Safety and efficacy of ex vivo expanded CD34 stem cells in murine and primate models

Background: Hematopoietic stem cell (HSC) transplantation has been widely applied to the treatment of malignant blood diseases. However, limited number of functional HSCs hinders successful transplantation. The purpose of our current study is to develop a new and cost-efficient medium formulation that could greatly enhance the expansion of HSCs while retaining their long-term repopulation and hematopoietic properties for effective clinical transplantation. Methods: Enriched human CD34(+) cells and mobilized nonhuman primate peripheral blood CD34(+) cells were expanded with a new, cost-efficient expansion medium formulation, named hematopoietic expansion medium (HEM), consisting of various cytokines and nutritional supplements. The long-term repopulation potential and hematologic-lineage differentiation ability of expanded human cells were studied in the non-obese diabetic/severe combined immunodeficiency mouse model. Furthermore, the efficacy and safety studies were performed by autologous transplantation of expanded primate cells in the nonhuman primate model. Results: HEM could effectively expand human CD34(+) cells by up to 129 fold within 9 days. Expanded HSCs retained long-term repopulation potential and hematologic-lineage differentiation ability, as indicated by (1) maintenance (over unexpanded HSCs) of immunophenotypes of CD38(-)CD90(+)CD45RA(-)CD49f(+) in CD34(+) cells after expansion; (2) significant presence of multiple human hematopoietic lineages in mouse peripheral blood and bone marrow following primary transplantation; (3) enrichment (over unexpanded HSCs) in SCID-repopulating cell frequency measured by limiting dilution analysis; and (4) preservation of both myeloid and lymphoid potential among human leukocytes from mouse bone marrow in week 24 after primary transplantation or secondary transplantation. Moreover, the results of autologous transplantation in nonhuman primates demonstrated that HEM-expanded CD34(+) cells could enhance hematological recovery after myelo-suppression. All primates transplanted with the expanded autologous CD34(+) cells survived for over 18 months without any noticeable abnormalities. Conclusions: Together, these findings demonstrate promising potential for the utility of HEM to improve expansion of HSCs for clinical application.State Scientific Key Projects for New Drug Research and Development [2011ZX09102-010-04, 2011ZX09401-027]; International Cooperation and Exchange Program, China [2013DFA30830]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Gut microbial composition changes in bladder cancer patients: A case-control study in Harbin, China

BACKGROUND AND OBJECTIVES: This study aimed to explore the changes of gut bacteria in bladder cancer patients. METHODS AND STUDY DESIGN: Newly diagnosed bladder cancer patients were recruited. All participants completed a questionnaire about personal behavior and diet. Pyrosequencing of the total genomic DNA extracted from human feces was carried out by Illumina HiSeq 2000. The copy number of target DNA for bacteria was determined by real-time quantitative PCR assay. Fecal short chain fatty acids contents were measured by gas chromatography (GC) analysis. The concentrations of lipopolysaccharide and D-lactic acid in serum were determined by enzyme-linked immunosorbent assay kits. RESULTS: Fruit intake was significantly lower than in healthy controls. The numbers of Clostridium cluster XI and Prevotella in bladder cancer patients decreased. The numbers of domain bacteria and Prevotella were significantly and positively associated with fruit intake (r=0.002, p<0.05 for domain bacteria; r=0.004, p<0.05 for Prevotella). The concentration of butyric acid decreased significantly in bladder cancer patients, and the quantities of fecal butyric acid were significantly and positively associated with fruit intake (r=0.610, p<0.01). The concentrations of lipopolysaccharide and D-lactic acid, two sensitive markers of gut permeability, were greater in bladder cancer patients. CONCLUSIONS: Dysbiosis of gut microbiota, decreased butyric acid concentrations and impaired intestinal structural integrity were found in bladder cancer patients, which might be associated with inadequate fruit intake

Benefits and risks of the hormetic effects of dietary isothiocyanates on cancer prevention

The isothiocyanate (ITC) sulforaphane (SFN) was shown at low levels (1-5 µM) to promote cell proliferation to 120-143% of the controls in a number of human cell lines, whilst at high levels (10-40 µM) it inhibited such cell proliferation. Similar dose responses were observed for cell migration, i.e. SFN at 2.5 µM increased cell migration in bladder cancer T24 cells to 128% whilst high levels inhibited cell migration. This hormetic action was also found in an angiogenesis assay where SFN at 2.5 µM promoted endothelial tube formation (118% of the control), whereas at 10-20 µM it caused significant inhibition. The precise mechanism by which SFN influences promotion of cell growth and migration is not known, but probably involves activation of autophagy since an autophagy inhibitor, 3-methyladenine, abolished the effect of SFN on cell migration. Moreover, low doses of SFN offered a protective effect against free-radical mediated cell death, an effect that was enhanced by co-treatment with selenium. These results suggest that SFN may either prevent or promote tumour cell growth depending on the dose and the nature of the target cells. In normal cells, the promotion of cell growth may be of benefit, but in transformed or cancer cells it may be an undesirable risk factor. In summary, ITCs have a biphasic effect on cell growth and migration. The benefits and risks of ITCs are not only determined by the doses, but are affected by interactions with Se and the measured endpoint

Locally advanced rectal cancer with dMMR/MSI-H may be excused from surgery after neoadjuvant anti-PD-1 monotherapy: a multiple-center, cohort study

ObjectiveExamine patients with locally advanced rectal cancer (LARC) with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) who received neoadjuvant immunotherapy (nIT), and compare the outcomes of those who chose a watch-and-wait (WW) approach after achieving clinical complete response (cCR) or near-cCR with those who underwent surgery and were confirmed as pathological complete response (pCR).MethodsLARC patients with dMMR/MSI-H who received nIT were retrospectively examined. The endpoints were 2-year overall survival (OS), 2-year disease-free survival (DFS), local recurrence (LR), and distant metastasis (DM). The efficacy of programmed cell death protein-1 (PD-1) inhibitor, immune-related adverse events (irAEs), surgery-related adverse events (srAEs), and enterostomy were also recorded.ResultsTwenty patients who received a PD-1 inhibitor as initial nIT were examined. Eighteen patients (90%) achieved complete response (CR) after a median of 7 nIT cycles, including 11 with pCR after surgery (pCR group), and 7 chose a WW strategy after evaluation as cCR or near-cCR (WW group). Both groups had median follow-up times of 25.0 months. Neither group had a case of LR or DM, and the 2-year DFS and OS in each group was 100%. The two groups had similar incidences of irAEs (P=0.627). In the pCR group, however, 2 patients (18.2%) had permanent colostomy, 3 (27.3%) had temporary ileostomy, and 2 (18.2%) had srAEs.ConclusionNeoadjuvant PD-1 blockade had high efficacy and led to a high rate of CR in LARC patients with dMMR/MSI-H. A WW strategy appears to be a safe and reliable option for these patients who achieve cCR or near-cCR after nIT

Clinical trials of CAR-T cells in China

Abstract Novel immunotherapeutic agents targeting tumor-site microenvironment are revolutionizing cancer therapy. Chimeric antigen receptor (CAR)-engineered T cells are widely studied for cancer immunotherapy. CD19-specific CAR-T cells, tisagenlecleucel, have been recently approved for clinical application. Ongoing clinical trials are testing CAR designs directed at novel targets involved in hematological and solid malignancies. In addition to trials of single-target CAR-T cells, simultaneous and sequential CAR-T cells are being studied for clinical applications. Multi-target CAR-engineered T cells are also entering clinical trials. T cell receptor-engineered CAR-T and universal CAR-T cells represent new frontiers in CAR-T cell development. In this study, we analyzed the characteristics of CAR constructs and registered clinical trials of CAR-T cells in China and provided a quick glimpse of the landscape of CAR-T studies in China

On the Extension of the Financial Reporting Conceptual Framework in the Context of International Convergence of the Accounting Standards:An Overview of the 2014 Special Symposium Organized by the Committee of Fundamental Accounting Theory for the Accounting Society of China

【中文摘要】由中国会计学会主办、上海大学管理学院承办的“中国会计学会会计基础理论专业委员会2014年学术研讨会”于2014年5月18日在上海召开。来自学术界与实务界的专家和学者分别从财务报告概念框架与会计基础理论关系、财务报告概念框架内容、我国未来财务报告概念框架制定等角度，对会计准则国际趋同下的财务报告概念框架问题，开展了深入的学术交流与研讨。 【Abstract】The 2014 Special Symposium, organized by the Committee of Fundamental Accounting Theory for the Accounting Society of China (ASC) , was held in the Management School of Shanghai University on May 18，2014. Experts and scholars from academia and practice exchanged ideas about the conceptual framework for financial reporting in the context of international convergence of accounting standards， especially about the relationships between the conceptual framework of financial reporting and accounting concepts and between the content of the conceptual framework of financial reporting and the application of the conceptual framework to companies in China