Showing papers by "Weidong Han published in 2019"

Orally Deliverable Nanotherapeutics for the Synergistic Treatment of Colitis-Associated Colorectal Cancer.

Abstract: Purpose: Colitis-associated colorectal cancer (CAC) poses substantial challenges for effective treatment. Currently, there is a considerable need for the development of orally bioavailable dosage forms that enable the safe and effective delivery of therapeutic drugs to local diseased lesions in the gastrointestinal tract. Experimental Design: In this study, we developed orally deliverable nanotherapeutics for the synergistic treatment of inflammatory bowel diseases (IBDs) and CAC. Water-insoluble curcumin (CUR) and 7-ethyl-10-hydroxycamptothecin (SN38), which served as anti-inflammatory and cytotoxic agents, respectively, were chemically engineered into hydrophilic mucoadhesive chitosan for the generation of chitosan-drug amphiphiles. Results: The resulting amphiphilic constructs formed core-shell nanostructures in aqueous solutions and were orally administered for in vivo therapeutic studies. Using a preclinical CAC mouse model, we showed that the orally delivered nanotherapeutics locally accumulated in inflamed intestinal regions and tumor tissues. Furthermore, the therapeutic synergy of the combined nanotherapeutics in CAC mice was evaluated. Compared with their individual drug forms, combined CUR and SN38 nanoparticles yielded synergistic effects to alleviate intestinal inflammation and protect mice from ulcerative colitis. Notably, the combinatorial therapy demonstrated a remarkable tumor shrinkage with only ~6% of the total tumors exceeding 4 mm in diameter, whereas ~35% of tumors were observed to exceed a diameter of 4 mm in the saline-treated CAC mice. These data suggest a new and reliable approach for improving the treatment of IBD and CAC. Conclusions: Our results showed that bioadhesive chitosan materials can be used to produce colloidal-stable nanotherapeutics that are suitable for oral delivery. Both nanotherapeutics exhibited substantial accumulation in inflamed intestinal regions and tumor tissues and showed good synergy for treating CAC, warranting further clinical translation.

CircUBAP2-mediated competing endogenous RNA network modulates tumorigenesis in pancreatic adenocarcinoma.

Abstract: We investigated the role of the competing endogenous RNA (ceRNA) network in the development and progression of pancreatic adenocarcinoma (PAAD). We analyzed the expression profiles of PAAD and normal pancreatic tissues from multiple GEO databases and identified 457 differentially expressed circular RNAs (DEcircRNAs), 19 microRNAs (DEmiRNAs) and 1993 mRNAs (DEmRNAs). We constructed a ceRNA network consisting of 4 DEcircRNAs, 3 DEmiRNAs and 149 DEmRNAs that regulates the NF-kappa B, PI3K-Akt, and Wnt signaling pathways. We then identified and validated five hub genes, CXCR4, HIF1A, ZEB1, SDC1 and TWIST1, which are overexpressed in PAAD tissues. The expression of CXCR4, HIF1A, ZEB1, and SDC1 in PAAD was regulated by circ-UBAP2 and hsa-miR-494. The expression of CXCR4 and ZEB1 correlated with the levels of M2 macrophages, T-regulatory cells (Tregs) and exhausted T cells in the PAAD tissues. The expression of CXCR4 and ZEB1 positively correlated with the expression of CTLA-4 and PD-1. This suggests that CXCR4 and ZEB1 proteins inhibit antigen presentation and promote immune escape mechanisms in PAAD cells. In summary, our data suggest that the circUBAP2-mediated ceRNA network modulates PAAD by regulating the infiltration and function of immune cells.

Tumor-suppressive function and mechanism of HOXB13 in right-sided colon cancer.

Abstract: Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ in their clinical and molecular features. An investigation of differentially expressed genes (DEGs) between RCC and LCC could contribute to targeted therapy for colon cancer, especially RCC, which has a poor prognosis. Here, we identified HOXB13, which was significantly less expressed in RCC than in LCC and associated with prognosis in RCC, by using 5 datasets from the Gene Expression Omnibus (GEO). Tissue sample analysis showed that HOXB13 was differentially expressed between normal and only RCC tumor tissues. HOXB13 inhibited colon cancer cell proliferation and induced apoptosis both in vitro and in vivo. Furthermore, we found that HOXB13 might be regulated by DNMT3B and suppress C-myc expression to exert antitumor effects via β-catenin/TCF4 signals in RCC. In conclusion, the current study is the first to demonstrate that HOXB13 has a tumor-suppressive effect in RCC. High expression levels of HOXB13 are associated with prolonged overall survival in patients with RCC. The DNMT3B-HOXB13-C-myc signaling axis might be a molecular target for the treatment of RCC.

Lymph node involvement in pancreatic neuroendocrine tumors: significance as a predictor of survival

Abstract: Whether regional lymph node involvement exerts significant effect on the prognosis still remains obscure for pancreatic neuroendocrine tumors. To clarify this association and identify predictors for lymph node involvement, we studied the data of patients aged >18 years with regional lymph node involvement histologically confirmed pancreatic neuroendocrine tumors from 2004 to 2014 in the Surveillance, Epidemiology, and End Results database (http://seer.cancer.gov/about). We evaluated Lymph node involvement as a prognostic factor by Cox regression. We reduced 9 variables of demographic and tumor characteristics to 5 potential predictors using least absolute shrinkage and selection operator (LASSO) regression model. We further constructed a lymph node involvement model by logistic regression. The model was verified by the verification set, and the visual expression of the model was realized by a nomogram. A total of 1545 cases of pancreatic neuroendocrine tumors were included in our study. Lymph node positivity was significantly associated with disease-specific survival (P < 0.001). Younger patients (P < 0.05), patients with tumors in the pancreatic head (P < 0.05), patients at high American Joint Committee on Cancer T stage (P < 0.001), and patients of an undifferentiated status (P < 0.05) showed a significantly higher possibility of developing lymph node involvement. The reliability of this model was verified by cross-validation between the training and testing set, and we obtained good discrimination and calibration power. This model also showed great performance in C-index and area under receiver operating characteristic curve. Lymph node positivity was an important negative prognostic predictor for pancreatic neuroendocrine tumor. We developed a lymph node involvement model based on the predictors including age, marital status, primary site, T status, and tumor grade. Key words: Surveillance; Epidemiology; and End Results database; logistic regression; lymph node involvement; nomogram; pancreatic neuroendocrine tumors

Chimeric antigen receptor, gene of chimeric antigen receptor, recombinant expression vector of chimeric antigen receptor, CD22-CD19 double-targeting T cell and application of cell

Abstract: The invention belongs to the field of tumor biological products, and particularly relates to an chimeric antigen receptor, a gene of the chimeric antigen receptor, the recombinant expression vector ofthe chimeric antigen receptor, a CD22-CD19 double-targeting T cell and application of the T cell. The chimeric antigen receptor is CD22ScFv-L-CD19ScFv-CD8-CD137-CD3zeta and comprises CD22ScFv, connecting peptide L, CD19ScFv, a hinge region and a transmembrane region of CD8, an intracellular signal structural domain of CD137 and an intracellular signal structural domain of the CD3zeta which are connected in series. According to the chimeric antigen receptor, the gene of the chimeric antigen receptor, the recombinant expression vector of the chimeric antigen receptor, the CD22-CD19 double-targeting T cell and the application of the T cell, when B-cell line hematological malignant tumors are treated, the T cell modified by the chimeric antigen receptor not only can specifically recognize a tumor cell which is only expressed by a single target spot of a CD19 antigen or a CD22 antigen, but also can recognize tumor cells co-expressed by the two target spots of the CD19 antigen and the CD22antigen, compared with the single target spot CAR T, the double target spots CAR T have stronger anti-tumor activity, so that the immune escape of the tumor cells expressed by the low-abundance antigen is avoided, and therefore the recurrence risk is reduced.

Integrated bioinformatics analysis to screen hub genes in the lymph node metastasis of thyroid cancer

Abstract: Thyroid cancer (TC) is one of the most common types of malignancy of the endocrine-system. At present, there is a lack of effective methods to predict neck lymph node metastasis (LNM) in TC. The present study compared the expression profiles from The Cancer Genome Atlas between N1M0 and N0M0 subgroups in each T1-4 stages TC in order to identify the four groups of TC LNM-associated differentially expressed genes (DEGs). Subsequently, DEGs were combined to obtain a total of 493 integrated DEGs by using the method of Robust Rank Aggregation. Furthermore, the underlying mechanisms of LNM were investigated. The results from Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses demonstrated that the identified DEGs may promote LNM via numerous pathways, including extracellular matrix-receptor interaction, PI3K-AKT signaling pathway and focal adhesion. Following construction of a protein-protein interaction network, the significance score for each gene was calculated and seven hub genes were screened, including interleukin 6, actinin α2, collagen type I α 1 chain, actin α1, calbindin 2, thrombospondin 1 and parathyroid hormone. These genes were predicted to serve crucial roles in TC with LNM. The results from the present study could therefore improve the understanding of LNM in TC. In addition, the seven DEGs identified may be considered as potential novel targets for the development of biomarkers that could be used in the diagnosis and therapy of TC.

Bispecific Chimeric Antigen Receptor Targeting Both CD19 and CD22 T Cell Therapy in Adults with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

Abstract: Background: Despite the impressive CR induced by CD19 CAR-T cell therapy in B-ALL, the high rate of complete responses is sometimes limited by the emergence of CD19-negative leukemia. Bispecific CAR-modified T cells targeting both CD19 and CD22 may overcome the limitation of CD19-negative relapse. Methods: Here, we report the design of a bispecific CAR that triggers robust cytolytic activity against target cells by targeting either CD19 or CD22. We performed a phase 1 trial of bispecific CAR T cell therapy in patients with relapsed/refractory precursor B-ALL at a dose that ranged from 1.7×106 to 3×106 CAR T cells per kilogram of body weight. Finding: MRD-negative CR was achieved in 6 out of 6 enrolled patients. Autologous CD19/CD22 CAR T cells proliferated in vivo and were detected in the blood, bone marrow, and cerebrospinal fluid. No neurotoxicity occurred in any of the 6 patients treated. Of note, one patient had a relapse with blast cells that no longer expressed CD19 and exhibited diminished CD22 site density approximately 5 months after treatment. Interpretation: In brief, autologous CD19/CD22 CAR T cell therapy is feasible and safe and mediates potent antileukemic activity in patients with relapsed/refractory B-ALL. Furthermore, the emergence of target antigen loss and expression downregulation highlights the critical need to anticipate antigen escape. Our study demonstrates the reliability of bispecific CD19/CD22 CAR T cell therapy in inducing remission in adult patients with relapsed/refractory B-ALL. Trial Registration: NCT03185494. Funding Statement: National Key Research and Development Program of China and National Natural Science Foundation of China. Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study protocols were approved by the institutional review board at the Chinese PLA general hospital, and the patients provided written informed consent. This clinical investigation was conducted according to the principles of the Declaration of Helsinki.

Recombinant expression vector and targeted T cells, and applications thereof

Abstract: The invention belongs to the field of tumor biological products, in particular, relates to a recombinant expression vector and targeted T cells, and applications thereof. The recombinant expression vector contains a nucleotide sequence capable of expressing RNAi and a nucleotide sequence capable of expressing a chimeric antigen receptor; RNAi can silence PD-1; the chimeric antigen receptor is ScFv-CD8-CD137-CD3[zeta]. The expression of a PD-1 gene in the T cells is inhibited by a genetic engineering method, so as to block a PD-1 signaling pathway. Experiments show that the knockdown of the PD-1 in the CART cells is possible to change a secretion pattern of cytokines, but enhance the resistance to PD-1-mediated immunosuppression. In addition, the PD-1 silenced CART cells prepared by the genetic engineering method not only combine the advantages of T cell therapy, but also relieve the regulation of immune test points, and can relieve the inhibition of the immune function of the CART cells by the tumor microenvironment to a great extent.

Chimeric antigen receptor and its gene and recombinant expression vector, CD19-CD20 dual targeting T cell and application thereof

Abstract: The invention belongs to the field of tumor biological products, in particular to a chimeric antigen receptor and its gene and a recombinant expression vector, CD19-CD20 dual targeting T cells and anapplication thereof. The chimeric antigen receptor is CD20ScFv-L-CD19ScFv-CD8-CD137-CD3 zeta, which includes CD20ScFv, ligation peptide L, CD19ScFv, a hinge region and a transmembrane region of CD8, an intracellular signal domain of CD137, and an intracellular signal domain of CD3 zeta which are connected in series in order. In the treatment of B cell line hematological malignancy, the chimeric antigen receptor-modified T cells of the present invention can not only specifically recognize tumor cells expressed by a single target of CD19 antigen or CD20 antigen, but also to recognize tumor cellsco-expressed by two targets of CD19 antigen and CD20 antigen, compared with single target CAR T, dual-target CAR T has stronger anti-tumor activity, which avoids immune escape of tumor cells with lowabundance antigen expression, and the risk of recurrence is reduced.