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.

Particularly interesting new cysteine-histidine rich protein (PINCH), as a newly discovered protein of LIM family members, may play a role in signal transduction of integrin and growth factor, and involved in the incidence and development of tumors. PINCH protein is overexpressed in tumor-associated stroma of several types of tumors. However, there is no study of the PINCH in esophageal cancer, therefore we investigated PINCH expression in esophageal squamous cell carcinomas and its clinicopathological significance in the patients. PINCH expression was immunohistochemically examined in 20 normal esophageal samples and 64 esophageal squamous cell carcinomas. The results showed that PINCH expression in the stroma of cancers was heterogeneous, and its positive rate (56%) was higher than that of normal esophageal mucosa (5%, p < 0.0001). The stronger staining was observed at the invasive edge of tumor when compared to the inner area of tumor. The rate of positive PINCH (90%) in the cases with lymph node metastasis was higher than that (41%) in the cases without metastasis (p < 0.0001). PINCH expression was not correlated with patients’ gender, age, tumor location, size and differentiation (p > 0.05). The results suggest that PINCH protein may be a marker of tumor associated-stroma involving tumor development, and predicting the ability of invasion and metastasis of esophageal squamous cell carcinoma.

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AIM:To evaluate whether celecoxib, a selective cyclooxygenase 2 (COX-2) inhibitor, could reduce the severity of gastric precancerous lesions following Helicobacter pylori (H pylori ) eradication.METHODS: H pylori -eradicated patients with gastric precancerous lesions randomly received either celecoxib (n = 30) or placebo (n = 30) for up to 3 mo. COX-2 expression and activity was determined by immunostaining and prostaglandin E 2 (PGE 2 ) assay, cell proliferation by Ki-67 immunostaining, apoptosis by TUNEL staining and angiogenesis by microvascular density (MVD) assay using CD31 staining. RESULTS:COX-2 protein expression was significantly increased in gastric precancerous lesions (atrophy, intestinal metaplasia and dysplasia, respectively) compared with chronic gastritis, and was concomitant with an increase in cell proliferation and angiogenesis. A significant improvement in precancerous lesions was observed in patients who received celecoxib compared with those who received placebo (P < 0.001). Of these three changes, 84.6% of sites with dysplasia regressed in patients treated with celecoxib (P = 0.002) compared with 60% in the placebo group, suggesting that celecoxib was effective on the regression of dysplasia. COX-2 protein expression (P < 0.001) and COX-2 activity (P < 0.001) in the gastric tissues were consistently lower in celecoxib-treated patients compared with the placebo-treated subjects. Moreover, it was also shown that celecoxib suppressed cell proliferation (P < 0.01), induced cell apoptosis (P < 0.01) and inhibited angiogenesis with decreased MVD (P < 0.001). However, all of these effects were not seen in placebo-treated subjects. Furthermore, COX-2 inhibition resulted in the up-regulation of PPARg expression, a protective molecule with anti-neoplastic effects.CONCLUSION: H pylori eradication therapy followed by celecoxib treatment improves gastric precancerous lesions by inhibiting COX-2 activity, inducing apoptosis, and suppressing cell proliferation and angiogenesis.

Background: Expression of the meningioma-associated protein (MAC30) was increased in several types of tumors, including esophageal, gastric and colon tumors, compared to normal tissue. MAC30 expression levels gradually increased from normal colorectal mucosa to primary colorectal cancer and colorectal cancer spreading to the lymph nodes. MAC30 expression was related to survival in patients with colorectal cancer. However, there is no study on MAC30 in oral squamous cell carcinoma (OSCC). Methods: Therefore, MAC30 expression in OSCC was investigated and possible associations of MAC30 expression with clinicopathological variables in OSCC have been analyzed. MAC30 expression was immunohistochemically examined in 20 normal oral mucosa and 43 OSCC specimens. Results: Expression levels of MAC30 in the cytoplasm markedly increased from normal oral epithelial cells to primary OSCC. Strong cytoplasmic staining was significantly higher in primary OSCC compared to normal oral mucosa samples (51 vs. 20%, p = 0.019). Furthermore, MAC30 expression levels in primary tumors of patients with lymph node metastasis exceeded levels in those without metastasis (65 vs. 35%, p = 0.048), and MAC30 expression in poorly differentiated tumors was higher than in well-differentiated ones (90 vs. 39%, p = 0.005). Conclusion: Overexpression of MAC30 in the cytoplasm of OSCC may predict nodal metastasis and poor differentiation.