Lianyu Chen

The IL-8/CXCR1 axis is associated with cancer stem cell-like properties and correlates with clinical prognosis in human pancreatic cancer cases

CXCR1, a receptor for CXCL8/IL-8, has recently been demonstrated to be associated with cancer stem cell (CSC) populations in certain types of human cancers. However, the effect of CXCR1 on CSC and its prognostic value in human pancreatic cancer remain unknown. In this study, we evaluated the expression of CXCR1 in human pancreatic duct adenocarcinoma (PDAC) and found that positive CXCR1 expression correlated with lymph node metastasis (P = 0.017) and a poor survival rate (HR, 3.748; 95% CI, 1.822 to 7.712; P < 0.001) in patients with PDAC. In addition, we identified significant positive correlations between CXCR1 and CD44 (P = 0.002) and CD133 (P = 0.017). Further functional studies confirmed that IL-8 addition increased sphere formation, CSC populations, and cell invasion of pancreatic cancer cells and that these effects could be reversed by antagonizing CXCR1 with a CXCR1-specific antibody. Therefore, our study demonstrated that the IL-8/CXCR1 axis is associated with the CSC-like properties of pancratic cancer cells and prognosis in human pancreatic cancer. This suggested a way of targeting pancreatic CSCs by disrupting IL-8/CXCR1 axis.

Analgesic effect of high intensity focused ultrasound therapy for unresectable pancreatic cancer.

Objective: To evaluate the pain-alleviating action, feasibility and efficacy of high intensity focused ultrasound (HIFU) for palliation of inoperable pancreatic cancer in humans. Methods: Forty patients with advanced pancreatic cancer were treated with HIFU. There were 13 patients with stage III, and 27 patients with stage IV disease. The locations of the tumours were as follows: head of pancreas in 9 patients, body and/or tail of pancreas in 31 patients. Pain relief, local tumour control rate, median survival and complications were monitored after HIFU treatment. The primary endpoint was to assess pain relief rate and pain relief time (PRT). Secondary endpoints included local progression-free survival time, overall survival (OS), and side effects. Results: There were no severe complications or adverse events related to HIFU therapy in any of the patients treated. Pain relief was achieved in 87.5% of patients, median PRT was 10 weeks. The median local progression-free survival time for all patients was 5 months. The median overall survival time was 10 months for patients with stage III disease, and 6 months for patients with stage IV disease. The median OS time, 6-month and 1-year survival rate for patients as a whole were 8 months, 58.8% and 30.1%, respectively. Conclusions: Although this study may have limitations, preliminary results demonstrate the safety of clinical application of HIFU for pancreatic cancer and reveal it to be a promising mode of treatment for palliation of pain associated with pancreatic cancers.

Tumor Microenvironment Varies under Different TCM ZHENG Models and Correlates with Treatment Response to Herbal Medicine

In traditional Chinese medicine (TCM), diagnosis of pathology and choice of treatment prescriptions are based on a method of differentiation of signs and symptoms known as syndrome differentiation or ZHENG. The cornerstone of TCM, ZHENG, relies on the gathering of clinical information through inspection, auscultation and olfaction, inquiry, and palpation. However, the biomolecular basis of the ZHENG remains unclear. In this study, we established mouse xenograft pancreatic cancer models with Shi-Re (Dampness-Heat), Pi-Xu (Spleen-Deficiency), or Xue-Yu (Blood-Stasis) ZHENG, which are regarded as the three major ZHENGs in pancreatic cancer. We found that tumors of the different ZHENG models exhibited significantly altered cancer-associated fibroblast (CAF) proliferative activity and tumor-associated macrophage (TAM) infiltration, which led to altered levels of CAF- and TAM-derived secreted cytokines such as SDF-1 and CCL5. The ZHENG model type also significantly influenced tumor growth, and administration of herbal medicine to the ZHENG model modified the tumor microenvironment. Therefore, this study partially unveiled the molecular basis of TCM ZHENG in pancreatic cancer.

Chinese Herbal Medicine Suppresses Invasion-Promoting Capacity of Cancer-Associated Fibroblasts in Pancreatic Cancer

Pancreatic cancer remains one of the leading causes of cancer-related deaths, due to aggressive growth, high metastatic rates during the early stage and the lack of an effective therapeutic approach. We previously showed that Qingyihuaji (QYHJ), a seven-herb Chinese medicine formula, exhibited significant anti-cancer effects in pancreatic cancer, associated with modifications in the tumor microenvironment, particularly the inhibition of cancer-associated fibroblast (CAF) activation. In the present study, we generated CAF and paired normal fibroblast (NF) cultures from resected human pancreatic cancer tissues. We observed that CAFs exhibited an enhanced capacity for inducing pancreatic cancer cell migration and invasion compared with NFs, while QYHJ-treated CAFs exhibited decreased migration and invasion-promoting capacities in vitro. The results of further analyses indicated that compared with NFs, CAFs exhibit increased CXCL1, 2 and 8 expression, contributing to the enhanced invasion-promoting capacities of these cells, while QYHJ treatment significantly suppressed CAF proliferation activities and the production of CAF-derived CXCL1, 2 and 8. These in vitro observations were confirmed in mice models of human pancreatic cancer. Taken together, these results suggested that suppressing the tumor-promoting capacity of CAFs through Chinese herbal medicine attenuates pancreatic cancer cell invasion.

The Molecular Mechanisms of Traditional Chinese Medicine ZHENG Syndromes on Pancreatic Tumor Growth

Background: Traditional Chinese medicine (TCM) syndromes (ZHENG in Chinese) are the abstraction from the comprehensive analysis of clinical information gained by the four main diagnostic TCM methods: observation, listening, questioning, and pulse analyses. Proper TCM diagnosis is the most important principle to guide the prescribing of Chinese herbs. Objective: To evaluate the specific effect of TCM ZHENG on tumor growth and to examine the molecular mechanisms underlying ZHENG and tumor growth. Methods: The authors established subcutaneous tumor models of pancreatic cancer ZHENG syndromes of Damp heat (Shi-Re) and Spleen deficiency (Pi-Xu). Tissue samples of the subcutaneous transplanted tumors from each model were studied versus control tumors. CCR5 and CXCR4 proteins in these tissues were assayed by immunohistochemical staining. The expression of CCR5/CCL5/CCL4/CCL3 and CXCR4/SDF-1 mRNA was investigated by reverse transcriptase—polymerase chain reaction (RT-PCR). SDF-1, CCL4, CCL5, and CCL3, which are ligands of CXCR4 and CCR5, were examined by ELISA. Results: The study found that tumor models with different ZHENG were successfully established in each group; the tumor growth of Shi-Re group was slower than that of the control group. It was found that there was a significant difference in CCR5 mRNA expression levels among the Pi-Xu, Shi-Re, and control groups. The results of immunohistochemistry staining revealed that the positive rate of CCR5 protein in Shi-Re group, Pi-Xu group, and control group was 25.00%, 53.33%, 83.33%, respectively. The Shi-Re group expressed the lowest levels of CCL5 and CCL4. Conclusion: The results of the study suggest that the existence of TCM ZHENG may influence the tumor growth in pancreatic cancer, which might be mediated by the expression of CCR5/CCL5/CCL4. This finding may lead to the development of TCM ZHENG as a prognostic indicator in pancreatic tumor growth.

High intensity focused ultrasound treatment for patients with advanced pancreatic cancer: A preliminary dosimetric analysis

Objective: To analyse the clinical dosimetry of high intensity focused ultrasound (HIFU) for the treatment of inoperable pancreatic cancer in humans. Methods: 136 patients with advanced pancreatic cancer were treated with HIFU, including 89 male and 47 female patients. The median targeted volume (Vt) was 31.1 cm3 (range: 9.8–102.1). The median of the average ultrasound power (Pavg) was 225 W (range: 117–399), and the median energy of the ultrasound (Etotal) was 278.3 kJ (range: 70.5–1195.2). Spearman rank correlation analysis for HIFU dosimetric analysis was conducted. Results: There was a significant correlation between greyscale changes after HIFU ablation and HIFU dose intensity (DI), Pavg, and unit time (Tu). However, no correlation was found between greyscale changes after HIFU ablation and gender, age, pancreatic cancer position, or depth of tumour. Conclusions: We preliminarily deem that dose intensity and sound power can act as good reference points for HIFU dosimetry in the treatment of pancreatic tumours using the Chongqing system. If there was no obvious change in the ultrasound-monitored image following HIFU treatment for pancreatic cancer, the Pavg and DI should be no less than 260 W and 11 kJ/cm3, respectively.

Complete Response of Hepatocellular Carcinoma to Sorafenib: A Case Report and Review of Literatures

Background: Sorafenib is the current standard treatment for advanced and unresectable hepatocellular carcinoma (HCC). Although the efficacy of sorafenib on the overall survival and time to progression has been repeatedly proven, clinically evident and sustainable response especially Complete Response (CR) is rarely observed after its treatment. Case Report: We report a case of a 64-year old female patient with unresectable HCC who received sorafenib treatment of more than 8 months following a Transarterial Chemoembolization (TACE) treatment. The patient had a rapid and complete response within 1 month of sorafenib treatment, which sustained for more than 7 months after the initiation of the therapy. Conclusions: This result suggests that sorafenib alone or its use with TACE may be useful in the treatment of unresectable HCC. Translational clinical trials are needed to identify and exploit the underlying mechanism for this superb but rare observation.

Switching and extension of transmission response, based on bending metamaterials

The electromagnetically-induced transparency (EIT)-like effects in planar and non-planar metamaterials (MMs) were investigated for microwave (GHz) frequencies. The specific MMs used in this study consisted of a cut-wire resonator and a ring resonator, where were placed on the top and the bottom layers, respectively. A transmission window was produced, due to the interference between bright- and bright-mode coupling. Using the numerical and the experimental results, we demonstrate that the bending of MM leads to enhanced transmission and bandwidth, as well as an additional EIT-like peak. This provides an effective way of realizing the tunable devices, including the switching sensors.

Is chronic hepatitis B infection a protective factor for the progression of advanced pancreatic ductal adenocarcinoma? An analysis from a large multicenter cohort study

Purpose Whether the progression of advanced pancreatic ductal adenocarcinoma (PDAC) patients could be affected by HBV exposure remains to be determined. Therefore, we conducted this study to assess the effect of HBV infection on PDAC progression among a large cohort in China. Methods A multicenter cohort study was conducted to explore whether liver metastasis and overall survival in locally advanced and metastatic PDAC could be affected by HBV infection. In this study, we collected 1,526 advanced PDAC patients at three participating hospitals - Shanghai Cancer Center, Changhai Hospital and Ruijin Hospital from 2004 to 2013. The association between HBV status and advanced PDAC progression was then examined. Results In multivariable Logistic regression model, chronic hepatitis B(CHB) infection was inversely associated with synchronous liver metastasis compared to non HBV infection (OR 0.41, 95% CI 0.19-0.85) for stage IV patients. In a multivariable Cox model, CHB infection (HR=0.11, 95% CI 0.02-0.82) is considered as a protective factor of metachronous liver metastasis compared to Non HBV infection for stage III patients. For stage IV patients, CHB infection was inversely associated with overall survival compared to non HBV infection (HR 0.70, 95% CI 0.51-0.95). Inactive carrier(IC) and resolved HBV infection showed no significant association with survival compared to non HBV infection. Conclusion This study indicated that CHB infection may serve as an independent factor which decrease synchronous or metachronous liver metastasis, and increase overall survival among advanced PDAC patients.

Overexpression of CBX3 in Pancreatic Adenocarcinoma Promotes Cell Cycle Transition-Associated Tumor Progression.

Background: Previous studies showed that Chromobox protein homolog 3 (CBX3) was overexpressed in several types of human cancers, however its pattern and role in pancreatic adenocarcinoma (PAAD) has not yet been understood. The aim of this study was to identify the expression and function of CBX3 in PAAD. Methods: Data of transcriptomic and protein expression of CBX3 in PAAD were collected from different databases and analyzed. The in vitro and in vivo role of CBX3 in PAAD was examined. Results: CBX3 was overexpressed in human PAAD tissues, which was associated with poor prognosis of overall and disease-free survival of the patients. Overexpression of CBX3 induced the in vitro proliferation, anchorage-free growth, migration and invasion of the PAAD cells, and led to in vivo growth of orthotoptic PAAD tumors in mice. GO and KEGG pathway analysis, as well as experimental observation showed that CBX3 may be associated with cell cycle transition of PAAD cells, and cyclin-dependent kinase 1 (CDK1) and proliferating cell nuclear antigen (PCNA) may mediate the tumor-promoting action of CBX3. CDK1 knockdown attenuated the cell cycle transition, proliferation and invasion of CBX3-overexpressing PAAD cells. Conclusion: Our findings suggest the tumor-promoting role of CBX3 in PAAD to be targeted by novel therapeutic strategies.