucovorin 20 mg m-2 and carboplatin (AUC5).

Adenocarcinoma↗
PubMed1997

Autografting in Philadelphia (Ph)+ chronic myeloid leukaemia using cultured marrow: an update of a pilot study.

Incubation of CML marrow in long-term culture (LTC) conditions may result in selection of normal (Ph-) LTC-initiating cells (LTC-IC) as early as 10 days, and in production of Ph- clonogenic cells and mature end cells within 5 weeks. This was the rationale for using marrow cells from 10-day-old LTC to autograft nine chronic phase CML patients, ineligible for HLA-matched sibling donor transplant, and who were selected on the basis of a pre-transplant screening LTC test. Of the transplanted patients three died; two of graft failure and one of therapy-related toxicity with 97% Ph- cells 16 months following the autograft. The reconstituting haemopoietic cells in the seven engrafted patients were 100% Ph- in four, > or = 90% Ph- in two and 71% Ph- in the seventh, with a duration of complete cytogenetic response of 6-12 months. Three patients reverted to chronic phase and 100% Ph+ haemopoiesis 27-36 months post-autograft. The other three patients remain in continuous haematological remission with 22% Ph- cells in one and complete cytogenetic remission in the other two 3-4 years post-autograft. IFN therapy was generally introduced on the first evidence of recurrence of Ph+ cells or of cytogenetic deterioration. Further strategies to modulate immune surveillance in vivo may improve the outcome of cultured marrow autografts which give an initial and rather prolonged bias towards Ph- haemopoiesis.

Adult↗
PubMed1997

Mutational analysis of the interacting cell death regulators CED-9 and CED-4.

The genes ced-3, ced-4 and ced-9 are central components in the cell death pathway of the nematode C. elegans. Ced-9, which functions to inhibit cell death, is homologous to the Bcl-2 family of mammalian anti-apoptotic genes. The ced-3 gene encodes a protein homologous to the caspases, a family of cysteine proteases involved in the execution of programmed cell death. It has recently been demonstrated that CED-4, an inducer of apoptosis for which no mammalian equivalent has been reported, can interact with CED-9 and Bcl-x(L). Here we confirm that CED-9 and CED-4 interact and using a series of deletion mutants, demonstrate that only short N-terminal deletions are tolerated in each molecule without loss-of-interaction. Two loss-of-function point mutations in different regions of CED-4 also lead to a significant loss of interaction suggesting further that the relevant interaction domains are not short linear sequences, but rather, are formed by more complex structural determinants in each molecule. Furthermore, we demonstrate that CED-4 not only interacts with Bcl-x(L) but also with its homologue, Bcl-2, and that the unstructured loop region present in Bcl-x(L) and Bcl-2 can regulate the CED-4 interaction. Lastly, we show that a BH3 peptide that can inhibit Bcl-2 family interactions also inhibits the interaction between Bcl-x(L) and CED-4.

Journal Article↗