Xinna Zhou

Effects of transplanted bone-marrow-derived mesenchymal stem cells in animal models of acute hepatitis

Our aim was to evaluate the therapeutic effects of bone-marrow-derived mesenchymal stem cells (BMMSCs) on ConA-induced hepatitis and to elucidate the possible mechanism involved. MSCs were isolated from bone marrow and their characteristics and anti-apoptotic effects on the L02 cell line were analyzed. The effect of intravenous infusion of BMMSCs on liver damage was also tested. Furthermore, the recruitment of donor BMMSCs to the liver of recipient animals and their effects on the activity of intrahepatic natural killer T (NKT) cells were investigated. BMMSCs ameliorated liver damage in a time- and dose-dependent manner. Donor BMMSCs were detected in the livers of recipient animals, suggesting that tissue damage stimulated the migration of BMMSCs. Transplanted BMMSCs also suppressed the activity of intrahepatic NKT cells, not only in the liver but throughout the body. The general infusion of BMMSCS ameliorated immunoregulatory activities by the suppression of intrahepatic NKT cells.

Non-genetic risk factors and predicting efficacy for docetaxel–drug-induced liver injury among metastatic breast cancer patients

Background and Aim:  Docetaxel has been chosen as one of the most popular anticancer drugs in the treatment of breast cancer for more than a decade. There is increasingly awareness for the occurrence of docetaxel and/or docetaxel–drug‐induced liver injury (DILI), although the underlying mechanism of occurrence and its risk factors remain unclear.

A novel molecular marker of breast cancer stem cells identified by cell-SELEX method.

BACKGROUND Breast cancer stem cells (CSCs) are thought to initiate mammary tumors and render them resistant to anti-cancer therapies. However, there are currently no ideal biomarkers to identify this minority population in breast cancer. OBJECTIVE To find out the oligonucleotides with high specificity and affinity for mammosphere cells using a high capacity ssDNA library. METHODS We used the cell-SELEX (systematic evolution of ligands by exponential enrichment process) method. MCF-7 cells were cultured in serum-free media to form mammosphere cells as enriched stem cells, and were used as the positive target cells. The normal breast epithelial MCF-10A and MCF-7sal cells, which are MCF-7 cells treated with Salinomycin, were used as the negative target cells. We collected the ssDNA pools that were bound to positive target cells, and could not bind negative target cells. RESULTS After 13 rounds of selection, we isolated the MS03 aptamer with high specificity and affinity for mammosphere cells. When compared with CD44(+)/CD24(-/low) cells, MS03(+) cells did not show any significant difference in sphere formation ability in vitro. In addition, 63.3% of MS03 aptamer-selected cells exhibited the CD44(+)/CD24(-/low) phenotype. Because the MS03 aptamer is synthesized easily and non-immunogenic, it is much more flexible than CD44/CD24 as a breast CSC biomarker. CONCLUSIONS The MS03 aptamer may become a promising molecular probe during diagnostic and therapeutic applications in breast cancer.

Breast Cancer Challenges and Screening in China: Lessons From Current Registry Data and Population Screening Studies

BACKGROUND As one of its responses to the increasing global burden of breast cancer (BC), China has deployed a national registration and BC screening campaign. The present report describes these programs and the initial results of these national BC control strategies, highlighting the challenges to be considered. MATERIALS AND METHODS The primary BC incidence and prevalence data were obtained from the Chinese National Central Cancer Registry. MapInfo software was used to map the geographic distribution and variation. The time trends were estimated by the annual percentage of change from 2003 to 2009. The description of the screening plans and preliminary results were provided by the Ministry of Health. RESULTS Chinese cancer registries were primarily developed and activated in the East and Coastal regions of China, with only 12.5% of the registries located in West China. Geographic variation was noted, with the incidence of BC higher in North China than in South China and in urban areas compared with rural areas. Of great interest, these registries reported that the overall BC incidence has been increasing in China, with an earlier age of onset compared with Western countries and a peak incidence rate at age 50. In response to this increasing incidence and early age of onset, BC screening programs assessed 1.46 million women aged 35-59 years, using clinical breast examinations and ultrasound as primary screening tools between 2009 and 2011. The diagnostic rate for this screening program was only 48.0/10(5) with 440 cases of early stage BC. Early stage BC was detected in nearly 70% of screened patients. Subsequently, a second-generation screening program was conducted that included older women aged 35-64 years and an additional 6 million women were screened. CONCLUSION The cancer registration system in China has been uneven, with a greater focus on East rather than West China. The data from these registries demonstrate regional variation, an increasing BC incidence, and an early age of onset. The 2009 to 2011 BC screening program targeting women aged 35-59 years had a low detection rate that resulted in a second-generation screening program that extended the cohort size and ages screened to 35-64 years. IMPLICATIONS FOR PRACTICE Cancer registration has been active in China for decades; however, a national survey of registries has not been routinely reported. This study used MapInfo to describe the reported data and found asymmetric registration activities, geographic variations in breast cancer (BC) burdens, and an increasing incidence with a peak at age 50. The initial Chinese BC screening programs focused on a relatively young population of women aged 35-59 years and had a low detection rate, but 69.7% of patients had early stage BC. Older women were included in the second-generation screening programs, and an additional 6 million women were screened. Consideration of regional variations and age is necessary to optimize the efficiency and utility of BC screening in China, with the ultimate goal to reduce BC mortality.

Adaptive T cell responses induced by oncolytic Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor therapy expanded by dendritic cell and cytokine-induced killer cell adoptive therapy

ABSTRACT Purpose: Although local oncolytic viral therapy (OVT) may enhance tumor lysis, antigen release, and adaptive immune responses, systemic antitumor responses post-therapy are limited. Adoptive immunotherapy with autologous dendritic cells (DC) and cytokine-induced killer cells (DC–CIK) synergizes with systemic therapies. We hypothesized that OVT with Herpes Simplex Virus-granulocyte macrophage-colony-stimulating factor (HSV-GM-CSF) would induce adaptive T cell responses that could be expanded systemically with sequential DC–CIK therapy. Patients and Methods: We performed a pilot study of intratumoral HSV-GM-CSF OVT followed by autologous DC–CIK cell therapy. In addition to safety and clinical endpoints, we monitored adaptive T cell responses by quantifying T cell receptor (TCR) populations in pre-oncolytic therapy, post-oncolytic therapy, and after DC–CIK therapy. Results: Nine patients with advanced malignancy were treated with OVT (OrienX010), of whom seven experienced stable disease (SD). Five of the OVT treated patients underwent leukapheresis, generation, and delivery of DC–CIKs, and two had SD, whereas three progressed. T cell receptor sequencing of TCR β sequences one month after OVT therapy demonstrates a dynamic TCR repertoire in response to OVT therapy in the majority of patients with the systematic expansion of multiple T cell clone populations following DC–CIK therapy. This treatment was well tolerated and long-term event free and overall survival was observed in six of the nine patients. Conclusions: Strategies inducing the local activation of tumor-specific immune responses can be combined with adoptive cellular therapies to expand the adaptive T cell responses systemically and further studies are warranted.

Recombinant human endostatin could eliminate the pro-angiogenesis priority of SP cells sorted from non-small cell lung cancer cells

PurposeTo ascertain the biologic significance of lung cancer Side population (SP) cells, which represent putative cancer stem cells (CSC) in the absence of consensus biomarkers for tumor-specific CSC.Materials and methodsWe sorted and analyzed the angiogenic features of SP cells, isolated from tumor cell lines based on the exclusion of the DNA dye Hoechst 33342, from the NSCLC cell lines A549 and H460.ResultsCompared with non-SP cells, mRNA of vascular endothelial growth factor (VEGF)-A, VEGF-B, angiopoietin (ang)-1, ang-2, fibroblast growth factor-2 (FGF-2), cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8) were over-expressed in SP cells accompanied by over-expression of ABCG2 and MDR1 mRNA. The supernatant of cultured SP cells could significantly induce migration of human umbilical vein endothelial cells, while recombinant human endostatin (Endostar 25®) could inhibit the migration.ConclusionsThis study revealed that the NSCLC SP cells might represent CSCs and possess pro-angiogenic properties, and antiangiogenesis represent a potential therapy.

Continuous DC-CIK Infusions Restore CD8 + Cellular Immunity, Physical Activity and Improve Clinical Efficacy in Advanced Cancer Patients Unresponsive to Conventional Treatments

BACKGROUND There are few choices for treatment of advanced cancer patients who do not respond to or tolerate conventional anti-cancer treatments. Therefore this study aimed to deploy the benefits and clinical efficacy of continuous dendritic cell-cytokine induced killer cell infusions in such patients. MATERIALS AND METHODS A total of 381 infusions (from 67 advanced cases recruited) were included in this study. All patients underwent peripheral blood mononuclear cell apheresis for the following cellular therapy and dendritic cells-cytokine induced killer cells were expanded in vitro. Peripheral blood T lymphocyte subsets were quantified through flow cytometry to address the cellular immunity status. Clinical efficacy and physical activities were evaluated by RECIST criteria and Eastern Cooperative Oncology Group scores respectively. Logistic regression model was used to estimate the association between cellular infusions and clinical benefits. RESULTS An average of 5.7±2.94x10(9) induced cells were infused each time and patients were exposed to 6 infusions. Cellular immunity was improved in that cytotoxic CD8+CD28+T lymphocytes were increased by 74% and suppressive CD8+CD28-T lymphocytes were elevated by 16% (p<0.05). Continuous infusion of dendritic cells-cytokine induced killer cells was associated with improvement of both patient status and cellular immunity. A median of six infusions were capable of reducing risk of progression by 70% (95%CI 0.10-0.91). Every elevation of one ECOG score corresponded to a 3.90-fold higher progression risk (p<0.05) and 1% increase of CD8+CD28- T cell proportion reflecting a 5% higher risk of progression (p<0.05). CONCLUSIONS In advanced cancer patients, continuous dendritic cell-cytokine induced killer cell infusions are capable of recovering cellular immunity, improving patient status and quality of life in those who are unresponsive to conventional cancer treatment.

Dendritic Cell/Cytokine-Induced Killer Cell Immunotherapy Combined with S-1 in Patients with Advanced Pancreatic Cancer: A Prospective Study

Purpose: Advanced pancreatic cancer has remained challenging to treat effectively. This study aimed to investigate the clinical effects and safety of immunotherapy with dendritic cells and cytokine-induced killer cells (DC-CIK) administered with the chemotherapy (CT) S-1 in this malignancy. Experimental Design: Consecutive patients (n = 47) with advanced pancreatic cancer were treated with either DC-CIK + S-1, DC-CIK alone, S-1 alone, or best supportive care. Results: DC-CIK plus S-1 produced significantly longer median OS and PFS (212 and 136 days) compared with DC-CIK (128 and 85 days), CT (141 and 92 days), or supportive care only (52 and 43 days; P < 0.001). After adjusting for competing risk factors, DC-CIK combined with S-1 and receipt of 2 or more cycles of DC-CIK treatment remained independent predictors of disease-free and overall survival (P < 0.05). Phenotypic analysis of PBMCs demonstrated that the CD3+, CD3+/CD4+, and CD8+/CD28+ T-cell subsets were elevated (P < 0.05), while the CD3+/CD8+, CD3+/CD16+/CD56+ and CD4+/CD25+ cell subsets were significantly decreased after DC-CIK cell therapy (P < 0.05). There were no grade 3 or 4 toxicities. In addition, the mutational frequency in cell-free tumor DNA (cfDNA) declined in 4 of 14 patients who received DC-CIK, and was associated with a more favorable survival. Conclusions: Treatment of advanced pancreatic cancer with combined DC-CIK infusions and S-1 was safe, resulted in favorable PFS and OS, and modulated the peripheral blood immune repertoire. Clin Cancer Res; 23(17); 5066–73. ©2017 AACR.

The prognostic value of peripheral CD4+CD25+ T lymphocytes among early stage and triple negative breast cancer patients receiving dendritic cells-cytokine induced killer cells infusion.

Objective This study aimed to assess the prognostic value of CD4+CD25+ T lymphocyte in peripheral blood among breast cancer patients treated with adoptive T lymphocytes immunotherapy. Methods 217 patients participated in the follow-up study. CD4+CD25+ proportion was measured by flow cytometry in peripheral T cells. The median survival was estimated by Kaplan-Meier curve, Log-rank test and Cox hazard proportion regression model, between groups of CD4+CD25+ proportion more than 5% and less than or equal to 5% in peripheral T cells. Results Peripheral CD4+CD25+ T lymphocytes had not a relationship with progression-free survival. It was featured that above 5% peripheral CD4+CD25+ proportion of T cells was related with the median overall survival by a shorten of 51 months (p < 0.05) with the HR 1.65 (95%CI 1.04, 2.62). Above 5% CD4+CD25+proportion of T cells produced the HR to be 1.76 (95%CI 1.07, 2.87) In stage 0-II patients, and 3.59 (95%CI 1.05, 12.29) in triple negative breast cancer patients. Conclusion Cellular immunity restoration recovered by adoptive T cell infusions which resulted in less proportion of peripheral CD4+CD25+T lymphocytes could be a potential prognostic indicator among early stage and triple negative patients.

Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

BACKGROUND The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities. METHODS 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded. RESULTS GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity. CONCLUSIONS These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.