Deferoxamine (DFO), an iron chelator, is commonly used to remove excess iron from the body. DFO has also been demonstrated to have anti-tumor effect. However, there is no available report on the effect of deferoxamine on mesenchymal stromal cells (MSCs). In this study, we first isolated tumor-associated MSCs (TAMSCs) from EG-7 tumors, which were positive for CD29, CD44, CD73, CD90 and CD105. Ex vivo cultured stem cells derived from tumor and bone marrow compartment were exposed to DFO. We demonstrated that DFO had growth-arresting and apoptosis-inducing effect on TAMSCs and bone marrow MSCs (BMMSCs). DFO also influenced the expression pattern of adhesion molecule VCAM-1 on both TAMSCs and BMMSCs. Notwithstanding its widespread use, our results here warrants caution in the application of DFO, and also highlights the need for careful evaluation of the bone marrow compartment in patients receiving DFO treatment. (C) 2016 Elsevier B.V. All rights reserved.
Acute pancreatitis (AP) is a rare manifestation of pancreatic cancer (PC). The relationship between AP and PC remains less distinct. From January 2009 to November 2015, 47consecutive patients with PC who presented with AP were reviewed for this study. Clinical features, clinicopathologic variables, postoperative complications, and follow-up evaluations of patients were documented in detail from our database. In order to identify cutoff threshold time for surgery, receiver operating curve (ROC) was built according to patients with or without postoperative complications. Cumulative rate of survival was calculated by using the Kaplan-Meier method. The study was conducted in accordance with the principles of the Declaration of Helsinki and the guidelines of West China Hospital. This study included 35 men (74.5%) and 12 women (25.5%) (mean age: 52 years), with a median follow-up of 40 months. AP was clinically mild in 45 (95.7%) and severe in 2 (4.3%). The diagnosis of PC was delayed by 2 to 660 days (median 101 days). Thirty-nine (83.0%) cases underwent surgery. Eight (17.0%) cases performed biopsies only. Of 39 patients, radical surgery was performed in 32 (82.1%) cases and palliative in 7 (19.9%) cases. Two (8.0%) patients were needed for vascular resection and reconstruction. Postoperative complications occurred in 12 (30.8%) patients. About 24.5 days was the best cutoff point, with an area under curve (AUC) of 0.727 (P=0.025, 95% confidence interval: 0.555-0.8999). The survival rate of patients at 1 year was 23.4%. The median survival in patients with vascular resection and reconstruction was 18 months, compared with 10 months in patients without vascular resection (P=0.042). For the primary stage (T), Tix was identified in 3 patients, the survival of whom were 5, 28, 50 months, respectively. And 2 of them were still alive at the follow-up period. The severity of AP was mainly mild. Surgical intervention after 24.5 days may benefit for reducing postoperative complications. Patients with vascular resection and reconstruction, thus achieving tumor-free margins, had a long-time survival.
The influence of the biological relationship between the donor and the recipient is rarely discussed in living donor liver transplantation (LDLT), although it is believed to be an important risk factor in other types of organ transplantations. A total of 272 consecutive patients undergoing adult to adult right lobe LDLT were retrospectively analyzed and stratified into a nonbiologically related (NBR) group (69 patients) and a biologically related (BR) group (203 patients). The preoperative data and postoperative outcomes of both recipients and donors were evaluated. More than two-thirds of the recipients had histories of HBV infection, and hepatocellular carcinoma (HCC) was the main reason for the patients undergoing LDLT in both groups. The percentage of female donors in the NBR group was more than the percentage in the BR group (P=0.000). There were no differences between the groups in postoperative laboratory testing or daily immunosuppression dose, and the complication rates in both the recipient and donor surgeries showed no significant differences. For patients with benign diseases, the cumulative 1-, 3-, 5-, and 10-year survival rate were 92.9% in the 4 periods in the NBR group and 89.1%, 87.6%, 83.7%, and 83.7%, respectively, in BR group, while for the patients diagnosed as HCC, if patients exceeding the Milan criteria were involved, the 5-year survival rate was 41.2%, compared to 82% for patients within the Milan criteria, which was nearly the same as for those with the benign disease. In conclusion, our findings suggested that the biological relationship between the donor and the recipient in adult to adult LDLT was not associated with the short-and long-term outcomes of recipients diagnosed with benign liver diseases and early stage HCC. Moreover, the criteria for patients diagnosed with HCC to undergo LDLT should be restrictively selected.
Epirubicin (EPI) is one of the most widely used anticarcinogens; however, serious side effects, including cardiomyopathy and congestive heart failure, limit its long-term administration. To overcome this problem, the HAIYPRH peptide ligand was used with EPI in the synthesis of a HAIYPRH-EPI conjugate. The anticancer activity and cellular uptake of the conjugate were measured and evaluated. The results of the present study indicated that the cytotoxicity of HAIYPRH-EPI was correlated with the expression of the cell surface transferrin receptor (TfR). The conjugate exerted high cytotoxicity and proapoptotic function when in an LN229 glioma cell line, which overexpresses surface TfR. It was hypothesized that transferrin (Tf) can promote cytotoxicity. Conversely, the conjugate exhibited very low cytotoxicity and proapoptotic function in a U87 glioma cell line, in which surface TfR expression was undetectable. In addition, fluorescence microscopy and flow cytometry methods were used to evaluate cellular uptake, and the results of these methods were consistent with the present hypotheses. The conjugate cellular uptake of the conjugate in LN229 cells was markedly higher compared with that in U87 cells, and it was hypothesized that Tf can enhance the uptake in LN229 cells. The cytotoxicity of HAIYPRH-EPI was dependent upon the expression of surface TfR. Considering that the majority of cancer cells have high rates of iron uptake and surface TfR is generally overexpressed on cancer cells, it was speculated by the authors that HAIYPRH-EPI may form part of an effective strategy for increasing the selectivity of EPI for cancer cells, as well as reducing its systemic toxicity. To confirm the hypothesis, the effects of HAIYPRH-EPI on non-cancerous cell lines were investigated. A future study will examine the side effects of HAIYPRH-EPI, using a suitable delivery system in an animal model.
Background: Multiple studies have reported evidence of an inverse association between parity and bladder cancer risk. However, a comprehensive and quantitative assessment of this association has never been conducted. We conducted this study to clarify this issue. Methods: Systematic search of PubMed and Embase was performed to identify all the studies. Studies were selected based on strict screening with inclusion and exclusion criteria. Summary relative risks (RR) with 95% confidence intervals (CI) were calculated by using a fixed-effect model, and the generalized least squares trend estimation was employed to compute study-specific RR and 95% CI per live birth increase. Heterogeneity and publication bias were also evaluated. Results: Twelve studies (6,214 cases and 2,693,350 non-cases) were eligible in this meta-analysis. The pooled RR of bladder cancer for parous versus nulliparous women was 0.76 (95% CI: 0.70-0.82). Results were similar in the studies that adjusted for BMI(RR = 0.66; 95% CI: 0.53-0.81), cigarette smoking (RR = 0.67; 95% CI: 0.57-0.79), and age (RR = 0.77; 95% CI: 0.71-0.84). The dose-response meta-analysis showed a lower bladder cancer risk (RR = 0.95; 95% CI: 0.92-0.98) for each live birth increase in parous women. No evidence of publication bias or significant heterogeneity was detected in the above-mentioned analyses. Conclusions: The finding from current meta-analysis suggest that parity may be related to decreased risk of bladder cancer.
To compare the ablation results, therapeutic responses and adverse reactions between a low dose (1.1 GBq) or high dose (3.7 GBq) of I-131 in low-/intermediate-risk differentiated thyroid cancer (DTC) patients. The factors influencing the ablation result and therapeutic response were also analyzed. The researchers used a random number table to randomly assign the enrolled patients to the low-dose group or high-dose group at a 1:1 ratio, and assessment of ablation result, therapeutic response, and adverse reactions evaluated 6 +/- 3 months after therapy. A total of 140 patients were enrolled in the study through October 2014-June 2015. Until February 2016, 132 patients completed the trial. 99 patients were re-examined under thyroid-stimulating hormone (TSH) stimulation 3-9 months after I-131 therapy. For the low-dose and high-dose groups, the success rates of ablation were 52.7 % (29/55) and 59.1 % (26/44), respectively. The ablation results did not differ significantly between the two groups (P = 0.548). One hundred and thirty two patients were re-examined 2-9 months after I-131 therapy. The low-dose group had an excellent response rate of similar to 80 % (53/66), an indeterminate response rate of similar to 20 % (13/66), and no cases with a biochemical incomplete response. The high-dose group had an excellent response rate of similar to 85 % (56/66), an indeterminate response rate of similar to 11 % (7/66), and a biochemical incomplete response rate of similar to 4 % (3/66). No significant differences in the therapeutic response were observed between the two groups (P = 0.087). Patients in stage N1b had a significantly lower success rate of ablation than those in stage N0 (P = 0.000). The success rate of ablation increased significantly with lower thyroglobulin (Tg) levels (P = 0.000). A pre-treatment Tg level was significantly associated with a higher excellent response rate (P = 0.002). Pre-treatment-stimulated Tg of 0.47 and 3.09 mu g/L were identified as cut-off values for predicting the ablation result and therapeutic response, respectively. The incidences of adverse reactions were 18 % (12/66) and 39 % (26/66) in the low-dose and high-dose groups, respectively, and this difference between the two groups was significant (P = 0.007). The result of thyroid remnant ablation and the response to therapy did not differ significantly between the two groups. The low-dose group had a lower incidence of adverse reactions than the high-dose group. N1b and pre-treatment-stimulated Tg were factors influencing the ablation result, whereas pre-treatment-stimulated Tg was a factor influencing the therapeutic response. Pre-treatment-stimulated Tg of 0.47 and 3.09 mu g/L were identified as cut-off values for predicting the ablation result and therapeutic response, respectively. The study protocol was approved by the Clinical Trials and Biomedical Ethics Committee of our hospital and registered on the Chinese Clinical Trial Registry under the registration number ChiCTR-IOR-15006139.
Breast cancer is the most common malignant disease in women, and metastasis formed at distant anatomic sites was the major cause of cancer-related mortality. Thus, a novel therapy target and progression biomarker for breast cancer metastasis was necessary. microRNA (miR)-376b has been demonstrated to regulate angiogenesis; however, its role in cancer metastasis remains elusive. In the present study, the expression of miR-376b in normal breast tissue, JC and 4T1 cells was determined by qPCR. Furthermore, in vitro and in vivo experiments were performed to determine the effect of miR-376b on breast cancer metastasis. The direct target of miR-376b was determined by the luciferase assay and western blotting. The results indicated that silencing of miR-376b by the miR-376-mimic significantly inhibited 4T1 cell migration and invasion in vitro. Lung metastasis was also evidently decreased after silencing of miR-376b in 4T1 cells. Moreover, the luciferase assay and western blotting identified that Hoxd10 is the direct target of miR-376b during the regulation of breast cancer metastasis. To the best of our knowledge, the present study was the first to demonstrate the promoting breast cancer metastasis role of miR-376b by directly targeting Hoxd10. Therefore, it would be a novel therapy target and prognostic biomarker for breast cancer.
Cucurbitacin B (CuB), a triterpenoid compound isolated from the stems of Cucumis melo, has long been used to treat hepatitis and hepatoma in China. Although its remarkable anti-cancer activities have been reported, the mechanism by which it achieves this therapeutic activity remains unclear. This study was designed to investigate the molecular mechanisms by which CuB inhibits cancer cell proliferation. Our results indicate that CuB is a novel inhibitor of Aurora A in multiple myeloma (MM) cells, arresting cells in the G2/M phase. CuB also inhibited IL-10-induced STAT3 phosphorylation, synergistically increasing the anti-tumor activity of Adriamycin in vitro. CuB induced dephosphorylation of cofilin, resulting in the loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-8. CuB inhibited MM tumor growth in a murine MM model, without host toxicity. In conclusion, these results indicate that CuB interferes with multiple cellular pathways in MM cells. CuB thus represents a promising therapeutic tool for the treatment of MM.
Purpose Long non-coding RNAs (lncRNAs) play important roles in the malignant behavior of cancer. HOTAIR, a well-studied lncRNA, contributes to breast cancer development, and overexpression of HOTAIR predicts a poor prognosis. However, the regulatory role of HOTAIR in the cancer stem-like cell (CSC) subpopulation remains largely unknown. Our goal was to determine the regulatory functions of HOTAIR in the processes of self-renewal capacity, tumor formation and proliferation of CSCs derived from breast cancer. Methods We first enriched and incubated the CSC population derived from breast cancer cell line MCF7 (CSC-MCF7) or MDA-MB-231 (MB231, CSC-MB231). Self-renewal capacity and tumor formation were assessed in vitro and in vivo to determine the stemness of CSCs. We assessed the impact on ectopically upregulated or downregulated expression of HOTAIR in CSCs by soft agar, self-renewal capacity and CCK-8 assays. The functional domain of HOTAIR was determined by truncation. RT-qPCR and semiquantitative Western blotting were performed to detect the expression levels of genes of interest. Chromatin IP (ChIP) was employed to detect the transcriptional regulatory activity of p53 on its target gene. Results After the identification of CSC properties, RT-qPCR analysis revealed that HOTAIR, but not other cancer-associated lncRNAs, is highly upregulated in both CSC-MCF7 and CSCMB231 populations compared with MCF7 and MB231 populations. By modulating the level of HOTAIR expression, we showed that HOTAIR tightly regulates the proliferation, colony formation, migration and self-renewal capacity of CSCs. Moreover, full-length HOTAIR transcriptionally inhibits miR-34a specifically, leading to upregulation of Sox2, which is targeted by miR-34a. Ectopic introduction of miR-34a mimics reverses the effects of HOTAIR on the physiological processes of CSCs, indicating that HOTAIR affects these processes, including self-renewal capacity; these effects are dependent on the regulation of Sox2 via miR-34a. Interestingly, tight transcriptional regulation of p53 by HOTAIR was found; accordingly, p21 is indirectly regulated by HOTAIR, resulting in cell cycle entry. Conclusion These results suggest that HOTAIR is a key regulator of proliferation, colony formation, invasion and self-renewal capacity in breast CSCs, which occurs in part through regulation of Sox2 and p53.
Interleukin 23 (IL-23) is an inflammatory cytokine which plays a vital role in autoimmune diseases as well as in tumorigenesis. However, the role of IL-23 in tumor procession is still controversial and the underlying mechanism remains unclear. Here we established a stable cell line overexpressing IL-23 to prove that IL-23 promoted tumor growth and pulmonary metastasis through induction of tumor-related inflammation and absence of immune surveillance. IL-23 promotes tumor-associate inflammatory response such as infiltration of M2 macrophages, neutrophils and their elevated secretions of immunosuppressive cytolcines transforming growth factor-beta (TGF-beta), IL-10 and vascular endothelial growth factor (VEGF) into tumor tissues, meanwhile the increase of the matrix metalloprotease MMP9. In addition, IL-23 increases the expression of the endothelial marker CD31 and proliferative marker Ki67 in tumors. Moreover, IL23 induces immunosuppression though reducing the infiltration of CD4(+) and CD8(+)T cells into tumor tissues. In conclusion, IL-23 is a considerable molecular in tumor progression, which simultaneously facilitates processes of pro-tumor inflammation, such as angiogenesis, immunosuppressive cytolcines as well as infiltrations of M2 macrophages and neutrophils, and suppresses antitumor immune responses through reduction of CD4(+) T cells and CD8(+) T cells. (C) 2016 Elsevier Inc. All rights reserved.