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Abnormal autophagic function and activated inflammasomes are typical features in the liver of patients with non-alcoholic steatohepatitis (NASH). Here, we explored whether gemigliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor for treatment of type 2 diabetes, can induce autophagy and regulate inflammasome activation as a potential NASH treatment independent of its anti-diabetic effect. Expression analysis was performed using human liver samples obtained from 18 subjects who underwent hepatectomy. We explored the function and mechanism of gemigliptin using a methionine- and choline-deficient diet (MCD)-induced NASH mouse model and HepG2 cells cultured in MCD-mimicking medium. Autophagy was suppressed by marked decreases in the expression of ULK1 and LC3II/LC3I ratio in human NAFLD/NASH patients, a NASH mouse model, and HepG2 cells cultured with MCD-mimicking media. Surprisingly, we found that the expression of p-AMPK decreased in liver tissues from patients with steatosis but was restored in NASH patients. The expression of p-AMPK in the NASH mouse model was similar to that of the control group. Hence, these results indicate that autophagy was reduced in NASH via an AMPK-independent pathway. However, gemigliptin treatment attenuated lipid accumulation, inflammation, and fibrosis in the liver of MCD diet–fed mice with restoration of ULK1 expression and autophagy induction. In vitro, gemigliptin alleviated inflammasome activation through induction of ULK1-dependent autophagy. Furthermore, gemigliptin treatment upregulated ULK1 expression and activated AMPK even after siRNA-mediated knockdown of AMPKα1/2 and ULK1, respectively. Collectively, these results suggest that gemigliptin ameliorated NASH via AMPK-independent, ULK1-mediated effects on autophagy. • The expression of p-AMPK was restored in NASH patients and NASH mouse models. • The expression level of ULK1 was reduced in liver tissues from NASH patients, NASH mouse models and in vitro model of NASH. • Gemigliptin ameliorated NASH through reduction of inflammsome activation by ULK1-mediated autophagy induction. • Our findings provide promising therapeutic strategies to ameliorate NASH caused by impairment of ULK1-mediated autophagy. [ABSTRACT FROM AUTHOR]

The diagnosis of primary Aspergillus appendicitis can be missed or delayed because of its rarity. We report our experience of a case of Aspergillus appendicitis complicating chemotherapy of leukemia. A 48-year-old man who was diagnosed with acute myeloid leukemia developed high fever and epigastric pain two weeks after administration of his fourth consolidation chemotherapy. Right lower quadrant tenderness and rebound tenderness were noticed on physical examination, and the abdomen and pelvis computed tomography suggested acute perforated appendicitis with localized peritonitis. Emergency laparoscopy showed an inflamed appendix, which was resected. Pathology reports revealed invasive aspergillosis in the appendix. The patient recovered after high-dose antifungal therapy, although he required prolonged hospitalization. Acute appendicitis is very rarely caused by fungi infection with an overall incidence of up to 1.15 %. Differential diagnosis of fungal appendicitis without pathology report is challenging due to low incidence. Isolated Aspergillus appendicitis is a rare disease that can progress without appropriate antifungal therapy even after surgical resection of the appendix. Surgeons should pay attention to pathology reports after appendectomy to avoid missing unusual cases, especially in immunocompromised patients. • Fungal infections principally occur in the immunocompromised. • Misdiagnosis and incorrect treatment are frequent in this rare disease entity. • Early diagnosis and prompt surgery with antifungal treatment is best [ABSTRACT FROM AUTHOR]

Abstract: Only few studies have evaluated the usefulness of the GLUT1 and p63 status of thyroid carcinomas in revealing tumorigenesis. We studied GLUT1, p53, and p63 immunoexpression in a total of 86 cases of various thyroid carcinoma types to determine the biological significance of GLUT1 and p63 expression in thyroid carcinomas. GLUT1 was detected in six cases of anaplastic carcinoma and in one case of poorly differentiated carcinoma with membranous staining. p63 was detected in five cases of anaplastic carcinoma, in one case of poorly differentiated carcinoma, and in five cases of papillary carcinoma with nuclear positivity. p53 was detected in six cases of anaplastic carcinoma, in one case of poorly differentiated carcinoma, and in one case of follicular carcinoma with nuclear positivity. Five of seven cases of anaplastic carcinoma expressed all three of these markers. The results suggest that GLUT1, p63, and p53 are not expressed in well-differentiated thyroid carcinomas, and that they are usually expressed late in the course of thyroid tumor progression. These data strongly suggest that in anaplastic carcinomas, impairment of p53-mediated repression results in increased GLUT1 and p63 expression, and that this probably reflects the differential regulation of hypoxia-responsive pathways and basal/stem cell regulatory pathways. [Copyright &y& Elsevier]

• RM involvement in gastric cancer ESD specimens was associated with upper third location, extended or beyond ESD criteria, and greater tumor size. • The gastric cancer with RM involvement showed more frequent poor differentiation, submucosal invasion, and lymphovascular invasion histologically. • The total length of involved RM was the most significant factor for predicting the residual tumor. Prediction of remnant tumor is important in determining subsequent treatment options for gastric cancer patients with positive resection margin (RM) after endoscopic submucosal dissection (ESD). Based on the assumption that pathologic factors, including the length and type of involved RM, could potentially predict residual tumor, we evaluated 451 ESD specimens in patients with early gastric cancer. Of 408 cases, 37 (9.1 %) showed positive RMs. RM involvement in gastric cancer ESD specimens was associated with extended or beyond ESD criteria, greater tumor size, poor differentiation, submucosal invasion, lymphovascular invasion, and upper third location. Among the 37 positive RM cases, residual tumor was present in seven (18.9 %). The presence of residual tumor was not significantly associated with any clinicopathologic parameters except for tumor size and RM status. The total length of the involved RM was the most significant factor associated with the presence of residual tumor (P < 0.008). A total length cut-off value of 6 mm yielded a sensitivity of 85.7 % and negative predictive value of 94.7 % for predicting remnant tumor at gastrectomy following ESD. In conclusion, when the ESD specimen exhibits positive RM, a quantitative assessment of the involved RM should be included in the pathology report, as this can help the clinician predict remnant tumor and determine appropriate future treatment. [ABSTRACT FROM AUTHOR]

Background Wnt5a, a non-canonical Wnt ligand, has been shown to play tumor-promoting or tumor-suppressive roles in different neoplasms. Increased Wnt5a expression and Wnt5a-dependent invasive activity that is mediated by one of its receptors, Ryk, have been reported in glioblastomas. Methods We investigated the protein expression of Wnt5a, its receptors Ryk and Ror2, and the canonical Wnt pathway marker β-catenin in 186 cases of glioblastoma and its variants. Associations with clinicopathological and molecular variables and prognosis were analyzed. Results All glioblastoma cases expressed Wnt5a, Ryk and Ror2 with a different grade. The expression of both Ryk and Ror2 correlated with that of Wnt5a in glioblastomas. The expression of β-catenin did not correlate with any of Wnt5a, Ryk or Ror2. Wnt5a expression was significantly different among subgroups of the glioblastoma. However, none of Wnt5a, Ryk or Ror2 had a prognostic impact on glioblastoma. For β-catenin, a shorter progression-free survival was noted in the glioblastoma with oligodendroglioma component (GBMO) subgroup. Conclusions Our results corroborated previous findings of Ryk-mediated Wnt5a effect, and suggested a role for Ror2 in the Wnt5a machinery in glioblastoma. [ABSTRACT FROM AUTHOR]

Abstract Background With the recent development of molecular tests for various biomarkers, it has become even more important to prepare adequate tissue samples. However, little is known about how the effect of cold ischemia time or formalin fixation time can affect KRAS mutation detection in colorectal cancer. Methods This study included the results of KRAS mutation tests for colorectal cancer in 401 specimens. We investigated clinicopathologic factors that may affect DNA quality of formalin-fixed, paraffin-embedded (FFPE) tissue including specimen type, cold ischemia time, and formalin fixation time and assessed the detection rate of the KRAS mutation in samples with varying DNA quality. Results Sample DNA quality for KRAS mutation test was better in biopsy specimens, which showed markedly shorter cold ischemia time and shorter formalin fixation time compared to resection specimens. A cold ischemia time of one hour or less was associated with better sample DNA quality. But the formalin fixation time was not a significant factor when it fell within the range performed in routine pathology diagnosis. When prolonged formalin fixation was tested, we confirmed that the specimen DNA quality gradually got worse from one month to three months. Conclusions The biopsy specimens showed better sample DNA quality for KRAS mutation test compared to resection specimens. In a routine diagnostic pathology setting, the cold ischemia time was an important factor affecting DNA quality and the formalin fixation had a wide time range for optimal DNA quality. [ABSTRACT FROM AUTHOR]

Abstract: Background: We performed a phase II study to evaluate the efficacy of bortezomib in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) as first-line treatment for patients with stage III/IV peripheral T-cell lymphomas (PTCLs) based on our phase I study results. Methods: Patients received bortezomib on days 1 and 8 at a dose of 1.6mg/m2 in addition to CHOP every 3weeks for a total of six cycles. Results: Forty-six patients were enrolled: PTCL, not otherwise specified (PTCL-NOS, n =16), extranodal NK/T-cell lymphoma, nasal type (ENKTL, n =10), angioimmunoblastic T-cell lymphoma (AITL, n =8), ALK-negative anaplastic large-cell lymphoma (ALCL, n =6), cutaneous T-cell lymphoma (CTCL, n =5) and hepatosplenic T-cell lymphoma (n =1). Thirty patients achieved complete response (CR, 65%) and the overall response rate was 76% (35/46). Although the CR rate of ENKTL was only 30% (3/10), three subtypes of PTCLs (PTCL-NOS, AITL and ALCL) showed 87% of overall response rate (ORR) (26/30) and 73% of CR rate (22/30). However, the 3-year overall survival and progression-free survival were 47% and 35%, respectively due to frequent relapse after remission. Grade 3/4 leucopenia was the most frequent toxicity whereas neurotoxicity was tolerable: grade 1 or 2 of peripheral neuropathy. Conclusions: The combined treatment of bortezomib and CHOP is an effective and feasible regimen for advanced-stage PTCLs other than ENKTL, with acceptable toxicity. However, future studies exploring new drug combinations are warranted to overcome relapse after remission. [Copyright &y& Elsevier]

Abstract: Purpose: Galectin-1 (Gal-1) is a 14-kDa laminin-binding galectin involved in several biological events including regulation of tumour proliferation and metastasis. In this study, we investigated the clinical significance of Gal-1 expression and its functional role in cell proliferation and invasion in epithelial ovarian cancer (EOC). Experimental design: We evaluated the expression of Gal-1 in 52 serous, 11 endometrioid, and 3 mucinous type EOC tumour samples from 66 patients by immunohistochemistry. In vitro experiments were performed to determine the function of Gal-1 in cell survival, proliferation, and invasion in EOC cells using siRNA and anginex, a Gal-1 inhibitor, as well as recombinant Gal-1 protein. Results: Patients with strong Gal-1 peritumoural staining had poorer progression-free survival (PFS) than patients with weak peritumoural staining (p =0.03). Inhibition of Gal-1 by siRNA or anginex resulted in the inhibition of cell growth and proliferation of HeyA8 and SKOV3ip1 cells. Moreover, the ability of cells to migrate was significantly reduced by treatment of cells with Gal-1 siRNA but was increased by treatment of cells with recombinant Gal-1. When we evaluated the interaction between fibroblasts (T HESCs) and cancer cells (A2780-CP20), we found that MMP-2 expression in cancer cells was affected by Gal-1 secreted by fibroblast cells, which suggests that Gal-1 in human fibroblasts might affect the invasive abilities of tumour cells. Conclusion: Our results suggest that Gal-1 expression is a potential prognostic factor for PFS and that Gal-1 could be a novel treatment target in EOC patients. [Copyright &y& Elsevier]