Cancer stem cells induced by chronic stimulation with prostaglandin E2 exhibited constitutively activated PI3K axis.

Previously, our group has demonstrated establishment of Cancer Stem Cell (CSC) models from stem cells in the presence of conditioned medium of cancer cell lines. In this study, we tried to identify the factors responsible for the induction of CSCs. Since we found the lipid composition could be traced to arachidonic acid cascade in the CSC model, we assessed prostaglandin E2 (PGE2) as a candidate for the ability to induce CSCs from induced pluripotent stem cells (iPSCs). Mouse iPSCs acquired the characteristics of CSCs in the presence of 10 ng/mL of PGE2 after 4 weeks. Since constitutive Akt activation and pik3cg overexpression were found in the resultant CSCs, of which growth was found independent of PGE2, chronic stimulation of the receptors EP-2/4 by PGE2 was supposed to induce CSCs from iPSCs through epigenetic effect. The bioinformatics analysis of the next generation sequence data of the obtained CSCs proposed not only receptor tyrosine kinase activation by growth factors but also extracellular matrix and focal adhesion enhanced PI3K pathway. Collectively, chronic stimulation of stem cells with PGE2 was implied responsible for cancer initiation enhancing PI3K/Akt axis.

Nanoparticles Containing Curcumin Useful for Suppressing Macrophages In Vivo in Mice.

To explore a novel method using liposomes to suppress macrophages, we screened food constituents through cell culture assays. Curcumin was one of the strongest compounds exhibiting suppressive effects on macrophages. We subsequently tried various methods to prepare liposomal curcumin, and eventually succeeded in preparing liposomes with sufficient amounts of curcumin to suppress macrophages by incorporating a complex of curcumin and bovine serum albumin. The diameter of the resultant nanoparticles, the liposomes containing curcumin, ranged from 60 to 100 nm. Flow cytometric analyses revealed that after intraperitoneal administration of the liposomes containing curcumin into mice, these were incorporated mainly by macrophages positive for F4/80, CD36, and CD11b antigens. Peritoneal cells prepared from mice injected in vivo with the liposomes containing curcumin apparently decreased interleukin-6-producing activities. Major changes in body weight and survival rates in the mice were not observed after administrating the liposomes containing curcumin. These results indicate that the liposomes containing curcumin are safe and useful for the selective suppression of macrophages in vivo in mice.

The novel Rac effector RIN-1 regulates neuronal cell migration and axon pathfinding in C. elegans.

Cell migration and axon guidance require proper regulation of the actin cytoskeleton in response to extracellular guidance cues. Rho/Rac small GTPases are essential regulators of actin remodeling. Caenorhabditis elegans CED-10 is a Rac1 homolog that is required for various cellular morphological changes and migration events and is under the control of several guidance signaling pathways. There is still considerable uncertainty regarding events following the activation of guidance receptors by extracellular signals and the regulation of actin dynamics based on spatiotemporally restricted Rac activity. Here we show that the VPS9 domain protein RIN-1 acts as a novel effector for CED-10 in C. elegans. The orthologous mammalian Rin1 protein has previously been identified as an effector for Ras GTPase and is now known to function as a guanine nucleotide exchange factor for Rab5 GTPase. We found that RIN-1 specifically binds to the GTP-bound form of CED-10 and that mutations in rin-1 cause significant defects in migration and axon guidance of restricted neuronal cell types including AVM and HSN neurons, in contrast to the various defects observed in ced-10 mutants. Our analyses place RIN-1 in the Slit-Robo genetic pathway that regulates repulsive signaling for dorsoventral axon guidance. In rin-1 mutants, actin accumulated on both the ventral and dorsal sides of the developing HSN neuron, in contrast to its ventral accumulation in wild type. These results strongly suggest that RIN-1 acts as an effector for CED-10/Rac1 and regulates actin remodeling in response to restricted guidance cues.

Colonoscopic findings and pathologic characteristics of Strongyloides colitis: a case series.

BACKGROUND/AIMS: Strongyloidiasis, which is caused by Strongyloides stercoralis, is one of the prevalent infections in the tropical and subtropical regions worldwide. The larvae mainly infect the small intestine and cause serious disseminated strongyloidiasis. Although upper gastrointestinal features in strongyloidiasis are well known, colonoscopic evaluation has not been established yet. The aim of this study is to clarify the characteristic findings on colonic lesions in strongyloidiasis. METHOD: From January 2005 to December 2009, 10 cases with strongyloidiasis underwent colonoscopy at a single center on an endemic island of Japan. The clinical and colonoscopic findings were analyzed retrospectively. RESULTS: Six (60%) cases had an immunocompromised condition, including human T lymphotropic virus type 1 infection, corticosteroids, and chemotherapy. Hyperinfection or disseminated strongyloidiasis was not presented. Endoscopic features included yellowish-white nodules, erythema, and loss of vascular pattern, which were mainly observed in the right colon. Pathological examination revealed the filariform Strongyloides larvae and the eosinophilic infiltration of the lamina propria. CONCLUSION: This study demonstrates that colonoscopic observation and biopsies are very useful to diagnose strongyloidiasis. Asymptomatic cases with strongyloidiasis can have colonic involvement. Yellowish-white nodules may be a characteristic finding of colonic lesions in strongyloidiasis and can be a cautious marker to prevent fatal disseminated strongyloidiasis in endemic regions.

Development of an active targeting liposome encapsulated with high-density colloidal gold for transmission electron microscopy.

Active targeting of the liposome is an attractive strategy for drug delivery and in vivo bio-imaging. We previously reported the specific accumulation of Sialyl Lewis X (SLX) liposome to inflamed tissue in arthritic model mice or tumor-bearing mice. SLX-liposome encapsulation with fluorescent substances allows for the visualization of these liposomes by the time-dependent transvascular accumulation of fluorescent signals in the histological sections. In the present study, we developed a new SLX-liposome encapsulated with colloidal gold for transmission electron microscopic observation. We herein describe the characterization of the colloidal gold-loaded SLX-liposomes and demonstrate its specific targeting to the endothelial cells of tumor blood vessels in tumor-bearing mice.

[Case report: periodical infliximab administration enabled closure of colostomy in fistulating perianal Crohn's disease].

A 29-year old woman with Crohn's disease was performed colostomy due to severe perianal abscess. Her disease had been easy to recur and she was admitted to hospital for intestinal bleeding caused by acute exacerbation in Crohn's disease on October 2006. The bleeding was stopped rapidly and clinical remission was maintained with bimonthly administration of infliximab. Finally, her colostomy was closed after 5 years 8 months. Periodical treatment of infliximab not only prevented recurrence but also enabled closure of colostomy in fistulating perianal Crohn's disease.

Novel biodegradable stents for benign esophageal strictures following endoscopic submucosal dissection.

The application of metallic stents for benign stenosis is limited due to long-term complications. We report here the results of the implantation of a novel biodegradable poly-L-lactic acid (PLLA) esophageal stent in two patients with benign esophageal stenosis after endoscopic submucosal dissection (ESD). Case 1 was a 64-year-old man who received ESD for an early squamous esophageal cancer in the middle esophagus. The mucosal defect was seven-eighths of the circumference, and the distal margin of the resection scar formed the stenosis. After balloon dilatation, the PLLA esophageal stent was endoscopically placed; for 6 months, he has not experienced any symptoms of re-stenosis. Case 2 consisted of a 62-year-old man who developed an early squamous esophageal cancer in the middle esophagus. The lesion was resected by ESD, and the mucosal defect was seven-eighths of the circumference. The resection scar formed the stenosis, and the PLLA esophageal stent was endoscopically placed. He also has not experienced any symptoms of re-stenosis for 6 months. In conclusion, the PLLA esophageal stent provides a new possibility for the management of benign esophageal strictures after ESD. Due to the biodegradable features of this stent, longer term studies are necessary to investigate the relationship between the expected disappearance of the stent and the patency of the stricture.

Usefulness of biodegradable stents constructed of poly-l-lactic acid monofilaments in patients with benign esophageal stenosis.

AIM: To report 13 patients with benign esophageal stenosis treated with the biodegradable stent. METHODS: We developed a Ultraflex-type stent by knitting poly-l-lactic acid monofilaments. RESULTS: Two cases were esophageal stenosis caused by drinking of caustic liquid, 4 cases were due to surgical resection of esophageal cancers, and 7 cases were patients with esophageal cancer who received the preventive placement of biodegradable stents for post-endoscopic mucosal dissection (ESD) stenosis. The preventive placement was performed within 2 to 3 d after ESD. In 10 of the 13 cases, spontaneous migration of the stents occurred between 10 to 21 d after placement. In these cases, the migrated stents were excreted with the feces, and no obstructive complications were experienced. In 3 cases, the stents remained at the proper location on d 21 after placement. No symptoms of re-stenosis were observed within the follow-up period of 7 mo to 2 years. Further treatment with balloon dilatation or replacement of the biodegradable stent was not required. CONCLUSION: Biodegradable stents were useful for the treatment of benign esophageal stenosis, particularly for the prevention of post-ESD stenosis.

Accumulation of liposome with Sialyl Lewis X to inflammation and tumor region: application to in vivo bio-imaging.

We prepared the liposome binding Sialyl Lewis X (SLX) on the surface in order to specifically and efficiently deliver substances (fluorescent materials, chemical substances, proteins, genes, etc.) to inflammation or tumor regions. The liposome with SLX (SLX-Lipo-Cy5.5), in which fluorescent substance Cy5.5 was included, was administered intravenously to arthritis or Ehrlich Ascites Tumor (EAT) bearing mouse, and the accumulation of liposome was observed using two types of in vivo fluorescent imaging equipment. The result was that the accumulation of SLX-Lipo-Cy5.5 to inflammation or tumor regions was significantly higher than the control liposome without sugar chain (Lipo-Cy5.5) at 24 and 48 h after administration. In addition, it was confirmed that this accumulation showed a shift of liposome from blood vessels to the surrounding tissues. Thus, it was proven that this liposome is useful not only as an in vivo bio-imaging reagent but also as a drug delivery system (DDS).

Evaluation of mucin expression patterns in gastric borderline (group III) lesions.

BACKGROUND: Recommendations for diagnosis and treatment of gastric borderline (group III) lesions remain controversial. We examined mucin expression patterns in endoscopically resected and forceps biopsy samples. METHODS: Sixty-three gastric lesions were histopathologically identified as belonging to group III on the basis of an endoscopic forceps biopsy. All of the patients underwent endoscopic resection, and the lesions were classified into group A (final diagnosis, adenocarcinoma) or group B (final diagnosis, adenoma). Immunostaining for MUC2, MUC5AC, MUC6, and CD10 was performed and the mucin phenotype determined. An additional 26 forceps biopsy samples from the above 63 patients were similarly evaluated. RESULTS: The proportion of complete gastric (positive for MUC5AC and MUC6) plus gastric-predominant phenotypes was significantly higher in group A (58.0%) than in group B (18.7%) lesions (P < 0.05). The proportion of the complete intestinal (positive for MUC2 and CD10) phenotype was significantly higher in group B (68.8%) than in group A (19.4%) (P < 0.05). Similar results were also observed in the 26 forceps biopsy samples histopathologically diagnosed as group III lesions. The proportion of samples with a diffuse Ki-67 immunostaining pattern was significantly higher in group A than in group B (P < 0.05). p53 expression was significantly higher in group A (29.2%) than in group B (4.3%) (P < 0.05). CONCLUSIONS: Immunostaining of forceps biopsy samples for the mucin phenotype may be helpful for diagnosing gastric borderline (group III) lesions.