Effect of Suplatast Tosilate on Antileukotriene Non-Responders with Mild-to-Moderate Persistent Asthma

ABSTRACTBackgroundImmunomodulatory therapy has been recently introduced for the management of asthma. Suplatast tosilate (ST), a new immune-modifying drug, is known to improve the airway function by inhibiting the release of Th-2 cytokines. However, its efficacy as a controller listed in the guideline, Global Initiative for Asthma 2005 has not been established. In this study we investigated the role of ST in leukotriene receptor antagonist (LTRA) non-responders with mild-to-moderate persistent asthma before initiating corticosteroids inhalation therapy.MethodsThis was a prospective open-level clinical trial. LTRAs was given to 41 patients with asthma for 4 weeks and clinical efficacy was assessed using daily symptom scores. The 10 patients, aged 2.5-8.5 years, who failed to show clinical improvement, were defined as LTRA non-responders. After a 1-week washout period, the efficacy of ST was investigated and compared with LTRA non-responders for the following 4 weeks.ResultsLTRA non-responders showed a significant improvement in the average symptom score, peak expiratory flow, use of rescue medication and the proportion of symptom-free days with ST therapy.ConclusionsST is a good choice for patients who have failed to respond to LTRAs. ST should therefore be added to the list of treatment options for such patients

Periostin Promotes Tumor Lymphangiogenesis

Background: Metastasis to regional lymph nodes via lymphatic vessels plays a key role in cancer progression. Tumor lymphangiogenesis is known to promote lymphatic metastasis, and vascular endothelial growth factor C (VEGF-C) is a critical activator of tumor lymphangiogenesis during the process of metastasis. We previously identified periostin as an invasion- and angiogenesis-promoting factor in head and neck squamous cell carcinoma (HNSCC). In this study, we discovered a novel role for periostin in tumor lymphangiogenesis. Methods and Findings: Periostin overexpression upregulated VEGF-C mRNA expression in HNSCC cells. By using conditioned media from periostin-overexpressing HNSCC cells, we examined tube formation of lymphatic endothelial cells. Conditioned media from periostin-overexpressing cells promoted tube formation. To know the correlation between periostin and VEGF-C, we compared Periostin expression with VEGF-C expression in 54 HNSCC cases by immunohistochemistry. Periostin expression was correlated well with VEGF-C expression in HNSCC cases. Moreover, correlation between periostin and VEGF-C secretion was observed in serum from HNSCC patients. Interestingly, periostin itself promoted tube formation of lymphatic endothelial cells independently of VEGF-C. Periostin-promoted lymphangiogenesis was mediated by Src and Akt activity. Indeed possible correlation between periostin and lymphatic status in periostin-overexpressing xenograft tumors and HNSCC cases was observed. Conclusions: Our findings suggest that periostin itself as well as periostin-induced upregulation of VEGF-C may promote lymphangiogenesis. We suggest that periostin may be a marker for prediction of malignant behaviors in HNSCC and a potential target for future therapeutic intervention to obstruct tumoral lymphatic invasion and lymphangiogenesis in HNSCC patients

MMP-10/Stromelysin-2 Promotes Invasion of Head and Neck Cancer

Background: Periostin, IFN-induced transmembrane protein 1 (IFITM1) and Wingless-type MMTV integration site family, member 5B (Wnt-5b) were previously identified as the invasion promoted genes of head and neck squamous cell carcinoma(HNSCC) by comparing the gene expression profiles between parent and a highly invasive clone. We have previously reported that Periostin and IFITM1 promoted the invasion of HNSCC cells. Here we demonstrated that Wnt-5b overexpression promoted the invasion of HNSCC cells. Moreover, stromelysin-2 (matrix metalloproteinase-10; MMP-10) was identified as a common up-regulated gene among Periostin, IFITM1 and Wnt-5b overexpressing HNSCC cells by using microarray data sets. In this study, we investigated the roles of MMP-10 in the invasion of HNSCC. Methods and Findings: We examined the expression of MMP-10 in HNSCC cases by immunohistochemistry. High expression of MMP-10 was frequently observed and was significantly correlated with the invasiveness and metastasis in HNSCC cases. Next, we examined the roles of MMP-10 in the invasion of HNSCC cells in vitro. Ectopic overexpression of MMP-10 promoted the invasion of HNSCC cells, and knockdown of MMP-10 suppressed the invasion of HNSCC cells. Moreover, MMP-10 knockdown suppressed Periostin and Wnt-5b-promoted invasion. Interestingly, MMP-10 overexpression induced the decreased p38 activity and MMP-10 knockdown induced the increased p38 activity. In addition, treatment with a p38 inhibitor SB203580 in HNSCC cells inhibited the invasion. Conclusions: These results suggest that MMP-10 plays an important role in the invasion and metastasis of HNSCC, and that invasion driven by MMP-10 is partially associated with p38 MAPK inhibition. We suggest that MMP-10 can be used as a marker for prediction of metastasis in HNSCC

microRNA-203 suppresses invasion and epithelial-mesenchymal transition induction via targeting NUAK1 in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) has a high capacity for invasion. To identify microRNAs (miRNAs) that regulate HNSCC invasion, we compared miRNA expression profiles between a parent HNSCC cell line and a highly invasive clone. The miR-200 family and miR-203 were downregulated in the clone. Here we focused on the role of miR-203 in invasion and epithelial-mesenchymal transition (EMT) induction in HNSCC. miR-203 was downregulated during EMT induction. Moreover, ectopic overexpression of miR-203 suppressed the invasion and induced mesenchymal-epithelial transition (MET) in HNSCC cells. Interestingly, we identified NUAK family SNF1-like kinase 1 (NUAK1) as a novel target gene of miR-203 by cyclopedic analysis using anti-Ago2 antibody. Increased expression of NUAK1 was observed during EMT induction, and ectopic expression of miR-203 delayed EMT induction by suppressing NUAK1 expression. Moreover, NUAK1 overexpression promoted the invasion of HNSCC cells. Importantly, NUAK1 expression was well correlated with poor differentiation, invasiveness, and lymph node metastasis in HNSCC cases. Overall, miR-203 has a tumor-suppressing role in invasion and EMT induction by targeting NUAK1 in HNSCC, suggesting miR-203 as a potential new diagnostic and therapeutic target for the treatment of HNSCC

ダイモウ ゲンパツ キョダイ GIST 1セツジョレイ

We report a case of giant gastrointestinal stromal tumor（GIST）primarily occurred in the greater omentum. A７８-year-old woman was referred to our hospital because of a giant abdominal tumor. Contrast-enhanced abdominal computed tomography（CT）showed a giant tumor measuring ２０×２４×１３cm in diameter in the abdominal cavity, consisting of heterogeneously enhanced solid and cystic lesions. Abdominal magnetic resonance imaging（MRI）after ３ weeks from the first medical examination showed the enlarged tumor measuring２４×２５×１７cm in diameter, the intensity of the solid lesion was low on T１weighted image, heterogeneously enhanced on T２weighted image and high on diffusion weighted image. At surgery, we confirmed the giant tumor continued to the omentum, and pressured the stomach, pancreas, and colon. The resected specimen weighed ８，３２５g containing of５，６４０ml of red-brown fluid. Histological examination showed the tumor consisted of proliferated spindle cells in a fascicular pattern and polynesic hemorrhage and necrosis. Immunohistochemically, the tumor cells were positive for c-kit and CD３４, and negative for S‐１００ protein and desmin, indicating a GIST in the greater omentum. The mitotic figures were in a４０／５０ high power field. In genetic testing, the tumor cells had exon１１mutation of c-kit gene. The woman started taking imatinib after operation and remains alive and recurrence-free

microRNA-203 suppresses invasion and epithelial-mesenchymal transition induction via targeting NUAK1 in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) has a high capacity for invasion. To identify microRNAs (miRNAs) that regulate HNSCC invasion, we compared miRNA expression profiles between a parent HNSCC cell line and a highly invasive clone. The miR-200 family and miR-203 were downregulated in the clone. Here we focused on the role of miR-203 in invasion and epithelial-mesenchymal transition (EMT) induction in HNSCC. miR-203 was downregulated during EMT induction. Moreover, ectopic overexpression of miR-203 suppressed the invasion and induced mesenchymal-epithelial transition (MET) in HNSCC cells. Interestingly, we identified NUAK family SNF1-like kinase 1 (NUAK1) as a novel target gene of miR-203 by cyclopedic analysis using anti-Ago2 antibody. Increased expression of NUAK1 was observed during EMT induction, and ectopic expression of miR-203 delayed EMT induction by suppressing NUAK1 expression. Moreover, NUAK1 overexpression promoted the invasion of HNSCC cells. Importantly, NUAK1 expression was well correlated with poor differentiation, invasiveness, and lymph node metastasis in HNSCC cases. Overall, miR-203 has a tumor-suppressing role in invasion and EMT induction by targeting NUAK1 in HNSCC, suggesting miR-203 as a potential new diagnostic and therapeutic target for the treatment of HNSCC

Peroxisome proliferator-activated receptor activity is involved in the osteoblastic differentiation regulated by bone morphogenetic proteins and tumor necrosis factor-α.

Recent studies have suggested possible adverse effects of thiazolidinediones on bone metabolism. However, the detailed mechanism by which the activity of PPAR affects bone formation has not been elucidated. Impaired osteoblastic function due to cytokines is critical for the progression of inflammatory bone diseases. In the present study, we investigated the cellular mechanism by which PPAR actions interact with osteoblast differentiation regulated by BMP and TNF-alpha using mouse myoblastic C2C12 cells. BMP-2 and -4 potently induced the expression of various bone differentiation markers including Runx2, osteocalcin, type-1 collagen and alkaline phosphatase (ALP) in C2C12 cells. When administered in combination with a PPAR alpha agonist (fenofibric acid) but not with a PPAR gamma agonist (pioglitazone), BMP-4 enhanced osteoblast differentiation through the activity of PPAR alpha. The osteoblastic changes induced by BMP-4 were readily suppressed by treatment with TNF-alpha. Interestingly, the activities of PPAR alpha and PPAR gamma agonists reversed the suppression by TNF-alpha of osteoblast differentiation induced by BMP-4. Furthermore, TNF-alpha-induced phosphorylation of MAPKs, NF kappa B, I kappa B and Stat pathways was inhibited in the presence of PPAR alpha and PPAR gamma agonists with reducing TNF-alpha receptor expression. In view of the finding that inhibition of SAPK/JNK. Stat and NF kappa B pathways reversed the TNF-alpha suppression of osteoblast differentiation, we conclude that these cascades are functionally involved in the actions of PPARs that antagonize TNF-alpha-induced suppression of osteoblast differentiation. It was further discovered that the PPAR alpha agonist enhanced BMP-4-induced Smad1/5/8 signaling through downregulation of inhibitory Smad6/7 expression, whereas the PPAR gamma agonist impaired this activity by suppressing BMPRII expression. On the other hand, BMPs increased the expression levels of PPAR alpha and PPAR gamma in the process of osteoblast differentiation. Thus, PPAR alpha actions promote BMP-induced osteoblast differentiation, while both activities of PPAR alpha and PPAR gamma suppress TNF-alpha actions. Collectively, our present data establishes that PPAR activities are functionally involved in modulating the interaction between the BMP system and TNF-alpha receptor signaling that is crucial for bone metabolism

タンカンナイ シュヨウセン オ ミトメ ゲンパツセイ カンナイ タンカンガン トノ カンベツ オ ヨウシタ イジセイ ダイチョウガン カンテンイ ノ 1セツジョレイ

The patient was a 68-year-old man who had undergone right hemicolectomy for ascending colon cancer, and pulmonary resection for lung metastases. After 10 months of operations, abdominal computed tomograms revealed a liver tumor with a biliary tumor thrombus in the segment 5 and a localized dilation of the intrahepatic bile duct. Endoscopic retrograde cholangiopancreatography showed obstruction, 2cm long, of the intrahepatic bile duct （B5） and dilation of the peripheral duct. Cytological examination of extracted bile showed adenocarcinoma. A right hepatic lobectomy was performed under the diagnosis of metastatic liver tumor with tumor development in the intrahepatic bile duct or intrahepatic cholangiocarcinoma. The resected specimen showed massive infiltration of the tumor into intrahepatic bile duct （B5） with forming a tumor thrombus. Histologically, the tumor was moderately differentiated adenocarcinoma, similar to the ascending colon cancer. The final diagnosis was liver metastasis of ascending colon cancer with intrabiliary tumor growth