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Biomedical subjects

Yuji Ohtsuki

Publications and source records attributed to Yuji Ohtsuki.

At least 37 records · Page 2Linked to original sources
PubMed2005

Non-specific interstitial pneumonia; as the first clinical presentation of various collagen vascular disorders.

Recently, we have experienced significant numbers of patients diagnosed with non-specific interstitial pneumonia (NSIP) by open lung biopsy or video-assisted thoracoscopic surgery. The purpose of this work was to describe the clinical features of patients with collagen vascular disorders (CVD) presenting NSIP in the absence of systemic involvement. This study also involved a retrospective review of patients with CVD presenting clinical and pathological evidence of NSIP in the absence of systemic manifestations of CVD. We found seven patients (six from our experience and one from literature review) with histologically proven NSIP who later developed typical CVD more than 6 months after the first presentation of NSIP. In these cases, it was difficult to speculate the development of CVD at the point of first presentation. Therefore, association of CVD should be considered in patients with NSIP even in the absence of classical systemic involvement.

Adult↗
PubMed2005

An adiponectin receptor, T-cadherin, was selectively expressed in intratumoral capillary endothelial cells in hepatocellular carcinoma: possible cross talk between T-cadherin and FGF-2 pathways.

T-cadherin is a unique receptor of adiponectin, which plays a critical role in various angiogenesis. In the present study, T-cadherin expression in tumor vessels of hepatocellular carcinoma (HCC) and, subsequently, the molecular mechanism, which induced T-cadherin expression in sinusoidal endothelial cells were investigated. Sinusoidal endothelium in nontumorous liver, chronic hepatitis, or liver cirrhosis expressed little or no T-cadherin. By contrast, T-cadherin was found in intratumoral capillary endothelial cells of 34 out of 63 HCC specimens. In positive cases, focal T-cadherin expression was found in well-differentiated HCC, whereas diffuse and intense T-cadherin expression was observed in poorly differentiated HCC specimens. T-cadherin was much expressed in intratumoral capillary endothelial cells in a less differentiated HCC region than that in a well-differentiated region in five specimens, in which various differentiated HCC components were coexistent. In a double-cell chamber assay, fibroblast growth factor-2 appeared to have a critical role to induce T-cadherin in cultured liver sinusoidal endothelial cells. The present finding indicated that T-cadherin was selectively expressed in intratumoral capillary endothelial cells of many HCCs, increasingly expressed as tumor progression, and T-cadherin may have a positive role in angiogenesis of HCC. In addition, cross talk between the signal pathways mediated by fibroblast growth factor-2 and adiponectin was suggested.

Cadherins↗
PubMed2005

Effect of combination therapy with a novel bisphosphonate, minodronate (YM529), and docetaxel on a model of bone metastasis by human transitional cell carcinoma.

PURPOSE: Transitional cell carcinoma (TCC) of the urinary tract is a chemosensitive tumor. Most deaths from TCC of the urinary tract are caused by metastasis, which is resistant to conventional chemotherapy. Frequent sites of metastases from TCC of the urinary tract are regional lymph nodes, liver, lung, and bone. Of these distant metastases, bone metastasis is consistently resistant to cisplatin-based conventional chemotherapy. Therefore, in this study, we investigated whether or not a newly developed minodronate, YM529, could prevent osteolytic bone metastasis of human TCC and also enhance the effect of docetaxel in a bone tumor model of athymic nude mice. EXPERIMENTAL DESIGN: In the present study, we evaluated the effect of in vitro treatment with minodronate and/or docetaxel on the proliferation by cell count, the induction of apoptosis by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, and the biological activity of osteoclast by pit formation assay in human bladder cancer cell line, UMUC-14, and mouse osteoclast cells. In vivo, we examined the effect of minodronate in a bone tumor model of athymic nude mice, in which the percutaneous intraosseal injection in the tibia of UMUC-14, leads to osteolytic bone tumor, as a bone metastasis model. To examine whether or not minodronate could inhibit tumorigenicity and enhance the effect of the chemotherapeutic agent, docetaxel, we gave minodronate i.p. and/or docetaxel i.p. to nude mice 3 days after an intraosseal tumor implantation. Moreover, proliferation and the induction of apoptosis of cancer cells and osteoclasts in bone tumors were determined by immunohistochemistry and the TUNEL assay. RESULTS: In vitro: In vitro treatment with docetaxel inhibited proliferation and resorption pit-forming activity and induced apoptosis of mouse osteoclast cells and UMUC-14 cells. In vitro treatment with minodronate inhibited proliferation and activity and induced apoptosis of mouse osteoclast cells but not UMUC-14 cells. The treatment with minodronate enhanced the inhibition of proliferation and activity by docetaxel in osteoclasts. In vivo: In vivo combination therapy with docetaxel and minodronate significantly reduced the tumor incidence compared with the control (P < 0.05) and also growth of intraossal TCC in athymic nude mice compared with the control (P < 0.001), single therapy with docetaxel (P < 0.01), and minodronate (P < 0.05). Drug-induced body weight loss was not significantly different in any treatment group. Therapy with minodronate significantly enhanced inhibition of proliferation by docetaxel in osteoclasts of bone tumors compared with the control (P < 0.01), single therapy with docetaxel (P < 0.01), and minodronate (P < 0.05). CONCLUSIONS: These studies indicate that combination therapy with minodronate and docetaxel may be beneficial in patients with bone metastasis of human TCC in the urinary tract.

Acid Phosphatase↗
PubMed2005

Overexpression of carbonic anhydrase-related protein XI promotes proliferation and invasion of gastrointestinal stromal tumors.

Three isoforms of carbonic anhydrase-related protein (CA-RP) are evolutionally well conserved among the CA gene family but lack classical CA activity. Although the biological function of CA-RPs is unknown, overexpression of CA-RP VIII has been reported in certain tumor types. Based on the finding that CA-RPs are commonly expressed in the neuronal cells, we investigated expression of all three CA-RPs in gastrointestinal stromal tumor (GIST). In contrast to no detectable signal of any of the three CA-RPs in intestinal cells of Cajal, immunohistochemical analysis showed distinct cytoplasmic expressions of CA-RPs VIII and XI in 13 (59%) and 20 (91%) of 22 GIST tissue specimens, respectively. The positive signals for both CA-RPs VIII and XI were more intense in the periphery than in the central part of GISTs, whereas no significant signal for CA-RP X expression was observed in any of the GISTs. These expression patterns of CA-RPs were consistently observed by reverse transcription-polymerase chain reaction-Southern blot and immunocytochemistry in the cultured GIST cell line GIST-T1. Ectopic expression of CA-RP XI in GIST-T1 cells induced cell proliferation and invasion in vitro. These findings indicate that CA-RP XI plays a role in the development of GIST.

Biomarkers, Tumor↗
PubMed2005

Levels of angiogenesis and expression of angiogenesis-related genes are prognostic for organ-specific metastasis of renal cell carcinoma.

BACKGROUND: To identify organ-specific, metastasis-related factors that can be used to predict the development and location of metastasis of clear cell renal cell carcinoma (CRCC), the authors assessed the angiogenesis and the expression of angiogenesis-related genes in primary and metastatic tumors. METHODS: They evaluated intratumoral microvessel density (MVD) by immunohistochemical staining, assessed the expression of angiogenesis-related genes by mRNA in situ hybridization, and determined the clinicopathologic characteristics of 92 archival specimens of primary and metastatic CRCCs from 54 patients. All 38 metastatic tumor specimens were resected from 24 patients. RESULTS: The pathologic stage (P=0.026) of the primary tumor specimen was an important predictor for metastasis, as were MVD (P=0.000025) and the ratio of matrix metalloproteinases (MMPs) to E-cadherin (M/E ratio; P=0.000041). In addition, primary tumor specimens resected from patients with metastatic CRCCs had high MVD, high levels of MMP-2 expression, and a high M/E ratio (P <0.05). Relative to the primary tumors, the metastatic tumors also had high MVD, overexpression of basic fibroblast growth factor, vascular endothelial growth factor, interleukin-8, MMPs, and a high M/E ratio (P <0.05). Multivariate analysis revealed that MVD and the M/E ratio in the primary tumor were independent prognostic factors for metastasis (P=0.049 and P=0.001, respectively). Furthermore, the M/E ratio in metastatic tumor specimens resected from the lung and lymph node was an independent prognostic factor for metastasis (P=0.01823 and P=0.03950, respectively). CONCLUSIONS: The current study indicated that angiogenesis and M/E ratio were specific predictors for metastases of RCC, especially to the lung or lymph node. Therefore, MMPs and E-cadherin could be relevant targets for novel therapeutic strategies to control or prevent the metastasis of RCC.

Aged↗
PubMed2005

Primary gastric small cell carcinoma: report of a case and review of the literature.

A 52-year-old man suffering from a pure-type primary gastric small cell carcinoma was treated with surgery and combination chemotherapy. The small cell carcinoma, approximately 6.5 cm in diameter, was situated in the posterior wall of the antrum and there were no distant metastases. Total gastrectomy and regional lymph node dissection was carried out. Histological examination revealed a solid pattern of proliferation of small cells with hyperchromatic, round nuclei and scant cytoplasm. Neoplastic cells infiltrated into the subserosal layer with severe lymphatic and vascular invasion. Regional lymph node cells were mostly replaced by tumor cells that stained positive for Grimelius, neuron-specific enolase (NSE), and synaptophysin. Accumulations of electron-dense core granules in the small neoplastic cells were seen by electron microscopy. Following surgery, the patient was treated with adjuvant chemotherapy consisting of cisplatin and etoposide. The patient is alive and recurrence free 3 years after surgical operation. We review 107 published cases of primary gastric small cell carcinoma, an extremely rare disease first reported in 1976. Small cell carcinoma is an aggressive, malignant tumor. Intensive chemotherapy is essential for patient survival even when curative surgical resection is carried out.

Carcinoma, Small Cell↗
PubMed2005

Idiopathic non-specific interstitial pneumonia: as an "autoimmune interstitial pneumonia".

Recently, we have experienced significant number of patients diagnosed with non-specific interstitial pneumonia (NSIP) by open lung biopsy or video-assisted thoracoscopic surgery. The purpose of this study is to compare clinical and pathological features of idiopathic NSIP and NSIP associated with underlying diseases (mainly autoimmune disorders). Forty-six patients with histologically proven NSIP were retrospectively collected. Twenty-four patients had underlying diseases (12 polymyositis/dermatomyositis, 5 systemic sclerosis, 2 rheumatoid arthritis, 2 Sjogren's syndrome, 1 ulcerative colitis, 1 primary biliary cirrhosis, and 1 multiple myeloma). Twenty-two of the 46 patients had no underlying diseases. It was very difficult to distinguish idiopathic NSIP and NSIP associated with underlying diseases, clinically and radiologically. Pathologically, Lymphocytic pneumonitis was demonstrated in both groups, and it was impossible to distinguish idiopathic NSIP and NSIP associated with underlying diseases. Since generalized symptoms were not observed in patients with idiopathic NSIP, and clinical and pathological features were identical to NSIP with several autoimmune disorders, we postulate new clinical entities of "autoimmune interstitial pneumonia" in cases without underlying diseases.

Adult↗
PubMed2005

Skeletrophin, a novel ubiquitin ligase to the intracellular region of Jagged-2, is aberrantly expressed in multiple myeloma.

Recent research has indicated that ligand-dependent activation of the Notch receptor in stromal cells plays a crucial role in the tumorigenesis of multiple myeloma. Ubiquitination of intracellular regions of Notch receptor and its ligands is important for Notch signal transduction. In vitro autoubiquitination analysis using recombinant proteins identified skeletrophin as a novel RING finger-dependent ubiquitin ligase. Skeletrophin bound the intracellular regions of the Notch ligand Jagged-2, but not to those of Delta-1, -3, -4, or Jagged-1. Skeletrophin, but not its RING-mutated form, ubiquitinized the intracellular region of Jagged-2. In malignant plasma cells from 23 of 40 multiple myeloma specimens, strong skeletrophin expression was observed, especially from patients with osteolytic bone lesions. Cytoplasmic localization, which may indicate Jagged-2 internalization, was found in many skeletrophin-positive myeloma cells. In contrast, skeletrophin was only weakly expressed in a few nonneoplasmic plasma cells in chronically inflamed tissues. Interestingly, exogenous expression of skeletrophin, but not the RING-mutated form, in Jagged-2-positive P3U1 myeloma cells induced Hes-1 (Hairy and Enhancer of Split homolog-1) gene expression in Notch receptor-positive bone marrow stromal cells through direct cell-cell contact. Thus, skeletrophin is a novel ubiquitin ligase that targets the intracellular region of Jagged-2 and is aberrantly overexpressed in multiple myeloma cells, possibly activating Hes-1 on stromal cells through ligand-dependent Notch signaling.

Basic Helix-Loop-Helix Proteins↗
PubMed2005

Skeletrophin, a novel RING molecule controlled by the chromatin remodeling complex, is downregulated in malignant melanoma.

Recent experiments have revealed that aberrant functionality of the chromatin remodeling complex is related to tumorigenicity in various malignant tumors. Skeletrophin is an actin-binding cytoskeleton-related molecule, which is induced by the overexpression of truncated human SWI1 (SMARCF1). Human SWI1 is a sub-unit of the chromatin remodeling complex and binds chromatin through its ARID (AT-rich interactive domain). Truncated SWI1 lacks one of the two glucocorticoid-receptor binding domains and inhibits the intact human SWI1 in a dominant negative manner. Skeletrophin, was therefore identified as a candidate molecule for the indication of change to a malignant phenotype due to the aberrant function of the chromatin remodeling complex. Surprisingly, the skeletrophin gene is located in 1p36.32, where the putative tumor suppressor gene of cutaneous malignant melanoma has long been postulated to be on. Cutaneous malignant melanoma is a highly aggressive tumor. To overcome the clinical problem of malignant melanoma and highly invasive and metastatic activity, it is important to unravel the molecular mechanism responsible for melanoma progression. Recent studies including those from our laboratories have elucidated that skeletrophin is a novel RING-HC type ubiquitin ligase and that the ubiquitin ligase pathway mediated by skeletrophin acts to oppose melanoma cell invasion. Here, we summarize the characterization of skeletrophin, with emphasis on its biological activity, the disruption of which is linked with melanoma progression.

Chromatin↗
PubMed2005

HIV-1 protease inhibitor induces growth arrest and apoptosis of human prostate cancer LNCaP cells in vitro and in vivo in conjunction with blockade of androgen receptor STAT3 and AKT signaling.

This study found that the HIV-1 protease inhibitor nelfinavir (NFV) induced growth arrest and apoptosis of human prostate cancer cells (LNCaP, DU145 and PC-3 cells), as measured by MTT and terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling (TUNEL) assays, respectively, on the third day of culture. In addition, NFV blocked androgen receptor (AR) signaling in association with downregulation of nuclear levels of AR in LNCaP cells as measured by reporter assay and western blot analysis. As expected, NFV downregulated the level of the AR target molecule prostate specific antigen in these cells. Moreover, NFV disrupted STAT3 signaling; protease inhibitors blocked interleukin-6-induced phosphorylation of STAT3 and inhibited STAT3 DNA binding activity in LNCaP and DU145 cells, as measured by western blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. Furthermore, NFV blocked AKT signaling in prostate cancer cells as measured by kinase assay with glycogen synthase kinase-3alpha/beta as a substrate. Importantly, NFV inhibited the proliferation of LNCaP cells presented as tumor xenografts in BALB/c nude mice without side-effects. Taken together, NFV inhibited the proliferation of prostate cancer cells in conjunction with blockade of signaling by AR, STAT3, and AKT, suggesting that this family of compounds might be useful for the treatment of individuals with prostate cancer.

Animals↗
PubMed2004

HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo.

We previously showed that HIV-1 protease inhibitors (PIs) slowed the proliferation of human myeloid leukemia cells and enhanced their differentiation in the presence of all-trans-retinoic acid. In this study, we found that PIs, including ritonavir, saquinavir, and indinavir, inhibited the growth of DU145 and PC-3 androgen-independent prostate cancer cells as measured by a clonal proliferation assay. Recent studies showed that ritonavir inhibited cytochrome P450 3A4 enzyme (CYP3A4) in liver microsomes. The CYP3A4 is involved in drug metabolism and acquisition of drug resistance. To clarify the drug interaction between ritonavir and other anticancer drugs, we cultured DU145 cells with docetaxel either alone or in combination with ritonavir. Ritonavir enhanced the antiproliferative and proapoptotic effects of docetaxel in the hormonally independent DU145 prostate cancer cells in vitro as measured by the clonogenic soft agar assay and detection of the activated form of caspase-3 and cleavage of poly(ADP-ribose) polymerase using Western blot analysis. Real-time PCR showed that docetaxel induced the expression of CYP3A4 at the transcriptional level, and ritonavir (10(-5) mol/L) completely blocked this induction. An ELISA-based assay also showed that ritonavir inhibited DNA binding activity of nuclear factor kappaB (NFkappaB) in DU145 cells, which is a contributor to drug resistance in cancer cells. Furthermore, combination treatment of docetaxel and ritonavir dramatically inhibited the growth of DU145 cells present as tumor xenografts in BNX nude mice compared with either drug alone. Importantly, docetaxel induced expression of CYP3A4 in DU145 xenografts, and ritonavir completely blocked this induction. Ritonavir also inhibited NFkappaB DNA binding activity in DU145 xenografts. Extensive histologic analyses of the liver, spleen, kidneys, bone marrow, skin, and subcutaneous fat pads from these mice showed no abnormalities. In summary, combination therapy of ritonavir and anticancer drugs holds promise for the treatment of individuals with advanced, drug resistant cancers.

Animals↗
PubMed2004

Distribution of CXCR3- or CCR4-positive cells in interstitial pneumonia associated with primary Sjogren's syndrome.

Patients with primary Sjogren's syndrome (SS) occasionally develop interstitial pneumonia (SS-IP), the prognosis of which is less grave compared with that of idiopathic pulmonary fibrosis (IPF). We examined distribution of helper T-cell subsets in open lung biopsy specimens from seven patients with SS-IP and, for comparison, ten patients with IPF. The expression of CXCR3 and CCR4, chemokine receptors associated in vitro with Th1 and Th2 cells, respectively, was analyzed in the mononuclear infiltrate using immunohistochemistry. The expression of CD4, CD8, and CD20 in the infiltrate was similarly examined. The positive cells were semiquantified in fibrosing areas and lymphoid clusters of both SS-IP and IPF. In fibrosing areas, CXCR3-positive cells were dominant over CCR4-positive cells in all cases of SS-IP, whereas the two types of cells showed no such difference in cases of IPF. Each of the CXCR3/CD4 and CXCR3/CCR4 ratios was significantly higher in SS-IP than in IPF ( P<0.05 and P<0.05, respectively). The CCR4/CD4 ratio showed a significantly lower value in SS-IP than in IPF ( P<0.05). In lymphoid clusters, prominent in SS-IP and few and small in IPF, CXCR3-positive cells predominated over CCR4-positive cells in both lung lesions. There was no significant difference of CXCR3/CCR4 ratio in lymphoid clusters between SS-IP and IPF ( P=0.33). These findings in SS-IP are in accordance with those reported in previous studies of the salivary glands of SS patients, where most of the infiltrating lymphocytes expressed CXCR3, and the expression of interferon-gamma was upregulated. In contrast, the Th2 cell dominance was reported in IPF in the previous studies. The present findings suggest that the pathogenesis of interstitial pneumonia is different between SS-IP and IPF in regard to the roles of helper T-cell subsets.

Aged↗
PubMed2004

Differential gene-expression profiling in the leukemia cell lines derived from indolent and aggressive phases of CD56+ T-cell large granular lymphocyte leukemia.

As a rule, T cell large granular lymphocyte (T-LGL) leukemia runs a chronic clinical course without need for therapy. Some cases, however, progress to an aggressive disease after the indolent clinical stage. The transformation mechanism into a high-grade malignancy has not been well studied. We have established 2 leukemia cell lines, MOTN-1 and PLT-2, derived from the same clone of CD56+ T-LGL leukemia in chronic and aggressive phases, respectively. The paired availability of such cell lines is valuable in biologic and genetic investigation of T-LGL leukemia. We used a microarray containing 406 cDNAs to elucidate alterations of gene expression between the 2 cell lines. We found a number of genes that were differentially expressed: 13 genes with increased expression and 3 genes with reduced expression in PLT-2 cells as compared to MOTN-1 cells. Increased expression of the dek, rac, Op18, CD6, CD58, CD106, Id2, ATF4, IRF5, ELL2 and D6 genes, and reduced expression of the GzmA and GzmK genes were confirmed by real-time quantitative reverse transcription-PCR, whose results paralleled the microarray data. These upregulated genes encode oncoproteins, cell surface antigens including molecules related to T cell proliferation, transcription factors, and a chemokine receptor. The two downregulated genes encode granzymes that play an important role for induction of cell death. These findings suggest that there is differential gene expression in different clinical phases of T-LGL leukemia and these differentially expressed genes would be potential targets for further studies to identify the genes involved in the transformation process of T-LGL leukemia.

CD56 Antigen↗
PubMed2004

Effect of carbonic anhydrase-related protein VIII expression on lung adenocarcinoma cell growth.

Carbonic anhydrase-related protein VIII (CA-RP VIII) is expressed in most non-small cell lung cancer, and especially strongly at the front of tumor progression. Screening analysis of CA-RP VIII expression in a panel of cultured lung cancer cell lines showed that a well differentiated adenocarcinoma cell line, PC-9, appeared to lack CA-RP VIII. Subsequently, CA8 cDNA was transfected with an expression vector into PC-9. Ectopic overexpression of CA-RP VIII reduced the growth of PC-9 cells on uncoated culture dishes, especially when the cultures were started at low cell density, but increased cell growth on laminin-coated dishes. Interestingly, ectopic CA-RP VIII expression markedly reduced caspase-3 activity induced by serum starvation and anti-cancer agents in PC-9 cells. The present findings suggest that CA-RP VIII expression promotes progression of lung cancer by multifarious mechanisms.

Adenocarcinoma↗
PubMed2004

Clinical features of eleven cases of Mycobacterium avium-intracellulare complex pulmonary disease associated with pneumoconiosis.

The relationship between silicosis and tuberculosis is well known. Also other mycobacteria such as Mycobacterium kansasii often occur in association with pneumoconiosis. However, there are few reports describing an association of M. avium-intracellulare complex (MAC) lung disease and pneumoconiosis. The purpose of the present study is to describe clinical features of MAC respiratory infection associated with pneumoconiosis. Eleven patients with MAC respiratory infection associated with pneumoconiosis (all men, 6 with silicosis and 5 with welders' pneumoconiosis) were collected. A determination of whether or not MAC caused pulmonary disease was made using the 1997 criteria required by the American Thoracic Society. Radiologically, cavity formation as well as upper lung field predominance of MAC disease were observed in 8 of 11 cases (72.7%). Two of 11 patients died of respiratory failure. Our present study clearly demonstrates that clinical features of MAC respiratory infection associated with pneumoconiosis were different from MAC without underlying diseases.

Aged↗