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Biomedical subjects

J Han

Publications and source records attributed to J Han.

At least 55 records · Page 3Linked to original sources
PubMed2001

Preoperative concurrent chemoradiotherapy for stage IIIA non-small cell lung cancer.

Thirty-one patients with stage IIIA non-small cell lung cancer (NSCLC) were treated with preoperative concurrent chemoradiotherapy (CCRT) followed by surgery. The treatment protocol could not be completed in eight patients. The acute hematologic toxicities of grade III or IV occurred in 48.4%, (15/31) after the first chemotherapy cycle, and in 39.1% (9/23) after the second cycle. The most common non-hematologic toxicity was radiation esophagitis. Surgery was attempted in 23 patients and successful in 22 patients (resection rate = 71.0%. Pathologic complete response and down-staging were achieved in 13.6% (3/22) and 68.2% (15/22). The median survival period, 2-year overall survival, local control and disease-free survival rates of all 31 patients and of 22 patients who underwent surgery were 19 months, 37.2%, 49.1%, 35.5%, and 19 months, 43.2%, 51.8%, 25.6%, respectively. On the basis of our observations, preoperative CCRT followed by surgery for stage IIIA NSCLC has resulted in outcomes comparable with those in previous reports.

Adult↗
PubMed2001

Monoclonal antibodies against human telomerase reverse transcriptase (hTERT): preparation, characterization, and application.

The catalytic subunit of human telomerase reverse transcriptase (hTERT), is the necessary and rate-limiting component to telomerase activation in cancer cells. To develop monoclonal antibodies (MAbs) against hTERT, a peptide-hTERT(9)-derived from specific motif T of hTERT was synthesized. Through fusion of splenocytes of BALB/c mice immunized with hTERT(9) with mouse myeloma cells, hybridomas were generated and clones secreting anti-hTERT(9) antibody were screened. After three rounds of limited dilution of candidate clones, three of which present stable and constant antibody production. The MAbs were hTERT(9)-specific and reactive with native hTERT of human cancer cells or tissues in Western blot and immunohistochemistry. The heavy chain variable regions from three hybridomas were cloned and sequenced confirming their mouse Ig derivation. The described investigation suggested that the generated MAbs to hTERT(9) could recognize native hTERT and be useful to cancer research.

Amino Acid Sequence↗
PubMed2001

Large cell neuroendocrine carcinoma of the lung: clinical, CT, and pathologic findings in 11 patients.

The purpose of this study was to describe the clinical, computed tomographic (CT), and pathologic findings of large cell neuroendocrine carcinoma (LCNEC) of the lung. CT and pathologic findings as well as clinical features of surgically proven LCNEC of the lung were reviewed retrospectively in 11 consecutive patients (eight men and three women; mean age, 63 years; range, 44-77 years). Chest CT showed peripheral mass or nodule (n = 8) and central mass with distal atelectasis (n = 3). Six tumors were accompanied by mediastinal (n = 3) and hilar (n = 3) lymph node enlargement at CT. On pathologic examination, all resected tumors showed necrosis of variable extent (mean: 38%, range; 10-70%). The areas of intrinsic lipoid pneumonia and tumor emboli in two patients appeared at CT as areas of ground-glass opacity surrounding the tumor. Mediastinal nodal metastases were seen in three (27%) patients. Pathologic staging of 11 patients was IB in six, IIA in one, IIB in one, IIIA in two, and IIIB in one. Follow-up data showed extrathoracic metastases in four patients at mean follow-up period of 15 months. One patient died of distant metastasis 5 months after the surgery. CT findings of LCNEC of the lung are nonspecific and similar to those of other non-small cell lung cancers and extrathoracic metastasis is seen in approximately one third of the patients with follow-up study.

Adult↗
PubMed2001

Role of CD36, the macrophage class B scavenger receptor, in atherosclerosis.

Recent work in the field of atherosclerosis has greatly expanded our knowledge of the pathogenesis of this disease. Scavenger receptors, including CD36, are thought to be most important early in the disease progression during macrophage uptake of modified LDL and foam cell formation. Genetically engineered murine models have been used to elucidate the contribution of the different scavenger receptors, to identify specific ligands related to LDL modifications, and to assess the possible therapeutic ramifications of targeting scavenger receptors. We have demonstrated a major role for CD36 in macrophage foam cell development and subsequent lesion development in vivo. Absence of CD36 in an atherogenic Apo E null background resulted in a 70% decrease in total lesion area in Western diet-fed mice. We have also made significant progress in our understanding of the regulation of expression of CD36 and have demonstrated that OxLDL can stimulate its own uptake by induction of CD36 gene expression. The mechanism by which OxLDL upregulates CD36 involves activation of the transcription factor, PPAR-gamma.

Arteriosclerosis↗
PubMed2001

Intrahepatic genetic inoculation of hepatitis C virus RNA confers cross-protective immunity.

Naturally occurring hepatitis C virus (HCV) infection has long been thought to induce a weak immunity which is insufficient to protect an individual from subsequent infections and has cast doubt on the ability to develop effective vaccines. A series of intrahepatic genetic inoculations (IHGI) with type 1a HCV RNA were performed in a chimpanzee to determine whether a form of genetic immunization might stimulate protective immunity. We demonstrate that the chimpanzee not only developed protective immunity to the homologous type 1a RNA after rechallenge by IHGI but was also protected from chronic HCV infection after sequential rechallenge with 100 50% chimpanzee infectious doses of a heterologous type 1a (H77) and 1b (HC-J4) whole-virus inoculum. These results offer encouragement to pursue the development of HCV vaccines.

Amino Acid Sequence↗
PubMed2001

Resistance to tumor necrosis factor-induced cell death mediated by PMCA4 deficiency.

We used retrovirus insertion-mediated random mutagenesis to generate tumor necrosis factor (TNF)-resistant lines from L929 cells. Using this approach, we discovered that the plasma membrane calcium ATPase 4 (PMCA4) is required for TNF-induced cell death in L929 cells. Under basal conditions, PMCA4-deficient (PMCA(mut)) cells have a normal phenotype. However, stimulation with TNF induces an abnormal increase in the intracellular calcium concentration ([Ca(2+)](i)). The substantially elevated [Ca(2+)](i) caused resistance to TNF-induced cell death. We found that an increase in the total volume of acidic compartments (VAC), mainly constituted by lysosomes, is a common event in cell death caused by a variety of agonists. The increased [Ca(2+)](i) in PMCA(mut) cells promoted lysosome exocytosis, which, at least in part, accounted for the inhibition of TNF-induced increase in VAC and cell death. Promoting lysosome exocytosis by calcium inhibited TNF-induced cell death in wild-type L929 cells, while inhibition of lysosome exocytosis or increase of VAC by sucrose restored the sensitivity of PMCA(mut) cells to TNF-induced cell death. Thus, increase of the volume of acidic compartment is a part of the cell death process, and the antideath effect of calcium is mediated, at least in part, by inhibition of the TNF-induced increase in VAC.

Animals↗
PubMed2001

p38 mitogen-activated protein kinase-dependent activation of protein phosphatases 1 and 2A inhibits MEK1 and MEK2 activity and collagenase 1 (MMP-1) gene expression.

Degradation of collagenous extracellular matrix by collagenase 1 (also known as matrix metalloproteinase 1 [MMP-1]) plays a role in the pathogenesis of various destructive disorders, such as rheumatoid arthritis, chronic ulcers, and tumor invasion and metastasis. Here, we have investigated the role of distinct mitogen-activated protein kinase (MAPK) pathways in the regulation of MMP-1 gene expression. The activation of the extracellular signal-regulated kinase 1 (ERK1)/ERK2 (designated ERK1,2) pathway by oncogenic Ras, constitutively active Raf-1, or phorbol ester resulted in potent stimulation of MMP-1 promoter activity and mRNA expression. In contrast, activation of stress-activated c-Jun N-terminal kinase and p38 pathways by expression of constitutively active mutants of Rac, transforming growth factor beta-activated kinase 1 (TAK1), MAPK kinase 3 (MKK3), or MKK6 or by treatment with arsenite or anisomycin did not alone markedly enhance MMP-1 promoter activity. Constitutively active MKK6 augmented Raf-1-mediated activation of the MMP-1 promoter, whereas active mutants of TAK1 and MKK3b potently inhibited the stimulatory effect of Raf-1. Activation of p38 MAPK by arsenite also potently abrogated stimulation of MMP-1 gene expression by constitutively active Ras and Raf-1 and by phorbol ester. Specific activation of p38alpha by adenovirus-delivered constitutively active MKK3b resulted in potent inhibition of the activity of ERK1,2 and its upstream activator MEK1,2. Furthermore, arsenite prevented phorbol ester-induced phosphorylation of ERK1,2 kinase-MEK1,2, and this effect was dependent on p38-mediated activation of protein phosphatase 1 (PP1) and PP2A. These results provide evidence that activation of signaling cascade MKK3-MKK3b-->p38alpha blocks the ERK1,2 pathway at the level of MEK1,2 via PP1-PP2A and inhibits the activation of MMP-1 gene expression.

Adult↗
PubMed2001

Gene suppression by tristetraprolin and release by the p38 pathway.

Tristetraprolin (TTP) is a zinc finger protein that has been implicated in the control of tumor necrosis factor (TNF) mRNA stability. We show here that TTP protein has a suppressive effect on promoter elements from TNF-alpha and interleukin-8 and that lipopolysaccharide (LPS) stimulation can release this suppression. The release in LPS-stimulated cells was found to be primarily mediated by the p38 pathway because activation of p38 is sufficient to remove the suppressive effect of TTP. Indeed, TTP seems to be a direct substrate of p38 in vivo since it is an excellent substrate of p38 in vitro, and mutation of potential phosphorylation sites in TTP prevents release of the suppression imposed on TNF transcription. We found TTP protein to be present at low levels in the resting macrophage cell line RAW 264.7 and to be quickly induced after LPS stimulation. The kinetics of TTP induction suggests a potential role of TTP as an important player in switching off LPS-induced genes after induction. In conclusion, TTP plays an important role in maintaining gene quiescence, and this quenching effect on transcription can be released by p38 phosphorylation of TTP.

Animals↗
PubMed2001

Apoptosis by pan-caspase inhibitors in lipopolysaccharide-activated macrophages.

Although apoptosis has been observed in macrophages during the course of infections, the mechanism of apoptosis in activated macrophages is not fully understood. This study shows that pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (ZVAD) or t-butyloxycarbonyl-Asp-fluoromethylketone (Boc-D) caused the death of lipopolysaccharide (LPS)-activated macrophages and RAW 264.7 cells with apoptotic features. The apoptosis was also observed in lipoprotein-treated bacteria but not in CpG oligonucleotide- or flagellin-treated macrophages, indicating a difference of cellular responses downstream of different Toll-like receptors. Consistent with the induction of cell death by pan-caspase inhibitors, no activation of known caspases was detected in LPS-ZVAD-treated cells, suggesting an involvement of unknown proapoptotic caspases in the cell death. ZVAD inhibited the activation of extracellular signal-regulated kinase (ERK) and p38 but not of nuclear factor (NF)-kappa B induced by LPS, suggesting that the ZVAD-sensitive molecule lies upstream of the ERK and p38 pathways but downstream of the divergent site of NF-kappa B and mitogen-activated protein kinases. Our results demonstrate that apoptosis of macrophages induced by LPS+ZVAD is independent from the known proapoptotic caspases and suggest that activity of an unidentified ZVAD-sensitive molecule(s) is involved in the survival of LPS-activated macrophages.

Amino Acid Chloromethyl Ketones↗
PubMed2001

p38 MAP kinase modulates liver cell volume through inhibition of membrane Na+ permeability.

In hepatocytes, Na+ influx through nonselective cation (NSC) channels represents a key point for regulation of cell volume. Under basal conditions, channels are closed, but both physiologic and pathologic stimuli lead to a large increase in Na+ and water influx. Since osmotic stimuli also activate mitogen-activated protein (MAP) kinase pathways, we have examined regulation of Na+ permeability and cell volume by MAP kinases in an HTC liver cell model. Under isotonic conditions, there was constitutive activity of p38 MAP kinase that was selectively inhibited by SB203580. Decreases in cell volume caused by hypertonic exposure had no effect on p38, but increases in cell volume caused by hypotonic exposure increased p38 activity tenfold. Na+ currents were small when cells were in isotonic media but could be increased by inhibiting constitutive p38 MAP kinase, thereby increasing cell volume. To evaluate the potential inhibitory role of p38 more directly, cells were dialyzed with recombinant p38alpha and its upstream activator, MEK-6, which substantially inhibited volume-sensitive currents. These findings indicate that constitutive p38 activity contributes to the low Na+ permeability necessary for maintenance of cell volume, and that recombinant p38 negatively modulates the set point for volume-sensitive channel opening. Thus, functional interactions between p38 MAP kinase and ion channels may represent an important target for modifying volume-sensitive liver functions.

Animals↗
PubMed2001

Pan-caspase inhibitor zVAD enhances cell death in RAW246.7 macrophages.

Even though the pan-caspase inhibitor zVAD has been widely used as an anti-apoptotic agent, inefficient prevention or even enhancement of cell death has been reported in certain cells. To further investigate its effects on cell death, three different cell types were exposed to various apoptotic stimuli in the presence or absence of zVAD. In Jurkat cells, zVAD protected against cell death induced by tumor necrosis factor (TNF), sodium nitroprusside (SNP) and etoposide, whereas in L929 cells cell death was increased. In RAW246.7 macrophages, zVAD showed similar effects as in L929 cells. However, unlike L929 cells, in which the cell death by TNF is known to be necrosis, RAW246.7 cells manifested features of apoptosis such as chromatin condensation and nuclear fragmentation. Induction of cell death by zVAD in lipopolysaccharide (LPS)-activated RAW246.7 cells also showed the same features as those observed in SNP- and etoposide-treated cells. Initiation of an apoptotic process by zVAD not only disputes the sole role of caspases in apoptosis but also suggests an anti-apoptotic function of certain caspase(s). Death of LPS-activated macrophages may be controlled by an anti-apoptotic caspase.

Adjuvants, Immunologic↗
PubMed2001

Malignant thymic epithelial tumors: CT-pathologic correlation.

OBJECTIVE: The purpose of our study was to describe and compare the CT and pathologic findings of atypical thymoma and thymic carcinoma. MATERIALS AND METHODS: Twenty-seven consecutive patients (14 men, 13 women ranging in age from 22 to 77 years [mean age, 52 years]) with pathologically proven atypical thymoma (n = 9) and thymic carcinoma (n = 18) constituted the study population. The chest CT findings in each of the 27 patients were reviewed retrospectively in consensus by two chest radiologists. These findings were correlated with pathologic findings. RESULTS: The tumors were located in the anterior mediastinum, and most tumors had a lobulated margin (24/27, 89%). Atypical thymomas were significantly smaller (mean, 4.7 cm) than thymic carcinomas (mean, 7.2 cm) (p = 0.041) on CT. The findings of invasion of the great vessels, lymph node enlargement, extrathymic metastases, and phrenic nerve palsy were seen only in patients with thymic carcinoma. The frequencies of necrosis, intratumoral calcification, pleural effusion, pleural implants, pericardial effusion, and obliteration of the mediastinal fat plane were not significantly different between atypical thymomas and thymic carcinomas (p > 0.05). Various histologic subtypes were included in thymic carcinoma. The tumor necrosis and calcification seen on CT were confirmed at pathologic examination. CONCLUSION: When a large thymic tumor appears with invasion of the great vessels, lymph node enlargement, phrenic nerve palsy, or extrathymic metastases on CT, thymic carcinoma rather than atypical thymoma should be considered.

Adult↗
PubMed2001

Quantification of ground-glass opacity on high-resolution CT of small peripheral adenocarcinoma of the lung: pathologic and prognostic implications.

OBJECTIVE: The purpose of our study was to correlate the high-resolution CT findings of small peripheral adenocarcinoma of the lung with underlying histopathology and to evaluate the prognostic implications of the CT findings. MATERIALS AND METHODS: The high-resolution CT findings of small peripheral adenocarcinoma of the lung in 224 patients were analyzed by two independent observers for location, size, marginal characteristics, and extent of ground-glass opacity and necrosis. The pathologic specimens were reviewed by an experienced lung pathologist. RESULTS: One hundred and thirty-two patients had bronchioloalveolar carcinoma and 92 had adenocarcinoma. The extent of ground-glass opacity was greater in bronchioloalveolar carcinomas (mean +/- SD, 29% +/- 31.6%) than in other adenocarcinomas (8% +/- 13.3%) (p < 0.001). The extent of ground-glass opacity was significantly greater in patients without recurrence (p = 0.020) and those without nodal (p = 0.017) or distant (p = 0.007) metastases than in patients with nodal or distant metastases or in whom the carcinoma had recurred. CONCLUSION: The extent of ground-glass opacity in a nodule is greater in bronchioloalveolar carcinomas than in other adenocarcinomas. Greater extent of ground-glass opacity also correlates with improved prognosis.

Adenocarcinoma↗
PubMed2001

IgG2a and igA co-expression by the natural autoantibody-producing murine B lymphoma T560.

The T560 B lymphoma produces polyreactive IgG2a with the features of natural autoantibody. All T560 cells bear and secrete IgG2a but a small fraction spontaneously co-express IgA. Cells secreting IgA alone cannot be detected. IgA secretion is enhanced by interaction of T560 cells either with activated T cells and cognate antigen, or with LPS, but not with cytokines, including IL-5 and TGF-beta. IgA and IgG2a mRNAs have identical V186.2. DFL 16 and JH1 sequences from framework 2 through JH1. PCR analysis reveals that previous recombination events have led to deletion of the mu, gamma3, gamma1, gamma2b constant region genes from both the productive and the unproductive chromosome but the former has retained gamma2a, epsilon and alpha, the latter only alpha. Digestion-circularization (DC)-PCR experiments provide formal proof of DNA recombination between Ca and the intron upstream of Cmu. Evidently, the productive chromosome has switched only as far as gamma2a, the unproductive all the way to the alpha constant region gene. The unproductive allele is transcriptionally active as evidenced by the presence of mRNA encoding Calphal inappropriately spliced to a cryptic splice site in the downstream intron of DQ52 (eliminated from the productive chromosome). A specific RT-PCR using oligonucleotide primers derived from the upstream initiation site of the Ialpha exon and from Calpha1 discloses that T560 cells contain alpha-germ line mRNA, presumably transcribed from the Ialpha-region of the productive chromosome, spliced to Calpha. Treatment with LPS stops production of these spliced transcripts suggesting that it may promote either DNA recombination in cells spontaneously transcribing Ialpha or a change in splicing such that Ialpha sequence is no longer joined to Calpha. Verification of the DC-PCR product by sequencing reveals that the T560 and B10.A IgA (Ig2b allotype) hinge is different from the BALB/c IgA (Ig2a allotype) hinge: it has two extra Cys and has eliminated the first Thr, a potential glycosylation site in BALB/c IgA.

Animals↗
PubMed2001

Focal organizing pneumonia: CT and pathologic findings.

The purpose of this study was to describe the CT findings of focal organizing pneumonia and to compare the findings with pathology. CT findings of histologically proven focal organizing pneumonias in 26 consecutive patients were analyzed. In 17 patients who had undergone surgical resections, the findings were correlated with pathology. Focal organizing pneumonias appeared as a nodule (n= 13) or a mass (n=13), ranging from 9 mm to 66 mm in diameter. Ground-glass opacity was seen in 6/13 (46%) nodules and 6.5/13 (50%) masses (k=.48) with an extent ranging from 5% to 75% (mean, 16%). In 4/26 (15%) patients, the extent was more than 50% of the lesion. They showed smooth (n=4), lobulated (n=8), spiculated (n=1), or lobulated and spiculated margin (n=13). On correlative analysis, nodule or mass on CT consisted histologically of intraalveolar exudate or microabscess, chronic inflammatory cell infiltration, fibrotic nodules, and polypoid granulation tissue in the alveolar or bronchiolar spaces. Ground-glass opacity consisted of interstitial fibrosis and chronic inflammatory cell infiltration and intraalveolar polypoid granulation tissue. Focal organizing pneumonia may simulate a lung cancer with variable appearances on CT and the findings reflect underlying histopathology of the disease.

Adult↗
PubMed2001

Development of cataractous macrophthalmia in mice expressing an active MEK1 in the lens.

PURPOSE: To characterize the extracellular signal-regulated kinase (ERK) pathway in the lens and to try to understand how this pathway contributes to lens function and cataractogenesis. METHODS: The members of the ERK pathway in the lens were examined by Western blotting, immunohistochemical staining, and kinase assay. A gain-of-function approach was used to perturb the ERK pathway in the lenses of transgenic mice via expression of a constitutively active mutant of the mitogen-activated protein kinase kinase 1 (MEK1(E)), the direct upstream kinase of the ERK1 and ERK2 kinases, under the alphaA-crystallin promoter. RESULTS: The presence of an active ERK pathway was found in lens epithelial cells and in differentiating fibers. Transgenic mice that expressed MEK1(E) developed postnatal cataracts as well as macrophthalmia. Distinct morphologic alterations, such as lens enlargement, swelling fiber cells, enlarged extracellular space, and vacuole formation, were observed in the lenses of these transgenic mice. A significant increase in the glucose transporter 1 (GLUT1) level, as well as in the glucose level, was detected in the lens. CONCLUSIONS: The MAP kinase pathway is involved in the regulation of glucose metabolism and balance in the mouse lens. Moreover, the alteration of MAP kinase activity in the lens is sufficient to cause cataract formation with enlarged extracellular space and vacuoles in the differentiating fibers. This transgenic mouse may provide a useful model for understanding the mechanism(s) for some aspects of human cataracts.

Animals↗
PubMed2001

[Effect of zinc on the activities of ATPase of erythrocyte membrane].

The effects of zinc on the activities of Na+, K(+)-ATPase and Ca2+, Mg(2+)-ATPase of erythrocyte membrane were studied both in vivo and in vitro. Male adult rats were divided into three groups and fed on diets with different concentration of zinc (2.2, 28 and 128 mg/kg diet). Eight rats of each group were sacrificed after 25 days and the activities of the two ATPase were measured. The rest rats were changed diet for an other seven days to detect the sensitivities of the ATPases. The activities of these ATPase were also determined in fresh human erythrocyte membrane treated with different concentration of zinc (0, 5, 10, 50, 100, 500 mumol/L). The results showed that the activities of both Na+, K(+)-ATPase and Ca2+, Mg(2+)-ATPase were in close relationship with zinc concentration, too low or too high zinc could decrease them. Compared with Na+, K(+)-ATPase, Ca2+, Mg(2+)-ATPase was more sensitive to zinc deficiency and in a slower reaction to zinc supplement, but it could stand higher zinc concentration. It was concluded that zinc played an important role on maintaining the normal activities of Na+, K(+)-ATPase and Ca2+, Mg(2+)-ATPase.

Animals↗