Treatment of acute lymphoblastic leukaemia with the second generation of CD19 CAR-T containing either CD28 or 4-1BB.

T cells modified with anti-CD19 chimeric antigen receptor (CAR) containing either CD28 or 4-1BB (also termed TNFRSF9, CD137) costimulatory signalling have shown great potential in the treatment of acute lymphoblastic leukaemia (ALL). However, the difference between CD28 and 4-1BB costimulatory signalling in CAR-T treatment has not been well elucidated in clinical trials. In this study, we treated 10 relapsed or refractory ALL patients with the second generation CD19 CAR-T. The first 5 patients were treated with CD28-CAR and the other 5 patients were treated with 4-1BB CAR-T. All the 10 patients were response-evaluable. Three patients achieved complete remission and 1 patient with extramedullary disease achieved partial response after CD28-CAR-T treatment. In the 4-1BB CAR-T treatment group, 3 patients achieved complete remission. Furthermore, FLT-3 ligand (FLT3LG) was highly correlated with response time and may serve as a prognosis factor. No severe adverse events were observed in these 10 treated patients. Our study showed that both CD28 CAR-T and 4-1BB CAR-T both worked for response but they differed in response pattern (peak reaction time, reaction lasting time and reaction degree), adverse events, cytokine secretion and immune-suppressive factor level.

Modeling and Assessment of GPS/BDS Combined Precise Point Positioning.

Precise Point Positioning (PPP) technique enables stand-alone receivers to obtain cm-level positioning accuracy. Observations from multi-GNSS systems can augment users with improved positioning accuracy, reliability and availability. In this paper, we present and evaluate the GPS/BDS combined PPP models, including the traditional model and a simplified model, where the inter-system bias (ISB) is treated in different way. To evaluate the performance of combined GPS/BDS PPP, kinematic and static PPP positions are compared to the IGS daily estimates, where 1 month GPS/BDS data of 11 IGS Multi-GNSS Experiment (MGEX) stations are used. The results indicate apparent improvement of GPS/BDS combined PPP solutions in both static and kinematic cases, where much smaller standard deviations are presented in the magnitude distribution of coordinates RMS statistics. Comparisons between the traditional and simplified combined PPP models show no difference in coordinate estimations, and the inter system biases between the GPS/BDS system are assimilated into receiver clock, ambiguities and pseudo-range residuals accordingly.

Construction of Aptamer-siRNA Chimera/PEI/5-FU/Carbon Nanotube/Collagen Membranes for the Treatment of Peritoneal Dissemination of Drug-Resistant Gastric Cancer.

Due to extensive metastasis, poor blood supply, and drug-resistant, there is still no effective clinical means to treat peritoneal dissemination of gastric cancer. Here, an aptamer-siRNA chimera (Chim)/polyethyleneimine (PEI)/5-fluorouracil (5-FU)/carbon nanotube (CNT)/collagen membrane is constructed, which could be divided into 15 layers with a thickness of 70-100 µm. Sustained release experiments show that the collagen membranes can control 5-FU release for more than 2 weeks. Aptamer-siRNA chimera can specifically bind to gastric cancer cells, enabling targeted delivery of 5-FU and silencing drug-resistant gene. In vitro experiments demonstrated that Chim/PEI/5-FU/CNT nanoparticles promoted the apoptosis of 5-FU-resistant gastric cancer cells, inhibited their invasion and proliferation. Animal experiments show that Chim/PEI/5-FU/CNT/collagen membrane significantly inhibits the expression of mitogen-activated protein kinase (MAPK), and effectively treats peritoneal dissemination of 5-FU-resistant gastric cancer. Compared with siRNA/PEI/5-FU/CNT group, ki-67 proliferation index, and matrix metallopeptidase 9 (MMP9) expression are significantly decreased in the Chim/PEI/5-FU/CNT group, while the proportion of apoptotic cells is markly increased. In conclusion, a chimera/PEI/5-FU/CNT/collagen membrane is constructed, which can effectively treat peritoneal dissemination of drug-resistant gastric cancer. The study provides a new therapeutic approach for relevant clinical treatment.

CD150highTreg cells may attenuate graft versus host disease and intestinal cell apoptosis after hematopoietic stem cell transplantation.

Combined transplantation of regulatory T cells (Treg cells) may significantly attenuate graft versus host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). Recent studies indicated that CD150+Treg cells could secret adenosine to maintain the quiescent status of HSCs. However, whether it is attributable to the attenuation of GVHD after HSCT is still unclear. In vitro studies revealed that CD150+Treg cells induced immune tolerance was comparable to that induced by CD150-Treg cells, but CD150+Treg cells can secret more adenosine, increase P-AMPK expression and regulate energy metabolism to induce the proliferation of HSC proliferation and inhibit their differentiation into dendritic cells. In this study, GVHD animal model was established, and combined transplantation of Treg cells and HSCs was performed. Results showed the survival time was significantly prolonged, the proliferation rate of HSCs increased significantly and the proportion of undifferentiated HSCs elevated significantly after CD150+Treg transplantation as compared to CD150-Treg transplantation. Immunohistochemistry revealed CD150+Treg cells could secret adenosine, activate AMPK expression and inhibit intestinal cell apoptosis and inflammation after HSCT. Taken together, this study indicates CD150+Treg cells can regulate energy metabolism to attenuate GVHD and intestinal cell apoptosis after HSCT.

Melatonin enhances arsenic trioxide-induced cytotoxicity by modulating autophagy in an acute promyelocytic leukemia cell line.

BACKGROUND: Arsenic trioxide (ATO)-containing therapeutic strategies are widely used in the treatment of acute promyelocytic leukemia (APL). Growing evidence has shown that melatonin enhances the radio- or chemo-sensitivity of numerous cancer cells. However, whether melatonin is capable of enhancing the cytotoxic effects of ATO in APL cells remains unknown. METHODS: The present study conducted a 24 h melatonin exposure followed by additional 12, 24 or 48 h ATO exposure in the APL cell line NB4 with or without autophagy-related protein 7 (ATG7) silencing by RNA interference. Cell cytotoxicity was evaluated by Cell Counting Kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays. Cell apoptosis was assessed by Annexin-V/propidium iodide assay and western blotting against cleaved caspase 3, Bax and Bcl-2. Autophagy was evaluated by western blotting against LC3. RESULTS: Pre-treatment with a non-cytotoxic dose of melatonin significantly enhanced ATO-mediated reduced cell viability and increased LDH release. Furthermore, melatonin pre-treatment also enhanced ATO-mediated increase in early and late apoptosis, as well as the expression of Bax and cleaved caspase 3, while further decreasing ATO-mediated reduced expression of Bcl-2. Concomitantly, melatonin pre-treatment increased LC3II expression and enhanced the ATO-mediated elevation in LC3II expression. However, autophagy inhibition by ATG7 silencing blocked the enhancing effects of melatonin on ATO-induced apoptosis and cytotoxicity. These findings indicated that melatonin pre-treatment enhances ATO-induced cytotoxicity by modulating ATG7-mediated autophagy. CONCLUSIONS: Melatonin could represent a valuable adjuvant to ATO in APL treatment, particularly in patients with ATO-resistant APL.

Tumor-associated macrophages increase the proportion of cancer stem cells in lymphoma by secreting pleiotrophin.

Tumor-associated macrophages (TAMs) are closely related to the occurrence and development of lymphoma, but their mechanism is still unclear. Here we collected peripheral blood and lymphoma tissue from patients with diffuse large B lymphoma. Results showed that the proportion of TAMs in high-risk group was significantly higher than that in low-risk group. Moreover, the expressions of pleiotrophin (PTN), PTPRZ1 (PTN receptor) and ß-catenin in lymphoma tissues of high-risk group were also significantly higher than those in low-risk group. Correlation analysis showed that the proportion of TAMs in lymphocyte was positively correlated with the expression of PTN and PTPRZ1 in lymphoma tissue. In vitro experimental results showed that TAM promoted the invasion and proliferation of lymphoma cells by secreting PTN. We also found that TAMs increased the proportion of cancer stem cells in lymphoma. Animal experiments showed that TAMs promoted lymphoma growth. Both Ki-67 proliferation index and CD44+cancer stem cells increased significantly in TAM group. Blocking PTN or ß-catenin partly inhibited these effects of TAMs. In conclusion, TAMs increased the proportion of cancer stem cells through PTN/ß-catenin pathway in lymphoma.