Diagnostic Value of Galectin-3, HBME-1, Cytokeratin 19, High Molecular Weight Cytokeratin, Cyclin D1 and p27kip1 in the Differential Diagnosis of Thyroid Nodules

The distinction between benign and malignant thyroid tumors is critical for the management of patients with thyroid nodules. We applied immunohistochemical staining for galectin-3, HBME-1, cytokeratin 19 (CK19), high molecular weight cytokeratin (HMWCK), cyclin D1 and p27kip1 in 295 thyroid lesions to determine their diagnostic accuracy. The expression of all markers was significantly associated with differentiated thyroid carcinoma (DTC).The sensitivity for the diagnosis of DTC was 94.7% with galectin-3, 91.3% with HBME-1, and 90.3% with CK19. The specificities of these markers were 95.5%, 69.7%, and 83.1%, respectively. Combining these markers, co-expression of galectin-3 and CK19 or galectin-3 and HBME-1 was seen in 93.2% of carcinomas but in none of the benign nodules. Comparing follicular variant of papillary carcinoma (FVPC) with follicular carcinoma (FC), the expression of galectin-3, CK19, and HMWCK was significantly higher in FVPC. When comparing FC with FA, the expression of galectin-3 and HBME-1 was significantly higher in FC. These results suggest that 1) galectin-3 is a useful marker in the distinction between benign and malignant thyroid tumors, 2) the combined use of HBME-1 and CK19 can increase the diagnostic accuracy, and 3) the use of CK19 and HMWCK can aid in the differential diagnosis between PC and FC

Therapeutic Co-targeting of WEE1 and ATM Downregulates PD-L1 Expression in Pancreatic Cancer

Purpose Pancreatic cancer (PC) is one of the most lethal cancers worldwide, but there are currently no effective treatments. The DNA damage response (DDR) is under investigation for the development of novel anti-cancer drugs. Since DNA repair pathway alterations have been found frequently in PC, the purpose of this study was to test the DDR-targeting strategy in PC using WEE1 and ATM inhibitors. Materials and Methods We performed in vitro experiments using a total of ten human PC cell lines to evaluate antitumor effect of AZD1775 (WEE1 inhibitor) alone or combination with AZD0156 (ATM inhibitor). We established Capan-1-mouse model for in vivo experiments to confirm our findings. Results In our research, we found that WEE1 inhibitor (AZD1775) as single agent showed anti-tumor effects in PC cells, however, targeting WEE1 upregulated p-ATM level. Here, we observed that co-targeting of WEE1 and ATM acted synergistically to reduce cell proliferation and migration, and to induce DNA damage in vitro. Notably, inhibition of WEE1 or WEE1/ATM downregulated programmed cell death ligand 1 expression by blocking glycogen synthase kinase-3 beta serine 9 phosphorylation and decrease of CMTM6 expression. In Capan-1 mouse xenograft model, AZD1775 plus AZD0156 (ATM inhibitor) treatment reduced tumor growth and downregulated tumor expression of programmed cell death ligand 1, CMTM6, CD163, and CXCR2, all of which contribute to tumor immune evasion. Conclusion Dual blockade of WEE1 and ATM might be a potential therapeutic strategy for PC. Taken together, our results support further clinical development of DDR-targeting strategies for PC.

A Rare Duodenal Subepithelial Tumor: Duodenal Schwannoma

Schwannomas are uncommon neoplasms that arise from Schwann cells of the neural sheath. Gastrointestinal schwannomas are rare among mesenchymal tumors of the gastrointestinal tract, and only a few cases have been reported to date. Duodenal schwannomas are usually discovered incidentally and achieving a preoperative diagnosis is difficult. Schwannomas can be distinguished from other subepithelial tumors on endoscopic ultrasonography; however, any typical endosonographic features of duodenal schwannomas have not been reported due to the rarity of these tumors. Immunohistochemistry is essential to distinguish schwannomas from gastrointestinal stromal tumors and leiomyomas. We report a case of duodenal schwannoma found incidentally during a health check-up endoscopy. On endoscopic ultrasonography, this tumor was suspected as a gastrointestinal stromal tumor; therefore, the patient underwent laparoscopic wedge resection of the tumor. Histopathology and immunohistochemistry confirmed that the duodenal lesion was a benign schwannoma

Induction of IL-10-producing CD4(+)CD25(+ )T cells in animal model of collagen-induced arthritis by oral administration of type II collagen

Induction of oral tolerance has long been considered a promising approach to the treatment of chronic autoimmune diseases, including rheumatoid arthritis (RA). Oral administration of type II collagen (CII) has been proven to improve signs and symptoms in RA patients without troublesome toxicity. To investigate the mechanism of immune suppression mediated by orally administered antigen, we examined changes in serum IgG subtypes and T-cell proliferative responses to CII, and generation of IL-10-producing CD4(+)CD25(+ )T-cell subsets in an animal model of collagen-induced arthritis (CIA). We found that joint inflammation in CIA mice peaked at 5 weeks after primary immunization with CII, which was significantly less in mice tolerized by repeated oral feeding of CII before CIA induction. Mice that had been fed with CII also exhibited increased serum IgG(1 )and decreased serum IgG(2a )as compared with nontolerized CIA animals. The T-cell proliferative response to CII was suppressed in lymph nodes of tolerized mice also. Production of IL-10 and of transforming growth factor-β from mononuclear lymphocytes was increased in the tolerized animals, and CD4(+ )T cells isolated from tolerized mice did not respond with induction of IFN-γ when stimulated in vitro with CII. We also observed greater induction of IL-10-producing CD4(+)CD25(+ )subsets among CII-stimulated splenic T cells from tolerized mice. These data suggest that when these IL-10-producing CD4(+)CD25(+ )T cells encounter CII antigen in affected joints they become activated to exert an anti-inflammatory effect

Regional outbreak of staphylococcal scalded skin syndrome in healthy children

Purpose : Staphylococcal scalded skin syndrome (SSSS) is a relatively uncommon superficial blistering skin disease that is due to Staphylococcus aureus. We had experienced a regional outbreak of SSSS over 3 years in healthy children. Methods : We retrospectively reviewed the medical records of those patients diagnosed as SSSS. Most of neonatal cases were nosocomial infections and excluded from the analysis. The clinical features, laboratory findings, the isolation and antibiotic resistance of S. aureus, the antibiotic management and other supportive treatments were analyzed. Results : Fifty-five patients with SSSS were admitted to our hospital from October 2001 to September 2004. The median age of patients was 3.0 years. Of the 55 patients, 9 were the generalized type, 13 were the intermediate type and 33 were the scarletiniform rash. All the patients were living in neighborhood of the Jinju area. S. aureus were isolated from 9 of the patients and all of the isolated S. aureus were methicillin resistant. All the patients except two were treated with intravenous flocloxacillin or nafcillin and/or cefotaxime. All the patients recovered during the follow-up period of 2 to 3 weeks. Conclusion : We experienced a regional outbreak of SSSS in previous healthy children. Further study for finding the carriers of S. aureus caused SSSS and preventing the spread of this disease is needed. Additionally, guidelines for treating SSSS due to methicillin resistant S. aureus should be established

Histological confinement of transglutaminase-mediated nit sheath crosslinking is essential for proper oviposition and egg coating in the human head louse, Pediculus humanus capitis

Background Head louse females secrete liquid gel, which is mainly composed of the louse nit sheath protein 1 (LNSP1) and LNSP2, when they lay eggs. The gel is crosslinked by transglutaminase (TG) to form the nit sheath, which covers most of the egg except the top operculum area where breathing holes are located. Knowledge on the selective mechanism of nit sheath solidification to avoid uncontrolled crosslinking could lead to designing a novel method of louse control, but no information is available yet. Methods To elucidate the crosslinking mechanisms of nit sheath gel inside the reproductive system of head louse females, in situ hybridization in conjunction with microscopic observation of the oviposition process was conducted. Results Histochemical analysis revealed that LNSP1 and LNSP2 are expressed over the entire area of the accessory gland and uterus, whereas TG expression site is confined to a highly localized area around the opening of posterior oviduct. Detailed microscopic observations of oviposition process uncovered that a mature egg is positioned in the uterus after ovulation. Once aligned inside the uterus, the mature egg is redirected so that its operculum side is tightly held by the ventral end of the uterus being positioned toward the head again and its pointed bottom end being positioned toward the dorsal end of the uterus, which functions as a reservoir for the nit sheath gel. Conclusions Physical separation of the TG-mediated crosslinking site from the ventral end of the uterus is necessary to avoid uncontrolled crosslinking inside the uterus and to ensure selective crosslinking over only the lower part of egg without any unwanted crosslinking over the operculum during oviposition. Graphical Abstrac

A multicenter phase II study of everolimus in patients with progressive unresectable adenoid cystic carcinoma

BACKGROUND: The aim of this study was to examine the efficacy and safety of everolimus in patients with progressive unresectable adenoid cystic carcinoma (ACC). METHODS: Histologically confirmed ACC patients with documented disease progression within 12 months prior to the study entry were eligible. Everolimus was given at a dose of 10 mg daily until progression or occurrence of unacceptable toxicities. The primary endpoint was a 4-month progression-free survival (PFS). RESULTS: A total of 34 patients were enrolled. The 4-month PFS probability was 65.5% (95% one-sided confidence interval [CI], 47.7 to infinity). Median PFS duration was 11.2 months (95% CI, 3.6 to 15.8). Complete or partial response was not achieved. Twenty-seven (79.4%, 95% CI, 63.2 to 89.6) patients showed stable disease (SD). Tumor shrinkage within SD criteria was observed in 15 patients (44.1%) and SD lasting 6 months was observed in 13 patients (38.2%). Four patients had disease progression. Among the 18 patients with both pre- and post-treatment (at 8 weeks) FDG-PET scans available, 8 patients (44.4%) showed a partial metabolic response, defined as a ≥25% reduction in maximum standardized uptake values (SUVmax). The most common adverse events were stomatitis, anemia, asthenia, and leukopenia. No unexpected everolimus related toxicities were reported. CONCLUSIONS: Everolimus showed promising efficacy and good tolerability in progressive unresectable ACC. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT0115284