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Purpose The discoidin domain-containing receptor tyrosine kinase 2 (DDR2) is known to contain mutations in a small subset of patients with squamous cell carcinomas (SCC) of the lung. Studying the DDR2 mutations in patients with SCC of the lung would advance our understanding and guide the development of therapeutic strategies against lung cancer. Materials and methods We selected 100 samples through a preliminary genetic screen, including specimens from biopsies and surgical resection, and confirmed SCC by histologic examination. DDR2 mutations on exons 6, 15, 16, and 18 were analyzed by Sanger sequencing of formalin-fixed, paraffin-embedded tissue samples. The functional effects of novel DDR2 mutants were confirmed by in vitro assays. Results We identified novel somatic mutations of DDR2 in two of the 100 SCC samples studied. One mutation was c.1745T>A (p.V582E) and the other was c.1784T>C (p.L595P), and both were on exon 15. Both patients were smokers and EGFR/KRAS/ALK-triple negative. The expression of the mutant DDR2 induced activation of DDR2 by the collagen ligand and caused enhanced cell growth and tumor progression. Moreover, dasatinib, a DDR2 inhibitor, showed potential efficacy against DDR2 L595P mutant-bearing cells. Conclusion Our results suggest that a mutation in DDR2 occurs naturally with a frequency of about 2% in Korean lung SCC patients. In addition, we showed that each of the novel DDR2 mutations were located in a kinase domain and induced an increase in cell proliferation rate.

Accumulating evidence suggests that the non-receptor tyrosine kinase c-Abl plays an important role in the progression of Parkinson's disease (PD) and c-Abl inhibition could be neuroprotective in PD and related α-synucleinopathies. Nilotinib, a c-Abl inhibitor, has shown improved motor and cognitive symptoms in PD patients. However, issues concerning blood-brain barrier (BBB) penetration, lack of selectivity and safety still remain. Radotinib HCl is a selective Bcr-Abl kinase inhibitor that not only effectively access the brain, but also exhibits greater pharmacokinetic properties and safety profiles compared to Nilotinib and other c-Abl inhibitors. Here, we show the neuroprotective efficacy of Radotinib HCl, a brain penetrant c-Abl inhibitor, in a pre-clinical model of PD. Importantly, in vitro studies demonstrate that the treatment of Radotinib HCl protects the α-synuclein preformed fibrils (PFF)-induced neuronal toxicity, reduces the α-synuclein PFF-induced Lewy bodies (LB)/Lewy neurites (LN)-like pathology and inhibits the α-synuclein PFF-induced c-Abl activation in primary cortical neurons. Furthermore, administration of Radotinib HCl inhibits c-Abl activation and prevents dopaminergic neuron loss, neuroinflammation and behavioral deficits following α-synuclein PFF-induced toxicity in vivo. Taken together, our findings indicate that Radotinib HCl has beneficial neuroprotective effects in PD and provides an evidence that selective and brain permeable c-Abl inhibitors can be potential therapeutic agents for the treatment of PD and related α-synucleinopathies.

Kim T, Jung E A, Song J Y, Roh J H, Choi J S, Kwon J E, Kang S Y, Cho E Y, Shin J H, Nam S-J, Yang J H & Choi Y-L (2012) Histopathology 60, 347–356 Prevalence of the CTNNB1 mutation genotype in surgically resected fibromatosis of the breast Aims: To investigate CTNNB1 mutation and β-catenin expression in resected breast fibromatosis and to identify potential molecular markers of fibromatosis of the breast. Methods and results: We selected 12 patients with fibromatosis of the breast who underwent surgical resection and were confirmed by histological examination. Ultrasonography findings for 10 patients were reviewed and only two cases were suspicious for fibromatosis on imaging. On core needle biopsy for pre-operative diagnoses, only three cases were histologically suspicious for fibromatosis. Mutations in exon 3 of CTNNB1 were detected by direct DNA sequencing in nine (75.0%) cases: all were c.121G>A (p.T41A), which was much more frequent in breast fibromatoses than in other soft tissue lesions. Nuclear β-catenin expression was observed in all cases and the level of expression was higher in cases with mutation. In eight of nine cases, the matched biopsy specimen showed the same CTNNB1 mutation status as the pre-operative specimen. Conclusions: In the majority of cases, clinical presentation and breast imaging are highly suspicious for carcinoma. Definitive pre-operative pathological diagnosis by core needle biopsy is difficult. CTNNB1 mutation and nuclear β-catenin expression are frequently detected in sporadic breast fibromatoses, suggesting their potential as a useful tool to distinguish breast fibromatoses from other neoplasms.

To evaluate the antihyperlipidemic activities of Orengedokuto (OT) and Daio-Orengedokuto (DOT), the inhibitory effects of these polyprescriptions on HMG-CoA reductase and pancreatic lipase and on the rat hyperlipidemic model induced by Triton WR-1339 were measured. OT potently inhibited HMG-CoA reductase but did not inhibit lipase. Among their ingredients, Coptidis Rhizoma was the most potent inhibitor, followed by Rhei Rhizoma. The HMG-CoA reductase-inhibitory activity of 80% EtOH extract was superior to that of water extract. However, DOT potently inhibited HMG CoA-reductase as well as pancreatic lipase. In the rat hyperlipidemic model induced by Triton WR-1339, OT and DOT decreased serum total cholesterol and low-density lipoprotein cholesterol levels. DOT also decreased serum triglyceride levels, but OT did not decrease it. These results suggest that the antihyperlipidemic activity of DOT may originate from the inhibition of pancreatic lipase as well as HMG-CoA reductase.

Polysaccharide lyases that can degrade glycosaminoglycans (GAGs) were identified in an anaerobic strain living in the human intestine. The strain was isolated from the stool of a healthy male and identified as Bacteroides sp. strain HJ-15. A detailed taxonomical study indicated the species is a strain of Bacteroides stercoris. The isolate was cultured and the polysaccharide lyase activity was partially purified. This enzyme preparation could act on GAGs containing either glucosamine or galactosamine suggesting the presence of both heparinases and chondroitinases. Various GAGs were incubated with the partially purified enzyme and the products formed were analyzed by strong anion-exchange high performance liquid chromatography and proton nuclear magnetic resonance spectroscopy. These studies demonstrated the presence of at least two types of polysaccharide lyases: heparin lyase and chondroitin sulfate lyase. The eliminative mechanism of these lyase enzymes was confirmed through the isolation of unsaturated disaccharide products. The heparin lyase acted on both heparin and acharan sulfate, a GAG recently isolated from Achatina fulica. The Bacteroides chondroitin lyase, acted on chondroitin sulfates A, B (dermatan sulfate), and C, resembling chondroitin lyase ABC. The presence of a GAG-degrading organism in human intestine may pose problems for the effective oral administration of GAG drugs.Key words: Bacteroides stercoris, glycosaminoglycan, nuclear magnetic resonance spectroscopy, polysaccharide lyase, heparinase, chondroitinase.

Polysaccharide lyases that can degrade glycosaminoglycans (GAGs) were identified in an anaerobic strain living in the human intestine. The strain was isolated from the stool of a healthy male and i...

By human intestinal bacteria, glycyrrhizin (18β-glycyrrhetic acid β-D-glucuronyl α-D-glucuronic acid, GL) and baicalin (baicalein β-D-glucuronic acid) were metabolized to glycyrrhetinic acid and baicalin, respectively. However, α-glucuronidase ofBacteroides JY-6 isolated from human intestinal bacteria hydrolyzed GL or 18β-glycyrrhetinic acid α-D-glucuronic acid to 18β-glycyrrhetic acid but did not baicalin. However,E. coli β-glucuronidase from human intestinal bacteria hydrolyzed baicalin to baicalein, but did not GL. β-Glucuronidase of mammalian tissues hydrolyzed both GL and baicalin.

T-cell lymphoblastic lymphoma is a highly aggressive tumor derived from lymphocyte of the thymus, which accounts for 2% of non-Hodgkin's lymphoma. The disease occurs most commonly in adolescent and young adult males. It often results in respiratory emergency because of high proliferation rate. In this case, we confirmed the rapid progression of T-cell lymphoblastic lymphoma through the chest CT scan with one week interval. Three days of empirical chemotherapy resulted in substantial reduction of mediastinal mass, pleural thickening and pleural effusion.

To investigate CTNNB1 mutation and β-catenin expression in resected breast fibromatosis and to identify potential molecular markers of fibromatosis of the breast.We selected 12 patients with fibromatosis of the breast who underwent surgical resection and were confirmed by histological examination. Ultrasonography findings for 10 patients were reviewed and only two cases were suspicious for fibromatosis on imaging. On core needle biopsy for pre-operative diagnoses, only three cases were histologically suspicious for fibromatosis. Mutations in exon 3 of CTNNB1 were detected by direct DNA sequencing in nine (75.0%) cases: all were c.121GA (p.T41A), which was much more frequent in breast fibromatoses than in other soft tissue lesions. Nuclear β-catenin expression was observed in all cases and the level of expression was higher in cases with mutation. In eight of nine cases, the matched biopsy specimen showed the same CTNNB1 mutation status as the pre-operative specimen.In the majority of cases, clinical presentation and breast imaging are highly suspicious for carcinoma. Definitive pre-operative pathological diagnosis by core needle biopsy is difficult. CTNNB1 mutation and nuclear β-catenin expression are frequently detected in sporadic breast fibromatoses, suggesting their potential as a useful tool to distinguish breast fibromatoses from other neoplasms.

The liver is an extranodal organ that is frequently invaded by lymphomas, with most cases involving secondary lymphomas (1). The image findings of hepatic lymphoma have been reported as variable, ranging from single or multiple nodules to diffuse infiltrates (1, 2). It is known that hepatic lymphomas show low signal intensity on T1 weighted images, high signal intensity on T2 weighted images, and low signal intensity on hepatobiliary phase image, using hepatocyte-specific contrast agents (3, 4). Here, we report an atypical case of hepatic lymphoma showing iso-signal intensity on hepatobiliary phase of contrast-enhanced MRI using gadoxetic acid (Gd-EOB-DTPA, Primovist; Bayer Schering Pharma, Berlin, Germany).

Vascular endothelial growth factor (VEGF) has proven to be one of the most effective growth factors for therapeutic angiogenesis. The biological efficacy of the adeno-associated virus (AAV) vector has recently been demonstrated in muscle tissues, including the heart. Apart from these promising insights into VEGF and the AAV vector, studies on VEGF gene transfer using the AAV vector have been limited. Here, we evaluate AAV-mediated VEGF gene transfer, both in vitro and in vivo, using the AAV-mVEGF vector that contains cDNA for murine VEGF(120) within an HCMV-driven expression cassette. Transient transfection of AAV-mVEGF plasmid significantly increased mVEGF expression in 293T cells. The secreted VEGF in the conditioned medium had strong biological activity, as confirmed by the Miles' vascular permeability assay. Transduction of 293T and HeLa cells with AAV-mVEGF stock of high titer, that is essentially adenovirus-free, showed significantly increased mVEGF expression above that of AAV-eGFP-transduced cells. When human umbilical vein endothelial cells were transduced, a higher level of mVEGF expression, together with higher cell counts, was observed compared to AAV-eGFP-transduced cells. In vivo transduction of mouse tibialis anterior muscle resulted in an increased level of mVEGF expression, and higher capillary-to-myofibre ratio, 8 weeks post-transduction. In a rat hindlimb ischemia model, regional blood flow, as well as the capillary-to-myofibre ratio, was significantly increased at 4 weeks post-transduction. These findings demonstrate the efficient delivery of the VEGF gene using an AAV vector, which has implications for angiogenic gene therapy in ischemic diseases.

Flavonoid glycosides were metabolized to phenolic acids via aglycones by human intestinal microflora producing alpha-rhamnosidase, exo-beta-glucosidase, endo-beta-glucosidase and/or beta-glucuronidase. Rutin, hesperidin, naringin and poncirin were transformed to their aglycones by the bacteria producing alpha-rhamnosidase and beta-glucosidase or endo-beta-glucosidase, and baicalin, puerarin and daidzin were transformed to their aglycones by the bacteria producing beta-glucuronidase, C-glycosidase and beta-glycosidase, respectively. Anti-platelet activity and cytotoxicity of the metabolites of flavonoid glycosides by human intestinal bacteria were more effective than those of the parental compounds. 3,4-Dihydroxyphenylacetic acid and 4-hydroxyl-phenylacetic acid were more effective than rutin and quercetin on anti-platelet aggregation activity. 2,4,6-Trihydroxybenzaldehyde, quercetin and ponciretin were more effective than rutin and ponciretin on the cytotoxicity for tumor cell lines. We insist that these flavonoid glycosides should be natural prodrugs.

Congenital cystic lesions of the lung are uncommon and a conjunction of two or more lesions is very rare. We report here on a case of coexisting intrapulmonary bronchogenic cyst and congenital cystic adenomatoid malformation in a 13-year-old female with a cystic mass in the right upper lobe of the lung. Computed tomography showed a cystic lesion measuring 2.5 cm with an air flu id level and surrounding multicystic lesions in the right upper lobe. On gross examination, the cut surface showed a cystic mass containing inspissated mucinous material, and the cystic mass was surrounded by multiple small cysts. Microscopically, the larger cystic cavity was lined with pseudostratified ciliated columnar epithelium. The submucosal tissue contained mucinous glands and plates of cartilage. The surrounding smaller cysts or irregular spaces were lined with bronchiolartype respiratory epithelium. We propose that this hybrid lung lesion may represent the missing link in a common embryologic pathway determined by the timing of mesenchymal and epithelial interactions.

We report a case of spindle cell epithelioma, a so-called benign mixed tumor of the vagina. The patient was a 35-year-old iparous woman who presented with a polypoid mass in the posterior wall of the lower vagina just above the hymenal ring. The tumor was relatively welldefined with an expansile margin and composed of stromal-type spindle cells with a myxoid stroma arranged in short fascicles and an irregular cord-like or reticular pattern. A few glandular structures lined by cuboidal cells with squamous metaplasia were also noted. Cellular atypia was not conspicuous and mitosis was not found. We examined this tumor immunohistochemically to identify the histogenesis. The coexpression of epithelial and mesenchymal markers in stromal-type spindle cells suggested a multipotential cell origin for this tumor. The patient has been well with no signs of recurrence during the 12 months after surgery.

Background : S100A4 has been implicated in invasion and metastasis of various malignant tumors. The aim of this study was to investigate whether or not S100A4 plays an important role in non-small cell lung carcinomas (NSCLCs). Methods : Sixty-seven patients with NSCLC including 37 with squamous cell carcinomas (SCCs) and 30 with adenocarcinomas (ADs) who had undergone surgical resection were analyzed. S100A4 expression was analyzed by immunohistochemistry using tissue microarray blocks. Results : S100A4 expression was positive in 56 (83.6%) of 67 NSCLC cases. ADs were more frequently S100A4 positive than SCCs (p = 0.017). However, no significant correlation was observed between S100A4 expression and age, gender, pT, pN or tumor, node and metastasis (TNM) stage. Two distant metastatic cases revealed an S100A4 positive reaction. Kaplan-Meier survival curves with the logrank test showed no correlation with 3-year survival (p = 0.782) or 5-year survival (p = 0.227) in either group of patients according to S100A4 expression. Conclusions : S100A4 expression was not correlated with age, gender, pT, pN or TNM stage or survival in patients with NSCLCs. Therefore, S100A4 expression may not be useful as a prognostic marker for NSCLCs. However, S100A4 expression showed a higher positivity in ADs than in SCCs.