Most hepatocellular carcinomas (HCCs) first occur as welldifferentiated HCCs, from which poorly differentiated HCC cells develop because of dedifferentiation. In this study, we try to clarify the changes of dedifferentiation and cell proliferative activity and their relationship in small HCCs (less than 3.0 cm in diameter) and try to learn the mechanism of these changes by analysing the expressions and genetic changes of proliferation-related genes p53 and ␤-catenin. Of 41 surgically resected small HCCs, 11 were identified to have tumor heterogeneity. DNA from the 11 small HCCs, consisting of 29 intratumoral lesions and 11 noncancerous liver tissues adjacent to HCCs, was extracted from paraffin embedded tissue sections. Exons 5-8 of p53 gene and exon 3 of ␤-catenin gene were amplified by polymerase chain reaction and analyzed by direct sequence. The serial sections were also immunostained by anti-Ki-67, p53 and ␤-catenin antibody. Immunohistochemistry showed that the p53 overexpression was significantly related to the proliferative activities as evaluated by Ki-67 immunostaining and to the histological differentiation. The expression of ␤-catenin was found to be heterogeneously distributed not only in various histological grades of the same tumor but also in areas of the same histological grade. p53 and ␤-catenin gene mutations were detected in 1 tumor respectively, both of which were second primary HCCs and also recurred later. The p53 mutation showed the same mutation pattern in heterogeneous subpopulations. ␤-catenin mutation was detected only in the less differentiated lesion but not in the well-differentiated lesion of tumor. In conclusion, our findings suggest that there was histological heterogeneity in small but established HCC, which was accompanied by increased proliferative activity and p53 overexpression. The overexpression of ␤-catenin may be related to the proliferative activity and dedifferentiation of HCC.

VEGF-A and VEGF-C are commonly overexpressed in human pancreatic cancer and may contribute to tumor growth and lymph node metastasis. There is no relationship between the expression of VEGF-A and VEGF-C in pancreatic cancer.

BackgroundType 1 diabetes (T1D) is a T cell-mediated autoimmune disease that causes a deficit of pancreatic islet β cells. The complexities of overcoming autoimmunity in T1D have contributed to the challenges the research community faces when devising successful treatments with conventional immune therapies. Overcoming autoimmune T cell memory represents one of the key hurdles.MethodsIn this open-label, phase 1/phase 2 study, Caucasian T1D patients (N = 15) received two treatments with the Stem Cell Educator (SCE) therapy, an approach that uses human multipotent cord blood-derived multipotent stem cells (CB-SCs). SCE therapy involves a closed-loop system that briefly treats the patient's lymphocytes with CB-SCs in vitro and returns the “educated” lymphocytes (but not the CB-SCs) into the patient's blood circulation. This study is registered with ClinicalTrials.gov, NCT01350219.FindingsClinical data demonstrated that SCE therapy was well tolerated in all subjects. The percentage of naïve CD4+ T cells was significantly increased at 26 weeks and maintained through the final follow-up at 56 weeks. The percentage of CD4+ central memory T cells (TCM) was markedly and constantly increased at 18 weeks. Both CD4+ effector memory T cells (TEM) and CD8+ TEM cells were considerably decreased at 18 weeks and 26 weeks respectively. Additional clinical data demonstrated the modulation of C–C chemokine receptor 7 (CCR7) expressions on naïve T, TCM, and TEM cells. Following two treatments with SCE therapy, islet β-cell function was improved and maintained in individuals with residual β-cell function, but not in those without residual β-cell function.InterpretationCurrent clinical data demonstrated the safety and efficacy of SCE therapy in immune modulation. SCE therapy provides lasting reversal of autoimmune memory that could improve islet β-cell function in Caucasian subjects.FundingObra Social “La Caixa”, Instituto de Salud Carlos III, Red de Investigación Renal, European Union FEDER Funds, Principado de Asturias, FICYT, and Hackensack University Medical Center Foundation.

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Intrahepatic cholangiocarcinoma (IHCC) is an aggressive cancer with a poor survival rate and is the second most common type of primary cancer of the hepatobiliary system. At present, the molecular mechanisms of IHCC initiation and progression remain unclear. Recent evidence has indicated that long non‑coding RNAs (lncRNAs) serve a crucial role in cancer development; however, the functional role of lncRNAs in IHCC has not been investigated in detail. In the present study, a marked overexpression of lncRNA colon cancer‑associated transcript 2 (CCAT2) was observed in IHCC cell lines and clinical specimens. Statistical analysis of IHCC clinicopathological characteristics and CCAT2 expression data revealed that high CCAT2 expression levels correlated with microvascular invasion, differentiation grade, tumor (T), lymph node (N), metastasis (M) and overall TNM stages of IHCC (P<0.05). Kaplan‑Meier analysis demonstrated that CCAT2 upregulation was associated with poor overall survival and progression‑free survival in IHCC. Furthermore, high CCAT2 expression was identified as an independent risk factor of IHCC poor prognosis in both univariate and multivariate Cox regression analyses. The role of CCAT2 in promoting IHCC cell proliferation, motility and invasion was further confirmed with in vitro assays. Therefore, CCAT2 may promote IHCC progression and metastasis, and may be a promising prognostic biomarker and therapeutic target in IHCC.