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Biomedical subjects

Toshihiro Nukiwa

Publications and source records attributed to Toshihiro Nukiwa.

At least 19 recordsLinked to original sources
PubMed2007

NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells: molecular targeting of angiogenic growth factor.

Hepatocyte growth factor (HGF) promotes cell growth and motility and also increases neovascularization. Multiple myeloma (MM) cells produce HGF, and the plasma concentration of HGF is significantly elevated in patients with clinically active MM, suggesting that HGF might play a role in the pathogenesis of MM. NK4, an antagonist of HGF, is structurally homologous to angiostatin, and our previous report showed that NK4 inhibited the proliferation of vascular endothelial cells induced by HGF stimulation. The purposes of this study were to elucidate the contribution of HGF to the growth of MM cells as well as to investigate the possibility of the therapeutic use of NK4. In vitro study showed that NK4 protein stabilized the growth of MM cell lines and regulated the activation of c-MET, ERK1/2, STAT3, and AKT-1. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was injected intramuscularly into Icr/scid mice bearing tumors derived from HGF-producing MM cells. AdCMV.NK4 significantly inhibited the growth of these tumors in vivo. Histologic examination revealed that AdCMV.NK4 induced apoptosis of MM cells, accompanied by a reduction in neovascularization in the tumors. Thus, NK4 inhibited the growth of MM cells via antiangiogenic as well as direct antitumor mechanisms. The molecular targeting of HGF by NK4 could be applied as a novel therapeutic approach to MM.

Animals↗
PubMed2006

Mutations in the SLC34A2 gene are associated with pulmonary alveolar microlithiasis.

RATIONALE: Pulmonary alveolar microlithiasis is an autosomal recessive disorder in which microliths are formed in the alveolar space. OBJECTIVES: To identify the responsible gene that causes pulmonary alveolar microlithiasis. METHODS: By means of a genomewide single-nucleotide polymorphism analysis using DNA from three patients, we have narrowed the region in which the candidate gene is located. From this region, we have identified a gene that has mutations in all patients with pulmonary alveolar microlithiasis. MEASUREMENTS AND MAIN RESULTS: We identified a candidate gene, SLC34A2, that encodes a type IIb sodium phosphate cotransporter and that is mutated in six of six patients investigated. SLC34A2 is specifically expressed in type II alveolar cells, and the mutations abolished the normal gene function. CONCLUSION: Mutations in the SLC34A2 gene that abolish normal gene function cause pulmonary alveolar microlithiasis.

Amino Acid Sequence↗
PubMed2006

Mouse and human cell activation by N-dodecanoyl-DL-homoserine lactone, a Chromobacterium violaceum autoinducer.

Chromobacterium violaceum produces autoinducers, including homoserine lactones (HSLs), for genetic regulation. Among the seven HSLs derived from C. violaceum we evaluated, only C(12)-HSL stimulated the production of inflammatory cytokines in mammalian monocytic cell lines through the activation of the NF-kappaB signaling pathway besides their quorum-sensing role, like 3-oxo-C(12)-HSL from Pseudomonas aeruginosa.

4-Butyrolactone↗
PubMed2006

Prospective phase II study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations.

PURPOSE: This study was undertaken to investigate the efficacy and the feasibility of gefitinib for chemotherapy-naïve patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. PATIENTS AND METHODS: The EGFR gene status in various tumor samples obtained from chemotherapy-naïve advanced NSCLC patients was examined by DNA sequencing of EGFR exons 18 to 23. Patients harboring EGFR mutations received gefitinib (250 mg/d) alone. The response rate, progression-free survival (PFS), and toxicity profile were assessed prospectively. RESULTS: Between June 2004 and October 2005, 75 patients were examined for the EGFR status, and 25 patients (33%) harbored EGFR mutations. EGFR mutations were significantly frequent in females (P < .01) and never or light smokers (P < .001). Sixteen patients with EGFR mutations were enrolled onto the study. The overall response rate in these patients was 75% (95% CI, 54% to 96%), and the disease control rate was 88% (95% CI, 71% to 100%). The median PFS time of these patients was 9.7 months (95% CI, 7.4 to 9.9 months). No life-threatening toxicity was observed. CONCLUSION: Treatment with gefitinib alone for chemotherapy-naïve NSCLC patients with EGFR mutations could achieve a high efficacy with acceptable toxicity. To assess the proper timing of gefitinib in such patients, a subsequent randomized trial comparing gefitinib with standard chemotherapy is warranted.

Adult↗
PubMed2006

Acute-onset sarcoidosis with erythema nodosum and polyarthralgia (Löfgren's syndrome) in Japan: a case report and a review of the literature.

Löfgren's syndrome is an acute form of sarcoidosis that is characterized by erythema nodosum (EN), bilateral hilar lymphadenopathy (BHL), and polyarthralgia or polyarthritis. This syndrome is common among white people, but is considered rare among Japanese people. We present the case of a 26-year-old Japanese woman with Löfgren's syndrome. The patient complained of polyarthritis and EN of the lower extremities that lasted for 3 months. A chest radiograph revealed BHL and nodular shadows. The angiotensin-converting enzyme (ACE) level was within the normal range. Transbronchial lung biopsy revealed a noncaseating granuloma with giant cells. Six Japanese cases of Löfgren's syndrome have been reported previously. Five of the seven Japanese patients with Löfgren's syndrome had normal ACE levels; all of them exhibited BHL. Löfgren's syndrome should be considered as a possibility when examining a patient with EN and articular symptoms, even if the patient is Japanese.

Adult↗
PubMed2006

Blockage of HGF/c-Met system by gene therapy (adenovirus-mediated NK4 gene) suppresses hepatocellular carcinoma in mice.

BACKGROUND/AIMS: Hepatocyte growth factor promotes cancer development through cell motility-promoting and angiogenic effects. NK4, a fragment of hepatocyte growth factor, acts as its receptor antagonist. We assessed effects of NK4 gene therapy against human hepatocellular carcinoma cells (HUH7) transplanted into mice. METHODS: NK4 gene transduction was mediated by adenovirus (AdCMV.NK4). LacZ expression adenovirus (AdCMV.LacZ) was used as a control. NK4 effects on HUH7 cells first were studied in vitro. Subcutaneous HUH7 tumors established in athymic nude mice were injected with AdCMV.NK4 (n=6) or AdCMV.Lacz (n=6). Finally, after HUH7 cells were injected into the portal vein in mice with severe combined immunodeficiency to establish hepatic tumors, mice systemically were injected with AdCMV.NK4 (n=6) or AdCMV.LacZ (n=6). RESULTS: NK4 inhibited hepatocyte growth factor-induced phosphorylation of c-Met in HUH7 cells. Invasion and migration of HUH7 cells were inhibited by NK4 transfection, which also suppressed growth of transplanted subcutaneous and liver tumors (p<0.001, p<0.01 respectively), and improved mouse survival (p<0.05). Angiogenesis assessed by small vessel density was significantly decreased in the NK4-treated group. CONCLUSIONS: NK4 inhibited tumor cell motility and angiogenesis, greatly suppressing growth of HUH7 tumors transplanted into mouse liver. NK4 gene therapy thus showed apparent promise for treatment of hepatocellular carcinoma.

Animals↗
PubMed2006

Multicenter phase I study of repeated intratumoral delivery of adenoviral p53 in patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the feasibility, safety, humoral immune response, and biologic activity of multiple intratumoral injections of Ad5CMV-p53, and to characterize the pharmacokinetics of Ad5CMV-p53 in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifteen patients with histologically confirmed NSCLC and p53 mutations were enrolled onto this phase I trial. Nine patients received escalating dose levels of Ad5CMV-p53 (1 x 10(9) to 1 x 10(11) plaque-forming units) as monotherapy once every 4 weeks. Six patients were treated on a 28-day schedule with Ad5CMV-p53 in combination with intravenous administration of cisplatin (80 mg/m2). Patients were monitored for toxicity, vector distribution, antibody formation, and tumor response. RESULTS: Fifteen patients received a total of 63 intratumoral injections of Ad5CMV-p53 without dose-limiting toxicity. The most common treatment-related toxicity was a transient fever. Specific p53 transgene expression was detected using reverse-transcriptase polymerase chain reaction in biopsied tumor tissues throughout the period of treatment despite of the presence of neutralizing antiadenovirus antibody. Distribution studies revealed that the vector was detected in the gargle and plasma, but rarely in the urine. Thirteen of 15 patients were assessable for efficacy; one patient had a partial response (squamous cell carcinoma at the carina), 10 patients had stable disease, with three lasting at least 9 months, and two patients had progressive disease. CONCLUSION: Multiple courses of intratumoral Ad5CMV-p53 injection alone or in combination with intravenous administration of cisplatin were feasible and well tolerated in advanced NSCLC patients, and appeared to provide clinical benefit.

Aged↗
PubMed2006

A phase II study of weekly paclitaxel combined with carboplatin for elderly patients with advanced non-small cell lung cancer.

We conducted this phase II study to explore the efficacy and safety of weekly paclitaxel combined with carboplatin in elderly patients with advanced non-small cell lung cancer (NSCLC). Elderly patients (> or = 70 years old) of stage IIIB, IV, or recurrent NSCLC with PS 0 or 1 were enrolled. Patients received paclitaxel at a dose of 70 mg/m2 on Days 1, 8, 15, and carboplatin at the target dose of the area under the curve (AUC) of six on Day 1 every 28 days for at least two cycles. Forty-two patients were enrolled and 40 patients were treated with a median of three cycles (range, 1-5). The overall response rate (ORR) was 45% (95% confidence interval, 30-60%). The median survival time (MST) was 14 months and the 1-year survival rate was 62%. Twenty-eight patients (70%) had grade 3/4 neutropenia and two patients (5%) experienced grade 3 febrile neutropenia. Non-hematological toxicities were generally mild to moderate and grade 3 peripheral neuropathy was seen in one patient (3%). There was one treatment-related death by infection due to neutropenia. Weekly paclitaxel and carboplatin combination chemotherapy was an effective and safe regimen in elderly patients with advanced NSCLC. A randomized trial comparing this treatment with the conventional tri-weekly regimen of paclitaxel and carboplatin is warranted.

Aged↗
PubMed2006

Dendritic cells modified to express fractalkine/CX3CL1 in the treatment of preexisting tumors.

Fractalkine (CX3CL1) is a unique membrane-bound CX3C chemokine that serves as a potent chemoattractant for lymphocytes. The hypothesis of this study is that dendritic cells (DC) genetically modified ex vivo to overexpress fractalkine would enhance the T cell-mediated cellular immune response with a consequent induction of anti-tumor immunity to suppress tumor growth. To prove this hypothesis, established tumors of different mouse cancer cells (B16-F10 melanoma, H-2b, and Colon-26 colon adenocarcinoma, H-2d) were treated with intratumoral injection of bone marrow-derived DC that had been modified in vitro with an RGD fiber-mutant adenovirus vector expressing mouse fractalkine (Ad-FKN). In both tumor models tested, treatment of tumor-bearing mice with Ad-FKN-transduced DC gave rise to a significant suppression of tumor growth along with survival advantages in the treated mice. Immunohistochemical analysis of tumors treated with direct injection of Ad-FKN-transduced DC demonstrated that the treatment prompted CD8+ T cells and CD4+ T cells to accumulate in the tumor milieu, leading to activation of immune-relevant processes. Consistent with the finding, the intratumoral administration of Ad-FKN-transduced DC evoked tumor-specific cytotoxic T lymphocytes, which ensued from in vivo priming of Th1 immune responses in the treated host. In addition, the anti-tumor effect provided by intratumoral injection of Ad-FKN-transduced DC was completely abrogated in CD4+ T cell-deficient mice as well as in CD8+ T cell-deficient mice. These results support the concept that genetic modification of DC with a recombinant fractalkine adenovirus vector may be a useful strategy for cancer immunotherapy protocols.

Adenoviridae↗
PubMed2006

Epidemiological and clinical features of idiopathic pulmonary alveolar proteinosis in Japan.

Idiopathic pulmonary alveolar proteinosis (IPAP) is a rare disease characterized by excessive amounts of lipoproteinaceous material in the alveolus. This report presents an interim analysis of nationwide epidemiological data from Japanese patients with pulmonary alveolar proteinosis, and the roles of serum markers for IPAP. (i) The nationwide demographic data from 166 Japanese patients with IPAP are shown. The female to male ratio was 1:2, and the average age was 51 +/- 14 years old (age range: 15-79 years) at registration or diagnosis. A total of 30% of patients with IPAP have a poor clinical course. In total, 30% of patients were treated with whole lung lavage therapy (WLL). Under WLL, the patients significantly improved in the short term, but 40% of the patients who underwent WLL worsened again. A new strategy such as granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy for intractable PAP is required. (ii) The correlation of serum KL-6, carcinoembryonic antigen, surfactant proteins D and A, and LDH with disease severity suggests their potential as disease markers. In contrast, serum anti-GM-CSF antibody did not correlate with disease severity, but is a specific marker for the diagnosis of IPAP. The combined measurements of the serum markers may well prove very useful for both the diagnosis and the management of IPAP patients.

Adolescent↗
PubMed2006

Granulocyte-macrophage colony-stimulating factor inhalation therapy for patients with idiopathic pulmonary alveolar proteinosis: a pilot study; and long-term treatment with aerosolized granulocyte-macrophage colony-stimulating factor: a case report.

Idiopathic pulmonary alveolar proteinosis (IPAP) is considered to be caused by an autoantibody to the granulocyte-macrophage colony-stimulating factor (GM-CSF), which neutralizes GM-CSF and therefore impairs the differentiation of alveolar macrophages. The authors have previously characterized the BAL fluid and alveolar macrophages obtained from three IPAP patients who were successfully treated with aerosolized GM-CSF and demonstrated restoration of the cell number, expression of surface marker, and phagocytic ability of the alveolar macrophages as well as a decrease in the autoantibody levels in the BAL fluid. The condition recurred in one of the patients after 20 months. This patient underwent a second and third course of GM-CSF inhalation therapy with the same dose and schedule as the first one. Since the second therapeutic intervention did not succeed in producing any improvement in the symptoms and disease markers, the authors used a new nebulizer and a liquid preparation of the drug instead of the lyophilized preparation for the third therapeutic session and this restored the respiratory function considerably. A 6-month maintenance therapeutic regimen with a lower GM-CSF inhalation frequency brought about a further improvement in the disease markers. The results suggest that the efficacy of GM-CSF inhalation therapy might be related to the drug preparation mode, choice of nebulizer, and duration of treatment.

Aerosols↗
PubMed2006

[A case of pulmonary Langerhans cell histiocytosis discovered by CT mass screening and followed by bronchoalveolar lavage].

A 42-year-old woman who had a cigarette index of 420 had many cavitary lesions predominantly in the upper areas of both lungs. The lesions were detected on a health examination using CT. Analysis with bronchofiberscopy showed increased CD1a positive cells in bronchoalveolar fluid (BALF). Histological examination by video-associated lung biopsy demonstrated that both S-100 and vimentin-positive cells were present in the peribronchial fibrotic lesions. From these data, this disease was diagnosed as pulmonary Langerhans cell histiocytosis (PLCH). Three months after the cessation of smoking, the cavity lesions disappeared. As the image findings improved, CD1a positive cells in BALF decreased (4.9% --> 1.8%) and the CD4/CD8 ratio in BALF increased (1.66 --> 6.16). So far, there is no report describing the time course of both CD1a positive cells and CD4/CD8 ratio in BALF after cessation of smoking in PLCH. These findings attract our interest on the PLCH.

Adult↗
PubMed2005

Suppression of metastasis of human pancreatic cancer to the liver by transportal injection of recombinant adenoviral NK4 in nude mice.

NK4, a 4-kringle fragment of hepatocyte growth factor (HGF), is an HGF antagonist that also acts as an angiogenesis inhibitor. NK4 strongly inhibits the infiltration, metastasis, and tumor growth of pancreatic cancer. The aim of our study was to evaluate the antitumor effect of adenovirus-mediated NK4 gene transfer to the liver on hepatic metastasis of pancreatic cancer in vivo. We constructed recombinant adenoviral NK4 (Ad-NK4), which encodes a secreted form of human NK4. Intrasplenic injection of Ad-NK4 induced high and relatively maintained expression of NK4 protein in the liver and suppressed the number and growth of metastatic foci in the liver in a nude mouse model. Microscopically, central necrosis was found even in small metastatic foci in Ad-NK4 treated mice. Immunohistochemical analysis of metastatic tumors showed a remarkable decrease in microvessel density and an increase in the number of apoptotic tumor cells after treatment with Ad-NK4. These results indicate that intraportal injection of Ad-NK4 may be a useful therapeutic modality for the clinical control of hepatic metastasis in pancreatic cancer.

Adenocarcinoma↗
PubMed2005

Infiltration of COX-2-expressing macrophages is a prerequisite for IL-1 beta-induced neovascularization and tumor growth.

Inflammatory angiogenesis is a critical process in tumor progression and other diseases. The inflammatory cytokine IL-1beta promotes angiogenesis, tumor growth, and metastasis, but its mechanisms remain unclear. We examined the association between IL-1beta-induced angiogenesis and cell inflammation. IL-1beta induced neovascularization in the mouse cornea at rates comparable to those of VEGF. Neutrophil infiltration occurred on day 2. Macrophage infiltration occurred on days 4 and 6. The anti-Gr-1 Ab-induced depletion of infiltrating neutrophils did not affect IL-1beta- or VEGF-induced angiogenesis. The former was reduced in monocyte chemoattractant protein-1-deficient (MCP-1(-/-)) mice compared with wild-type mice. After day 4, clodronate liposomes, which kill macrophages, reduced IL-1beta-induced angiogenesis and partially inhibited VEGF-induced angiogenesis. Infiltrating macrophages near the IL-1beta-induced neovasculature were COX-2 positive. Lewis lung carcinoma cells expressing IL-1beta (LLC/IL-1beta) developed neovasculature with macrophage infiltration and enhanced tumor growth in wild-type but not MCP-1(-/-) mice. A COX-2 inhibitor reduced tumor growth, angiogenesis, and macrophage infiltration in LLC/IL-1beta. Thus, macrophage involvement might be a prerequisite for IL-1beta-induced neovascularization and tumor progression.

Animals↗
PubMed2005

Granulocyte-macrophage colony-stimulating factor and lung immunity in pulmonary alveolar proteinosis.

The anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody is inferred to cause idiopathic pulmonary alveolar proteinosis (iPAP): the antibody neutralizes GM-CSF and thereby impairs differentiation of alveolar macrophages. Administration of GM-CSF improves respiratory function of patients with iPAP, as confirmed in this study using aerosolized GM-CSF. To elucidate its mechanism, we characterized bronchoalveolar lavage fluid and alveolar macrophages obtained from three patients with iPAP who were treated successfully with aerosolized GM-CSF. Cell number, expressions of surface mannose receptor and the transcription factor PU.1, and phagocytic ability of alveolar macrophages were all restored to control levels. With treatment, the neutralizing capacity of GM-CSF activity was reduced markedly, concomitant with the decreasing autoantibody levels. Interestingly, the amount of GM-CSF autoantibody complex also decreased. In one case in which the complex was analyzed, the majority of GM-CSF binding the complex was endogenous protein, suggesting that the complex is removed immediately from the lung after treatment. Our study shows that GM-CSF administration engenders a decrease in the neutralizing capacity against the protein in the lungs. Thereby, it facilitates restoration of the normal function of alveolar macrophages.

Administration, Inhalation↗