[Show abstract][Hide abstract] ABSTRACT: Increasing evidence has showed that hypoxia inducible factor-1 (HIF1) has an important role in hypoxia-induced lipid accumulation, a common feature of solid tumors; however, its role remains to be fully elucidated. Adipose differentiation‑related protein (ADRP), a structural protein of lipid droplets, is found to be upregulated under hypoxic conditions. In the present study, an MCF7 breast cancer cell line was used to study the role of ADRP in hypoxia‑induced lipid accumulation. It was demonstrated that hypoxia induced the gene expression of ADRP in a HIF1‑dependent manner. Increases in the mRNA and protein levels of ADRP was accompanied by increased HIF1A activity. In addition, a significant decrease in the mRNA and protein levels of ADRP were detected in presence of siRNA targeting HIF1A. Using a dual‑luciferase reporting experiment and chromatin immunoprecipitation assay, the present study demonstrated that ADRP is a direct target gene of HIF1, and identified a functional hypoxia response element localized 33 bp upstream of the transcriptional start site of the ADRP gene. Furthermore, the present study demonstrated the role of ADRP in low density liporotein (LDL) and very‑LDL uptake‑induced lipid accumulation under hypoxia. The knockdown of ADRP did not reduce HIF1‑induced lipid accumulation under hypoxia. Together, these results showed that ADRP may be not involved in HIF1-induced lipid accumulation.
Preview · Article · Oct 2015 · Molecular Medicine Reports
[Show abstract][Hide abstract] ABSTRACT: RNA binding proteins (RBPs) and microRNAs (miRNAs) are two of the most important post-transcriptional regulators of gene expression, and their aberrant expression contributes to the development of human malignancies. Let-7, one of the most well-known tumor suppressors, is frequently down-regulated in a variety of human cancers. The RBP LIN28A/LIN28B, a direct target of the let-7 family of miRNAs, is an inhibitor of let-7 biogenesis and is frequently up-regulated in cancers. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors is reportedly involved in cancer development, contributing to cellular proliferation, cell death resistance, angiogenesis, metastasis, metabolism reprogramming, tumor-associated inflammation, genome instability, acquiring immortality and evading immune destruction. In this review, we summarized the mechanisms of LIN28A/LIN28B and let-7 loop aberrant regulation in human cancer and discussed the roles and potential mechanisms of the LIN28A/LIN28B and let-7 loop in regulating the hallmarks of cancer. The crosstalk between LIN28A/LIN28B and let-7 loop and certain oncogenes (such as MYC, RAS, PI3K/AKT, NF-κB and β-catenin) in regulating hallmarks of cancer has also been discussed.
[Show abstract][Hide abstract] ABSTRACT: Surgery, chemotherapy, and radiotherapy have presented with the ability of killing tumor cells, as well as damaging the immune function, which can be corrected by the immunotherapy. The purpose of this perspective cohort study was to evaluate the efficacy of postoperative immunotherapies of tumor lysate-loaded dendritic cells (DC), in vitro DC-activated T (DC-AT), and activated T cells (ATC) combined with chemotherapy on the survival of patients with operable colorectal cancer. A total of 253 patients with primary colorectal cancer resection including 181patients receiving postoperative simple chemotherapy (control group) and 72 patients receiving immunotherapies of DC, DC-AT, and ATC combined with chemotherapy during the corresponding period (immunotherapy group) were enrolled in this perspective cohort study. The survival of these patients was analyzed. The immunotherapy group presented a higher 5-year overall survival rate than the control group (75.63 vs 67.81 %, P = 0.035), as well as 3-year overall survival rate (87.07 vs 74.80 %, P = 0.045). For patients with advanced cancer (TNM stages III and IV), immunotherapy significantly promotes mean survival than control subjects (59.74 ± 3.21 vs 49.99 ± 2.54 years, P = 0.034). Patients who received more than three cycles of immunotherapies had a higher 5-year overall survival rate than those with less than three cycles (82.10 vs 69.90 %, P = 0.035). No serious adverse effect was observed in the immunotherapy group. Postoperative immunotherapies with DC, DC-AT, and ATC combination can promote the survival of patients with operable colorectal cancer (Clinical Trials, ChiCTR-OCH-12002610).
[Show abstract][Hide abstract] ABSTRACT: Cancer stem cells represent a small subset of tumor cells which have the ability to self-renew and generate the diverse cells that comprise tumors. They are responsible for local tumor recurrence and distant metastasis. The inability to target cancer stem cells with current immune approaches may contribute to treatment failure. Novel immunotherapeutic strategies which specifically target cancer-initiating cells may improve their efficacy. In the implementation of such a strategy, ALDEFLUOR+/ALDHhigh has served as a reliable marker to isolate cancer stem cells from a number of tumor types in animal models and human tumors. Cancer stem cells are resistant to conventional tumor therapy. Nonspecific immunologic targeting of cancer stem cells by NK cells, NKTs, or γδT cells have been reported. In vitro-generated, cancer stem cell-primed T cells specifically targeting cancer stem cells of human xenographs have also been described. Recently, cancer stem cell vaccine has been shown to be capable of inducing protection against tumors in immunocompetent mice. In these models the mechanisms involved specific targeting of cancer stem cells by cancer stem cell-primed T cells and antibodies. Finally, targeting the tumor microenvironment, e.g., IL-6 neutralization or IL-6R blockade, or interrupting the CXCR1/IL-8 interaction may provide novel strategies to enhance immunological targeting of cancer stem cell by T cell and cancer stem cell vaccines. In this chapter, we will review these immunologic approaches to targeting cancer stem cells.
[Show abstract][Hide abstract] ABSTRACT: To explore the clinical application of laparoscopy in gastrointestinal abdominal emergency.
Clinical data of 44 cases with undefined acute abdomen undergoing laparoscopic surgery from October 2008 to October 2011 were analyzed retrospectively. Sixty-five cases treated by regular surgery during the same period were enrolled as controls.
In laparoscopic surgery group, 42 cases were diagnosed under laparoscopy(95.5%, 42/44). Thirty-four (77.3%,34/44) patients received operation successfully after diagnosis, including 20 of total laparoscopy, 14 of assistant small incision. Compared with control group, laparoscopic group had shorter length of incision[(6.7±2.2) cm vs. (15.8±3.4) cm], less blood loss[(51.4±30.3) ml vs. (117.9±49.5) ml], faster recovery of postoperative gastrointestinal function[postoperative oral intake(15.0±6.1) d vs. (30.5±8.4) d], shorter hospital stay[(5.6±4.2) d vs. (8.4±4.8) d] (all P<0.05), lower complication rate, and less surgical cost(P>0.05).
Laparoscopy is safe and effective in treating gastrointestinal abdominal emergency and therapeutic operation can be performed after a definite diagnosis.
No preview · Article · Oct 2013 · Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery
[Show abstract][Hide abstract] ABSTRACT: To explore the prognostic factors of anorectal malignant melanoma (ARMM).
Medical records and follow-up data of 34 patients with ARMM treated in the Chinese PLA General Hospital from March 1993 to November 2011 were analyzed retrospectively.
There were 26 abdominoperineal resections(APR) and 8 wide local excisions (WLE). Twenty patients underwent postoperative adjuvant therapy, including chemotherapy in 14 cases, radiotherapy in 2 cases, traditional Chinese medicine therapy in 4 cases and immunotherapy in 16 cases. Postoperative follow-up was carried out in all the patients and the mean follow-up period was 27 months. The 1-, 3- and 5-year overall survival rates were 76.3%, 39.6% and 20.6% respectively, while the 1-, 3- and 5-year disease-free survival rates were 60.6%, 30.8% and 12.8% respectively. APR and postoperative immunotherapy could significantly reduce the local recurrence rate. According to the Kaplan-Meier method, gross type of tumor, mural involvement, lymph metastasis, and clinical staging had significant effects on overall survival, while lymph metastasis and postoperative immunotherapy on disease-free survival. Cox proportional hazards model indicated that the clinical staging and postoperative immunotherapy were significant predictive factors.
Early diagnosis and correct choice of surgical method are the keys to the treatment. Postoperative immunotherapy can prolong disease-free survival.
No preview · Article · May 2013 · Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery
[Show abstract][Hide abstract] ABSTRACT: Monolayer tumor culture models have been used for evaluating the antitumor activity of immune cells in vitro. However, their value in this research is limited. We used human gastric cancer cells (BGC823) and collagen hydrogel as a matrix to establish an engineered three-dimensional (3-D) tumor culture model in vitro. Tumor cells grew in 3-D culture and formed spheroids in the collagen matrix. Evaluation of the antitumor activity of cytokine-induced killer (CIK) cells revealed that, compared with the 2-D cell culture models, CIK cells migrated towards the tumor cells and destroyed the spheroids and tumor cells in the engineered 3-D tumor culture model. The cytotoxicity of CIK cells against the tumor cells in the engineered 3-D tumor culture model was lower than that in 2-D tumor culture models at 12-36 h post-interaction, but there was no significant difference in the cytotoxicity at later time points. Further analysis indicated that dendritic cell-activated CIK cells had a significantly higher level of cytotoxicity against tumor cells, compared with CIK and anti-CEA/CD3-treated CIK cells, in the engineered 3-D tumor culture model. Our data suggest that the engineered 3-D gastric tumor culture model may better mimic the interaction of immune cells with tumor cells in vivo than the 2-D tumor culture models, and may be used for evaluating the antitumor activity of immune cells in vitro.
[Show abstract][Hide abstract] ABSTRACT: The Da Vinci system is a newly developed device for colorectal surgery. With advanced stereoscopic vision, lack of tremor, and the ability to rotate the instruments surgeons find that robotic systems are ideal laparoscopic tools. Since conventional laparoscopic total mesorectal excision is a challenging procedure, we have sought to assess the utility of the Da Vinci robotic system in anterior resections for rectal cancer.
Between November 2010 and December 2011, a total of 22 patients affected by rectal cancer were operated on with robotic technique, using the Da Vinci robot. Data regarding the outcome and pathology reports were prospectively collected in a dedicated database.
There were no conversions to open surgery and no postoperative mortality of any patient. Mean operative time was (220 ± 46) minutes (range, 152 - 286 minutes). The median number of lymph nodes harvested was (14.6 ± 6.5) (range, 8 - 32), and the circumferential margin was negative in all cases. The distal margin was (2.6 ± 1.2) cm (range, 1.0 - 5.5 cm). The mean length of hospital stay was (7.8 ± 2.6) days (range, 7.0 - 13.0 days). Macroscopic grading of the specimen was complete in 19 cases and nearly complete in three patients.
Robotic anterior resection for rectal surgery is safe and feasible in experienced hands. Outcome and pathology findings are comparable with those observed in open and laparoscopy procedures. This technique may facilitate minimally invasive radical rectal surgery.
No preview · Article · Jan 2013 · Chinese medical journal
[Show abstract][Hide abstract] ABSTRACT: Adoptive cellular transfer has been employed for cancer immunotherapy, including patients with gastric cancer. However, little is known about the distribution of effector cells after their injection via different pathways. In this study, we used human gastric cancer cells (BGC823) tagged with enhanced green fluorescent protein (EGPF) to establish a subcutaneous gastric cancer model in nude mice. Cytokine-induced killer (CIK) cells and cytotoxic T lymphocytes (CTLs) were generated from human peripheral blood and labeled with red fluorescent PKH26. A portion of CIK cells was armed with CEA/CD3-bispecific single-chain antibody. When CIK cells were injected into nude mice with established subcutaneous gastric cancer via peritumoral (p.t.), intravenous (i.v.) and intraperitoneal (i.p.) infusion respectively, the distribution of cells was observed using a live fluorescence imaging system. We found that only a very small number of CIK cells could travel to the tumor site after i.p. or i.v. infusion, and they inhibited subcutaneous tumor growth in vivo only immediately following injection. In contrast, p.t. injection resulted in a significantly higher accumulation of CIK cells at the tumor site for 48 hours and mediated the greatest tumor inhibition compared with the other two injection methods. In addition, we compared the antitumor activity of CIK, CEA/CD3-bscAb-CIK and CTL cells in vitro and in vivo after p.t. injection. Among the three types of immune cells, CTLs demonstrated the strongest antitumor activity both in vitro and in vivo. CEA/CD3-bispecific single chain antibody could effectively link T lymphocytes and tumor cells expressing CEA, and resulted in significantly higher accumulation of CIK cells at the tumor site compared with the parental CIK cells. This study indicates that peritumoral injection of immune effector cells by minimally invasive surgical procedures represents an effective delivery method of adoptive cellular immunotherapy. Tumor-specific immune cells, such as CTLs, are a better choice of effector cells than CIKs in cellular immunotherapy. Furthermore, CD3+ immune cells armed with the CEA/CD3-bispecific single chain antibody could more effectively travel to and accumulate at the site of tumors expressing CEA, such as gastric cancer.
[Show abstract][Hide abstract] ABSTRACT: With the development of minimally invasive surgery in China, the da Vinci surgical system was used more and more widely in gastrointestinal surgery. This paper summarizes the development history of the artificial intelligence-assisted surgery system, the application and in the promotion of gastrointestinal surgery in China. Application of this new technology promotes further the innovation and development of minimally invasive surgery, and will drive leap in the field of gastrointestinal minimally invasive surgery.
No preview · Article · Aug 2012 · Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery
[Show abstract][Hide abstract] ABSTRACT: Adoptive cellular immunotherapy (ACI) has been demonstrated to be a promising cancer therapeutic, however, the distribution of immune cells injected into a tumor-bearing body is unclear. In this study, we investigated the tumor-targeting capacity of cytokine-induced killer (CIK) cells and cytotoxic T lymphocytes (CTLs) in a human gastric carcinoma orthotopic mouse model using a near-infrared fluorescence imaging system. CIK cells and tumor-specific CTLs were prepared with the near-infrared fluorescent dye DiR. As expected, no significant change in the proliferation rate or antitumor activity of CIK cells and CTLs was noted after labeling with DiR. Furthermore, a gastric carcinoma orthotopic model was established using a fibrinogen-thrombin method in nude mice followed by intraperitoneal infusion of the labeled immune cells into nude mice with established gastric carcinoma. Dynamic tracing of the immune cells was performed using a fluorescence-based live imaging system. Concentrated fluorescence signals were observed for a minimum of two weeks at the tumor site in mice infused with either CIK cells or CTLs with a peak signal at 48 h. Notably, CTLs were more persistent at the tumor site and exhibited a more intense antitumor activity than CIK cells following infusion. These results provided visual evidence of the tumor-targeting capacity of immune cells in live animals.
Preview · Article · Aug 2012 · Experimental and therapeutic medicine
[Show abstract][Hide abstract] ABSTRACT: Most studies of cancer stem cells (CSC) involve the inoculation of cells from human tumors into immunosuppressed mice, preventing an assessment on the immunologic interactions and effects of CSCs. In this study, we examined the vaccination effects produced by CSC-enriched populations from histologically distinct murine tumors after their inoculation into different syngeneic immunocompetent hosts. Enriched CSCs were immunogenic and more effective as an antigen source than unselected tumor cells in inducing protective antitumor immunity. Immune sera from CSC-vaccinated hosts contained high levels of IgG which bound to CSCs, resulting in CSC lysis in the presence of complement. CTLs generated from peripheral blood mononuclear cells or splenocytes harvested from CSC-vaccinated hosts were capable of killing CSCs in vitro. Mechanistic investigations established that CSC-primed antibodies and T cells were capable of selective targeting CSCs and conferring antitumor immunity. Together, these proof-of-concept results provide a rationale for a new type of cancer immunotherapy based on the development of CSC vaccines that can specifically target CSCs.
[Show abstract][Hide abstract] ABSTRACT: To analyze clinical and pathological of lymph node skip metastasis of rectal cancer and discuss the meaning of the high vascular ligation.
A retrospective analysis of 207 cases for radical resection of rectal cancer was made, meanwhile the skip metastasis of the roots of the inferior mesenteric artery lymph nodes was studied. Combined with clinical data, the relevance of clinical and pathological factors with the skip metastasis was analyzed.
The 207 cases of rectal cancer patients surgical resection specimen detected 2305 pieces of lymph node, the transfer of 168 patients with. The statistical analysis found that skip metastasis related with tumor differentiation (χ(2) = 113.65, P = 0.037) and depth of tumor invasion (χ(2) = 108.22, P = 0.042), but gender, age, location, size, preoperative carcinoembryonic antigen level, gross type and tissue types factors were not significantly correlation.
Preoperative differentiation of cancer and tumor invasion depth assessment can help prompt the existence of lymph node skip metastasis. The assessment of the risk of skip metastasis for patients should be performed the high vascular ligation and lymph node dissection.
No preview · Article · Mar 2012 · Zhonghua wai ke za zhi [Chinese journal of surgery]
[Show abstract][Hide abstract] ABSTRACT: We investigated the antitumor reactivity of adoptively transferred effector B cells and the mechanisms by which they may mediate tumor regression in a spontaneous metastases model.
4T1 breast cancer cells were inoculated into the flanks of syngeneic Balb/C mice to prime draining lymph nodes. Tumor-draining lymph nodes (TDLN) were harvested and B cells activated ex vivo with lipopolysaccharide and anti-CD40 monoclonal antibody. These activated B cells were adoptively transferred into mice inoculated with 4T1 tumor in the mammary fat pad. The induction of host T-cell immunity was evaluated.
Activated 4T1 TDLN B cells secreted immunoglobulin G (IgG) in response to tumor cells which was immunologically specific. These activated B cells were capable of mediating specific lysis of tumor cells in vitro. Transfer of these activated B cells alone mediated the inhibition of spontaneous metastases to the lung. Examination of the host revealed that the transfer of these B cells resulted in the induction of tumor-specific T-cell immunity as measured by cytotoxicity and cytokine (IFNγ and granulocyte-macrophage colony-stimulating factor) production. The combined transfer of activated T and B cells from TDLN resulted in tumor regression, which was greater than either cell population alone, with host B cells capable of producing IgG that mediated lysis of tumor in the presence of complement.
We have found that appropriately primed B cells can mediate tumor regression by itself and confers host T-cell antitumor immunity. Furthermore, effector B cells can serve as a useful adjunct in adoptive T-cell therapy.
Preview · Article · Jun 2011 · Clinical Cancer Research