Medicine has encountered unprecedented problems associated with changes in nature, society, and environment, as well as with new human quests for survival, longevity, and health. In the meantime, the development of medicine is facing challenges that resulted from the over-division and specialization of disciplines and the fragmentation of medical knowledge. To construct a new medical system that is more suitable for human health and disease treatment, holistic integrative medicine (HIM), which regards the human body as a holistic entity, organically integrates the most advanced knowledge and theories in each medical field and the most effective practices in various clinical specialties to revise and adjust on the basis of social, environmental, and psychological conditions. HIM is the inevitable and necessary direction for the future development of medicine. In this article, we illustrated the connotation of HIM, the differences between HIM and other medical conceptions, and the practice of HIM in recent years.

•Psychological disorders may be potential causative factors in tumor development.•Psychological stress can undermine immune function through multiple biological and behavioral pathways to some extent.•In a way, immune dysfunction is correlated with the biology of cancer.•Cancer is partly seen as a somatopsychic disorder.Although not fully proven yet, in a way, cancer is seen as a disorder correlated with somatopsychic factors such as worry and depression. Previous epidemiological and experimental studies have revealed the potentially causative roles of psychological disorders in tumor development. According to some studies, psychological stress can undermine immune function through multiple biological and behavioral pathways, which may be one of the causes for carcinogenesis. The findings that malignant cells express antigens that can be recognized by immune cells and that immune effector mechanisms are tumoricidal has increased our understanding of the relationship between immune function and the biology of cancer. Integrative treatment methods, including yoga, massage, music, and mindfulness-based therapy have been found to be helpful in cancer therapy partly because they can reduce stress and improve mood.Download high-res image (165KB)Download full-size image

Traditional Chinese medicine (TCM) is one of the unique cultural treasures of Chinese; it represents a significant feature and prominent advantage of the healthcare cause in China. Data in this paper were fromWorld Health Organization, Chinese Bureau of Statistics, China National Knowledge Infrastructure, and PubMed. In recent years, TCM has established a solid foundation in Europe, which made great strides in legislation, education, research, and international exchange, and has enjoyed a vast development space in the continent. Now, TCM is embracing unprecedented development opportunities in Europe. At the same time, the stiff international competition poses a grave threat to China’s TCM industry. With multiple cultural, legal, and institutional challenges, as well as talent shortages in the way, TCM is now facing many difficulties in Europe. To fully prepare and enact active and vigorous steps to seize opportunities, we should have a clear picture about the serious challenges hampering TCM development in Europe. The TCM development at overseas markets has shifted from a spontaneous trade activity into a national strategy spearheaded by the government and participated in by multiple stakeholders. We should make a systematic, comprehensive, and sustainable push in fields such as TCM therapy, healthcare, education, research, culture, and industry development. The ultimate goal is to bring TCMs to the global market and allow them to play a role in safeguarding public health along with modern medicines.

Gastric carcinogenesis occurs when gastric epithelial cells transition through the initial, immortal, premalignant, and malignant stages of transformation. Epigenetic regulations contribute to this multistep process. Due to the critical role of epigenetic modifications , these changes are highly likely to be of clinical use in the future as new biomarkers and therapeutic targets for the early detection and treatment of cancers. Here, we summarize the recent findings on how epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNAs, regulate gastric carcinogenesis, and we discuss potential new strategies for the diagnosis and treatments of gastric cancer. The strategies may be helpful in the further understanding of epigenetic regulation in human diseases.

Hepatopulmonary syndrome (HPS) is a pulmonary complication observed in patients with chronic liver disease and/or portal hypertension, attributable to an intrapulmonary vascular dilatation that may induce severe hypoxemia. Microvascular dilation and angiogenesis in the lung have been identified as pathologic features that drive gas exchange abnormalities in experimental HPS. Pulse oximetry is a useful screening test for HPS, which can guide subsequent use of arterial blood gases. Contrast-enhanced echocardiography, perfusion lung scanning, and pulmonary arteriography are three currently used diagnostic imaging modalities that identify the presence of intrapulmonary vascular abnormalities. The presence of HPS increases mortality and impairs quality of life, but is reversible with liver transplantation. No medical therapy is established as effective for HPS. At the present time, liver transplantation is the only available treatment for HPS.

Uncontrolled proliferation is a key characteristic of gastric carcinogenesis and the precise mechanisms underlying the altered proliferation behaviors of GC cells have not been clearly elucidated. miRNAs has been suggested to play a crucial role in the pathogenesis and development of various cancers. In the present study, we employed an impedance-based real-time cell electronic sensing (RT-CES) system to detect the effects of ectopically expressed miRNAs on GC cell proliferation.miRNA mimics were transfected into gastric cancer cell line SGC7901 and the effect of individual miRNA on the proliferation rate of the cells was measured by the RT-CES system. The screening results were validated with qRT-PCR and miR-137 was selected for further research. The effects of ectopically expressed miR-137 on GC cell growth and cell cycle progress were measured using MTT assay and flow cytometry. The target gene of miR-137 was predicted using different bioinformatics tools and the direct interaction between miR-137 and the 3’-UTR was confirmed with a luciferase reporter assay. The in vivo effect of miR-137 on GC cell proliferation was examined with a tumor-bearing nude mouse model. The correlation between miR-137 expression and patients’ prognosis was explored in a cohort of 38 patients. Prognosis was explored in a cohort of 38 patients.Ectopic expression of miR-137 was sufficient to inhibit GC cell proliferation both in vitro and in vivo. Bioinformatics prediction and luciferase reporter assay revealed CDK6 as a target gene through which miR-137 exerted an inhibitory function. Moreover, miR-137 expression positively correlated with better prognosis.Our data indicated an important regulatory role of miR-137 in GC cell proliferation and that it may be explored as a prognostic marker for GC.

Chemoresistance remains the most significant obstacle to successful chemotherapy for leukemia, and its exact mechanism is still unknown. In this work, we used the cell-surface capturing method together with quantitative proteomics to investigate differences in the glycoproteomes of adriamycin-sensitive and adriamycin-resistant leukemia cells. Two quantitative methods, isotopic dimethyl labeling and SWATH, were used to quantify glycoproteins, and 35 glycoproteins were quantified by both methods. High correlation was observed between the glycoproteins quantified by the above two methods, and 15 glycoproteins displayed a consistent significant change trend in both sets of quantitative results. These 15 proteins included classical multidrug resistance-related glycoproteins such as ABCB1 as well as a set of novel glycoproteins that have not previously been reported to be associated with chemoresistance in leukemia cells. Further validation with quantitative real-time PCR and Western blotting confirmed the proteomic screening results. Subsequent functional experiments based on RNA interference technology showed that CTSD, FKBP10, and SLC2A1 are novel genes that participate in the acquisition and maintenance of the adriamycin-resistant phenotype in leukemia cells.

Gastric cardia adenocarcinoma (GCA) is a unique malignant tumor for its characteristics different from gastric and esophageal cancer epidemiologically and pathologically. The incidence of GCA has steadily increased for the last three decades and many patients are diagnosed with advanced stage because of the lack of typical and obvious symptoms at an early stage. To gain insight into the molecular mechanisms of GCA of advanced stage, we investigated the microarray expression profile of long non-coding RNAs of 12 advanced stage GCA patients. Long non-coding RNAs (lncRNAs) lack protein-coding potential and are over 200 bp in length. LncRNAs are known to be involved in the multifactor and multistep processes of tumor development and metastasis. In this study, we performed lncRNA transcriptome profiling of GCA biopsy tissue from 12 GCA patients who were confirmed by pathology to have developed lymph node metastasis and 12 paired non-cancerous gastric cardia tissues to determine if a gene expression profile unique to the lymph node metastasis group could be detected. Comparison of differentially expressed transcripts between the groups identified eight pathways that corresponded to down-regulated transcripts and 18 pathways that corresponded to up-regulated transcripts (p value cut-off 0.05). Gene ontology analysis showed that the up-regulated transcripts were most highly enriched in SRP-dependent cotranslational protein targeting to membrane, cytosolic ribosome, and structural constituent of ribosome, and the down-regulated transcripts were highly enriched in carboxylic acid transport, focal adhesion, and cation binding. This study shows that lncRNAs dysregulation exerts important roles in human GCA lymph node metastasis, indicating that lncRNAs are novel candidate biomarkers for the clinical diagnosis of advanced stage GCA and that could be targets for further therapy.

LRPPRC is a multifunctional protein involved in mitochondrial gene expression and function, cell cycle progression, and tumorigenesis. We analyzed LRPPRC gene expression in 253 paired cases of gastric cancer and noncancerous regions and six gastric cancer cell lines to demonstrate the importance of LRPPRC expression for the prediction of prognosis of gastric cancer. Our results showed that LRPPRC expression in gastric cancer tissues is significantly higher than that in paired control tissue (P < 0.001). Patients with higher LRPPRC expression showed a poorer overall survival rate than those with lower LRPPRC expression (P < 0.001). Multivariate analysis demonstrated that lymph node metastasis (N), distant metastasis (M), TNM stage, and LRPPRC expression were independent prognostic factors for gastric cancer (P = 0.004, 0.002, 0.017, 0.004 respectively).Moreover, Western blotting showed that LRPPRC expression was increased in SGC7901, BGC823, MKN45, and XGC9811cells. The in vitro proliferation assay showed that LRPPRC expression is inversely associated with gastric cancer cells growth. Our results indicated that LRPPRC could be used as a predictive marker for patient prognosis of gastric cancer and may be a novel therapeutic target for gastric cancer in future.

Krüppel-like factor 8 (KLF8), a downstream transcription factor of transforming growth factor-β1 (TGF-β1), has a role in tumorigenesis, tumor progress and epithelial-to-mesenchymal transition (EMT) induction. Recent studies mainly focused on its role in breast cancer and hepatocellular carcinoma; however, little is studied in gastric cancer. Here, we aim to explore whether KLF8 is involved in TGF-β1-induced EMT in gastric cancer cells.Western blot and real-time PCR assays were used to detect the expression of KLF8, E-cadherin and vimentin in gastric cancer cell line SGC7901 treated with or without TGF-β1. The lentivirus-mediated RNA interference technique was used to knock down the expression of KLF8 in gastric cancer cell line SGC7901. In vitro, the ability of cell migration and invasion were measured by transwell and wound healing assays; the cell motility was detected by high content screening assay.TGF-β1 could induce EMT via down-regulating E-cadherin and up-regulating vimentin expression in gastric cancer cells. Further study found that TGF-β1 could induce KLF8 expression at the protein and mRNA levels in gastric cancer cells (P < 0.05). Western blot and real-time PCR assays found that small interference RNA (siRNA)-mediated KLF8 silence blocked TGF-β1-induced EMT-like transformation and subsequently reversed the loss of E-cadherin and gain of vimentin. In vitro, inhibition of KLF8 decreased TGF-β1-prompted cell migration, invasion and motility.KLF8, a transcription factor, is involved in TGF-β1-induced EMT in gastric cancer cells and may be a novel therapeutic target for the treatment of gastric cancer.

Liver fibrosis is characterized by accumulation of extracellular matrix. Our previous study found that osteopontin (OPN) increased in plasma of cirrhotic patients and indicative of cirrhosis staging. The present study was designed to investigate the expression of OPN in liver tissues and plasma of cirrhotic patients and further explore the role of OPN in human hepatic stellate cell (HSC) activation.We used immunohistochemical staining and enzyme-linked immunosorbent assay to evaluate the expression level of OPN in liver tissues and plasma from cirrhotic patients, respectively. We produced lentivirus particles and infected target cell to manipulate OPN expression. Infection efficiency was determined by real-time RT-PCR and western blot. Cell proliferation was determined using CCK8 assay, and phenotypes of HSC activation were determined by real-time RT-PCR. OPN promoter activity was determined by dual luciferase reporter assay.We found that OPN expression in human cirrhotic liver tissues was upregulated compared to normal controls. In addition, its expression correlated with Child-Pugh classification, MELD score and the occurrence of complications. We further explored OPN level in patients’ plasma and showed that its level correlated with transforming growth factor-β1 (TGF-β1). In human HSC cell line LX-2, we found that change of OPN expression level could not only affect the proliferation of cells but also the TGF-β1 mediated HSC activation. Moreover, OPN was increased by TGF-β1 stimulation and regulated by TGF-β1 at transcription level.OPN is upregulated in liver tissues and plasma of cirrhotic patients and promotes TGF-β1 mediated HSC activation.

Recent studies proved that inflammatory bowel disease (IBD) patients had a higher risk of thromboembolism and a Factor V Leiden mutation that prevents the efficient inactivation of factor V, which leads to thromboembolism and thus contributes to a high potential risk of IBD. However, the relationship between Factor V Leiden mutation and IBD remains controversial.We conducted a systematic review with meta-analysis of studies assessing the association of Factor V Leiden mutation with the risk of IBD in humans. We extracted the number of IBD and control subjects with or without Factor V Leiden mutation from each study and conducted this analysis using a fixed-effects model.Nineteen studies met the inclusion criteria and were included in the meta-analysis. No significant heterogeneity was found in results across the 19 studies (I2 = 18.8%, P = 0.23), which showed a slight but not significant increase in the risk of IBD with Factor V Leiden mutation in the general population (summary odds ratio [OR] 1.13, 95% confidence interval [CI] 0.87–1.46). Taking into account ethnic differences, further study exhibited a slight but not significant increase in risk of IBD with Factor V Leiden mutation in Europeans (summary OR 1.20, 95% CI 0.88–1.64). However, Factor V Leiden mutation was significantly associated with a higher risk of thromboembolism in IBD patients (summary OR 5.30, 95% CI 2.25–12.48). No publication bias was found in this study.This meta-analysis indicated that although Factor V Leiden mutation was not significantly associated with the risk of IBD, it was significantly associated with a higher risk of thromboembolism in IBD patients.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit cell growth and metastasis, and induce cell apoptosis in cancerous cells. They have been shown to reduce incidence and mortality of gastric cancer by an unknown mechanism. NSAIDs often exert their effects by Cox-2 inhibition, and Cox-2 is overexpressed in gastric cancer cells. Nevertheless, when gastric cancer cells were treated with different NSAIDs, the non-Cox-2-inhibiting R-flurbiprofen was most effective at reducing proliferation of gastric cancer cells in vitro. R-Flurbiprofen prevented the metastatic characteristics of gastric cancer cells in vitro, and reduced tumor size and metastasis in vitro, when gastric cancer cells were injected into nude mice. R-Flurbiprofen also affected multidrug resistance, increasing the sensitivity of resistant gastric cancer cells to chemotherapeutic agents. Mechanistically, R-flurbiprofen was found to have pleiotropic effects, changing levels of cell cycle factors like Cyclin D1 and CKD4, apoptotic protwins like caspase3 and Bcl-2, and protwins that affect metastasis, like metalloproteases. Consistent with reports on other cancer cell types, NSAID treatment with R-flurbiprofen increased levels of the tumor suppressor neurotrophin receptor (p75NTR) in gastric cancer cells. The anticancer effects of R-flurbiprofen were found to require induction of p75NTR via the p38 signaling pathway, suggesting a possible mechanism of action.Keywords: gastric cancer; p75; R-Flurbiprofen;

Mitotic arrest-deficient 2 (MAD2) is one of the essential mitotic spindle checkpoint regulators, and it can protect cells from aberrant chromosome segregation. The Mad2 gene is very rarely mutated in many kinds of human cancer, but aberrantly reduced expression of MAD2 has been correlated with defective mitotic checkpoints in several human cancers. We have previously found that the MAD2 expression level is also shown to be associated with the multidrug resistance of tumour cells. In this study, we constructed a small interfering RNA (siRNA) eukaryotic expression vector of MAD2 and downregulated MAD2 expression in the gastric cancer cell line SGC7901 by transfection of MAD2-siRNA. SGC7901 cells stably transfected with the MAD2-siRNA exhibited significantly increased expression of phosphorylated survivin protein and enhanced drug resistance. Furthermore, MAD2-siRNA suppressed the proliferation of SGC7901 cells and inhibited tumour formation in athymic nude mice. This study clearly reveals that downregulation of MAD2 could regulate the cell cycle, increase proliferation, and improve the drug resistance of gastric cancer cells by regulating the activation of phosphorylated survivin. It also suggests both that MAD2 might play an important role in the development of human gastric cancer and that silencing the MAD2 gene may help to deal with the multidrug resistance of gastric cancer cells.

To identify the role of epithelial cellular adhesion molecule (EpCAM) in gastric cancer growth and explore the potential value of EpCAM monoclonal antibody as new therapeutic strategy for gastric cancer.The expression of EpCAM was determined by immunohistochemistry staining in gastric cancer tissues, RT-PCR and Western blot in cell lines. EpCAM expression in cell lines was downregulated by small interfering RNA. Then the effects of EpCAM on gastric cancer cell growth in vivo and in vitro were determined by MTT, FCM analysis, clone formation assay and tumor formation assay. Additionally, western blot was used to detect the effect of EpCAM on cell cycle-relevant factor cyclin D1.EpCAM was found to be overexpressed in gastric cancer tissues and cell lines. Downregulation of EpCAM resulted in a decrease of cell proliferation and cell cycle arrest in AGS and SGC7901 cells, which had high endogenous EpCAM expression. EpCAM downregulation also suppressed tumor formation in nude mice. Moreover, EpCAM repression in gastric cancer cells could downregulate cyclin D1.EpCAM was a potential oncogene and contributed to the growth of gastric cancer. Our data first provided compelling evidence of potential value of EpCAM in the therapy of gastric cancer in clinic.

Proteomic study was used to explore new multidrug resistance (MDR)-related proteins and clarify novel mechanism of MDR in gastric cancer.Two-dimensional gel electrophoresis and the PDQuest software analysis were applied to compare the differential expression of MDR-related proteins in gastric cancer SGC7901 cells and drug-resistant SGC7901 cells (SGC7901/VCR) induced by vincristine sulfate (VCR). The differential protein dots were excised and further analyzed by matrix-assisted laser desorption ionization-time of flight mass spectrometry analysis (MALDI-TOF-MS).Nine differential expression proteins between the two cell lines were successfully identified by MALDI-TOF-MS. Triosephosphate isomerase (TPI), a glycolytic pathway enzyme, was identified as a downregulated protein in SGC7901/VCR cells. Further, Western blot analysis and semiquantitative RT-PCR confirmed its decreased expression in SGC7901/VCR cells. Sense vector pcDNA3.1-TPI was constructed and transfected into SGC7901/VCR. The sensitivity of TPI-SGC7901/VCR cells to adriamycin (ADR), VCR, 5-fluorouracil and cis-dichlorodiamine platinum, as well as the accumulation and retention to ADR, were significantly increased when compared to their control cell lines.These results provide new MDR-related protein candidates, which are differentially expressed in the MDR cell line and its parental cell line including TPI, which may participate in the VCR-mediated MDR in human gastric cancer. Upregulation of TPI expression could partially reverse multidrug-resistant phenotype of SGC7901/VCR, which suggests that TPI may be an anti-drug resistance agent in gastric cancer and the candidate target to develop novel therapeutics for better treatment of gastric cancer.

Akt (also known as protein kinase B, PKB) is involved in a variety of biological processes, for example cell development, proliferation, and angiogenesis. Clinical studies in support of the idea that increased activity of Akt could contribute directly to gastric carcinogenesis are rare, however. In this study we discovered that phospho-Akt1 was overexpressed in human gastric cancers and its levels correlated with tumor differentiation and pTNM. Akt1 activation promoted cell survival, because the phosphatidylinositol 3-kinase(PI3K) inhibitor LY294002 inhibited Akt1 phosphorylation and inhibited cell growth, especially in cells with active Akt1. Dominant negative Akt inhibited proliferation of gastric cancer cells and induced G1 cell-cycle arrest whereas constitutively active Akt increased cell proliferation. We have therefore identified Akt1 as an active kinase that contributes to gastric cancer progression and promotes proliferation of gastric cancer cells.

Colorectal cancer is one of the most prevalent malignancies in the world. Chinese researchers and clinical doctors had been working hard in the last 12 years, exploring efficient and convenient methods for screening and early diagnosis. The 12 years research works indicated that SFOBT plus colonoscopy was the best detecting protocol for mass screening of colorectal cancer. Serial combined testing for tumor markers plus colonoscopy is the most commonly used strategy for early diagnosis. However, still no optimum method for early diagnosis was generally accepted by most researchers. Due to intrinsic defects of the techniques, several screening and diagnostic methods should be combined to bring each advantage into full play, in order to elevate the diagnostic level of colorectal cancer.

Peritoneal dissemination in gastric cancer is the most frequent cause of the noncurative resection and recurrence after curative resection. We, therefore, evaluated the feasibility of a peptide, which was obtained by screening a random phage display library, in the treatment of peritoneal metastases of gastric cancer. In this study, a novel cell line, GC9811-P, with a high potential peritoneal metastasis of gastric cancer derived from its parental cell line, GC9811, was established. Using a phage display library, we isolated a specific peptide that selectively bound to GC9811-P cells rather than its parental GC9811cells. The isolated phage-displaying peptide, SMSIASPYIALE (named peptide PIII), was obtained after four rounds of selection, showing a tendency to preferentially bind to GC9811-P cells compared with a panel of other gastric cancer cell lines, and preferentially accumulate in peritoneal metastasis tumor tissue in comparison with control organs, peritoneum, liver, pancreas, spleen, lung, and kidney. Further study showed that synthetic peptide PIII could significantly inhibit adhesive and invasional ability of GC9811-P cells and could effectively block the corresponding phage binding to the GC9811-P cells, whereas, exposure of the cells to various concentrations of peptide PIII showed no obvious cell growth inhibition. Furthermore, a highly reproducible animal experimental model of gastric cancer with peritoneal dissemination was established in nude mice by injecting a suspension of the cell line into the gastric wall of nude mice. Animals intraperitoneally treated with peptide PIII in this model or another animal model of gastric cancer with peritoneal dissemination established using MKN45 cells showed suppressed tumor metastasis to peritoneum and significantly prolonged survival. In conclusion, the selected peptide PIII was a biologically active peptide and could effectively inhibit peritoneal dissemination of gastric cancer.

Rho family members are known to regulate malignant transformation and motility of cancer cells, but the clinicopathological significance of RhoC remains unclear yet in the case of gastric cancer. In this study, we evaluated the protein expression level of RhoC in gastric cancer tissues and cell lines. Results showed that only weak staining of RhoC was detected in 3 of 33 non-tumorous cases by immunohistochemistry. The expression of RhoC was significantly higher in gastric cancer tissues (23/42, 54.8%) than in non-tumorous tissues (p < 0.01). Further analysis demonstrated that RhoC had high specificity (80.0%) in detecting gastric carcinomas with metastatic potential. RhoC was positively expressed in 18 out of 20 metastases (90.0%), even higher than that in primary gastric cancer tissues. Western blot showed that RhoC was up-regulated in five different gastric cancer cell lines but not expressed in SV40-transformed immortal gastric epithelial cell GES-1. Overexpression of RhoC GTPase in GES-1 cells could produce the motile and invasive phenotype but did not alter the monolayer growth rate. To further study the functions of RhoC, we took the powerful siRNA technology to knock down the expression of RhoC in SGC7901 cells. It was shown that down-regulation of RhoC did not affect the proliferation of SGC7901 cells. However, interference of RhoC expression could inhibit migration, invasion, and anchorage-independent growth of SGC7901 cells. In conclusion, RhoC may play a very important role in the metastasis of gastric carcinoma. Therapeutic strategies targeting RhoC and RhoC-mediated pathways may be a novel approach for treating metastasis of gastric cancer.

Pluripotent stem cells have shown great therapeutic promise because of their natural capacity to regenerate damaged tissue. Likewise, autologous stem cells or genetically modified stem cells have already been successfully applied in animal or clinical experimental studies including cardiopathy, diabetic disease, system lupus erythema, pancreatic disease, and liver disease. In these studies regarding stem cell transplants in different diseases, identifying the location of implanted cells and distinguishing them from endogenous cells is the first and most important step. Moreover, different tracing techniques were applied in different studies for their different sensitivity, dynamic range, convenience and reliability of their assays. Therefore, we will here review different tracing techniques and their applications in stem cell transplants, including both experiment studies and preclinical trials.

BackgroundResearch achievement is essential for promotion in most Chinese medical institutions, causing enormous pressure among clinicians. We believe ours is the first nationwide questionnaire survey about clinicians' attitude to the current title promotion system. The aim of this study is to investigate the present title promotion mechanism and put forward policy recommendations.MethodsWe surveyed doctors from regions with different economic development, from a variety of geographical locations, with different degrees of professional title, and working at different levels of hospital in 31 districts in China. Clinicians completed a 29-item survey which included questions about demographic characteristics, work conditions, promotion conditions, the existing promotion system, and suggestions for reform. We used descriptive analysis to compile our findings. The Chinese Academy of Engineering Ethics Committee reviewed the protocol and exempted it from additional ethical approval.Findings7020 questionnaires were sent out and 6953 were analysed. 85·8% (5965/6953) of respondents are under great pressure, primarily from desire for promotion (4915 [70·7%]). Much less pressure was reported from doctor–patient tensions (4638/6953 [66·7%]) or work demands (4460 [64·1%]). 67·3% (4678/6953) of respondents reported research achievement was decisive for promotion, while working performance was reported as decisive by 38·8% (2699). 92·2% (6414/6953) reported a belief that the current system for promotion is problematic and 83·7% (5823) that the most important problem is excessive emphasis on research accomplishment. 88·5% (6150/6953) reported that working performance is unduly ignored for promotion. 77·6% (5394/6953) reported having seen people resort to improper means to achieve promotion, and 43·8% (3044) would consider using illicit means themselves. 79·3% (5516/6953) suggested the characteristics of each class of hospital be accommodated in any reform, and 72·9% (5071) suggested that title appraisal should be associated with clinical performance.InterpretationDoctors should be encouraged to pursue research. However, the current appraisal system with a focus on scientific publication and low emphasis on clinical practice has put burdens onto clinicians and our results suggest this system could lead to academic misconduct. A new appraisal system that takes into account working performance, professional skills, and innovation capacity should be established. For doctors working in community and rural areas, the new system should take limited account of innovation capacity. The survey was limited by the huge number and variety of classifications of clinicians.FundingChinese Academy of Engineering (2014-ZD-09)

Aims: Calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP), a component of the ubiquitin-mediated proteolysis, could bind SKP1-CUL1-F box protein complex and participate in beta-catenin degradation, which was found to be related to the malignant phenotypes of gastric cancer and renal cancer. However, the role of CacyBP/SIP in pancreatic cancer progression still remains unclear. Therefore, the aim of the present study was to investigate the expression and clinical significance of CacyBP/SIP in pancreatic cancer. Methods: Immunohistochemistry was carried out on paraffin-embedded sections of pancreatic cancer and normal pancreatic tissues. In addition, Western blot and semiquantitative RT-PCR were carried out to analyze mRNA and protein expression of CacyBP/SIP in 8 pairs of freshly resected pancreatic cancer and their adjacent nontumorous tissue. Results: CacyBP/SIP expression was significantly increased in pancreatic cancer tissue (28/68 or 41.2%) and correlated with differentiation degree, higher TNM (tumor, node, metastasis) stage and distance metastasis. Also, mRNA and protein expression of CacyBP/SIP were found to be at higher levels in almost all cancer tissues compared to adjacent tissues. Conclusions: CacyBP/SIP protein might play an important role in the process of pancreatic carcinogenesis and high-level CacyBP/SIP expression might be related to the malignant potential of pancreatic cancer.

BackgroundFish consumption may protect against colorectal cancer, but results from observational studies are inconsistent; therefore, a systematic review with a meta-analysis was conducted.MethodsRelevant studies were identified by a search of MEDLINE and EMBASE databases to May 2011, with no restrictions. Reference lists from retrieved articles also were reviewed. Studies that reported odds ratio (OR) or relative risk estimates with 95% confidence intervals (CIs) for the association between the consumption of fish and the risk of colorectal, colon, or rectal cancer were included. Two authors independently extracted data and assessed study quality. The risk estimate (hazard ratio, relative risk, or OR) of the highest and lowest reported categories of fish intake were extracted from each study and analyzed using a random-effects model.ResultsTwenty-two prospective cohort and 19 case-control studies on fish consumption and colorectal cancer risk met the inclusion criteria and were included in the meta-analysis. Our analysis found that fish consumption decreased the risk of colorectal cancer by 12% (summary OR, 0.88; 95% CI, 0.80-0.95). The pooled ORs of colorectal cancer for the highest versus lowest fish consumption in case-control studies and cohort studies were 0.83 (95% CI, 0.72-0.95) and 0.93 (95% CI, 0.86-1.01), respectively. There was heterogeneity among case-control studies (P < .001) but not among cohort studies. A significant inverse association was found between fish intake and rectal cancer (summary OR, 0.79; 95% CI, 0.65-0.97), and there was a modest trend seen between fish consumption and colon cancer (summary OR, 0.96; 95% CI, 0.81-1.14). This study had no publication bias.ConclusionOur findings from this meta-analysis suggest that fish consumption is inversely associated with colorectal cancer.

AimsThe pathological roles of Notch receptors in renal cell carcinoma (RCC) are still unclear, although Notch receptors have been shown to have an effect on many malignant tumours. Therefore, in this study, we examined the patterns of expression and clinical significance of Notch receptors in RCC.MethodsEighty-four cases of renal cell carcinoma tissues were detected by immunohistochemistry. Eleven paired fresh surgical renal cell carcinoma and adjacent non-neoplastic renal samples were analysed by Western blot and reverse transcriptase polymerase chain reaction. In addition, the expression of Notch receptors in renal cancer cell lines (A498 and 786-O) and human normal kidney tubule epithelial cell lines (HK-2 and HKC) were analysed by Western blot.ResultsThe expression levels of Notch1 and Notch4 were absent or significantly decreased in renal cell carcinoma tissues compared with the adjacent non-neoplastic tissues [Notch1: 22.6% (19/84) versus 78.7% (59/75); Notch4: 27.4% (23/84) versus 73.3% (55/75); p < 0.05). Moreover, the levels of expression of Notch1 and Notch4 were also markedly down-regulated in human renal cancer cell lines. Notch1 was negatively correlated with tumour stage, while Notch4 expression had no significant association with pathological parameters. The levels of expression of Notch2 and Notch3 were minimally detected in tumours and non-neoplastic tissues.ConclusionOur findings indicated that the expression of Notch receptors was deregulated and Notch signalling might play an important role in the progress of renal cell carcinoma.

Identifying an effective therapeutic target is pivotal in the treatment of gastric cancer. In this study, we investigated the expression of p75 neurotrophin receptor (p75NTR) in gastric cancer and the impact of its alteration on tumor growth. p75NTR expression was absent or significantly decreased in 212 cases of gastric cancers compared with the normal gastric mucosa (P < .05). Moreover, p75NTR expression was also lost or significantly decreased in various human gastric cancer cell lines. p75NTR inhibited in vitro growth activities and caused dramatic attenuation of tumor growth in animal models by induction of cell cycle arrest. Upregulation of p75NTR led to downregulation of cyclin A, cyclin D1, cyclin E, cyclin-dependent kinase 2, p-Rb, and PCNA, but to upregulation of Rb and p27 expressions. Conversely, downregulating p75NTR with specific siRNA yielded inverse results. The rescue of tumor cells from cell cycle progression by a death domain-deleted dominant-negative antagonist of p75NTR (Δp75NTR) showed that the death domain transduced antiproliferative activity in a ligandindependent manner and further demonstrated the inhibitive effect of p75NTR on growth in gastric cancer. Therefore, we provided evidence that p75NTR was a potential tumor suppressor and may be used as a therapeutic target for gastric cancer.

The present study aimed to investigate the potassium currents and further explore the role of potassium channels in drug response of gastric cancer cells. By patch-clamp technique, potassium currents of human gastric cancer cell SGC7901 were recorded in the mode of voltage clamp. Both 4-aminopyridine (4-AP) and tetraethylammonium (TEA) could almost completely block this current. The chemotherapeutic drugs, adriamycin or 5-fluorouracil could significantly increase the K+ current density on SGC7901 cells in a dose-dependent manner. 4-AP or TEA was found to restrain adriamycin-induced apoptosis and enhance multidrug-resistant phenotype of SGC7901 cells. Up-regulation of Kv1.5, which has been found widely expressed in gastric cancer cells including SGC7901, increased the K+ current density and sensitivity of SGC7901 cells to multiple chemotherapeutic drugs, whereas down-regulation of Kv1.5 enhanced the drug-resistant phenotype of SGC7901 cells. In conclusion, potassium channels may exert regulatory effects on multidrug resistance by regulating drug-induced apoptosis in gastric cancer cells.

Background and aimNotch signaling controls cellular differentiation and proliferation. Deregulated expression of Notch receptors is observed in a growing number of malignant tumours, however, the role of Notch signaling in hepatocellular carcinoma is still unknown. To address this, the expression of Notch receptors in human hepatocellular carcinoma was examined in both protein and ribonucleic acid levels.Patients and methodsFifty-three hepatocellular carcinoma tissue sections were detected by immunohistochemistry. Three paired fresh surgical hepatocellular carcinoma and adjacent nontumour liver samples were analyzed by Western blot and reverse transcriptase polymerase chain reaction. Immunohistochemistry, Western blot and reverse transcriptase polymerase chain reaction are reliable methods to examine the expression of protein and RNA.ResultsAll of the four Notch receptors were expressed in the neoplastic cells of hepatocellular carcinoma tissues with different intensity and extensity. Notch1 and Notch4 were expressed in both cytoplasm and nucleus, and all of the nuclear staining showed up in the cytoplasm-positive cases. Cytoplasmic and nuclear Notch1 was detected in 88.7% (47/53) and 9.4% (5/53) of hepatocellular carcinoma tissues, respectively; positive rates of Notch4 were 67.9% (36/53) in cytoplasm and 52.8% (31/53) in nucleus. Notch2 and Notch3 were only in cytoplasm, with positive rates of 26.4% (14/53) and 52.8% (28/53), respectively. Compared with adjacent nontumour liver, Notch1 (cytoplasmic) and Notch4 (nuclear) were up-regulated (P < 0.05, P < 0.05), Notch2 was down-regulated (P < 0.05), while Notch1 (nuclear), Notch3 and Notch4 (cytoplasmic) showed no difference between hepatocellular carcinoma and adjacent nontumour liver. Western blot and reverse transcriptase polymerase chain reaction analysis showed a consistent result.ConclusionOur findings indicate that the expression of Notch receptors was deregulated and Notch signaling might be involved in the development of hepatocellular carcinoma.

Background and aimsOsteopontin (OPN) is known to be associated with metastasis in many types of cancers. Since OPN is a highly phosphorylated and glycosylated protein, the modification after transcription is very important to its function. In hepatocellular carcinoma (HCC), the elevated expression of OPN at mRNA levels and its relationship with metastasis and poorer prognosis of the patients have been reported. However, the prognostic impact of OPN at protein levels on the patients with hepatitis B virus (HBV)-related HCC after hepatectomy is still limited.Patients and methodsThe expression of OPN was examined at protein level by using immunohistochemistry in 72 patients who underwent hepatectomy for HBV-related HCC, and its prognostic significance in disease-free and overall survival of the patients was also analyzed by log-rank test and multivariate Cox regression analyses.ResultsThirty-nine of 72 (54.17%) HBV-related HCC specimens were positive for OPN with cytoplasmic staining. OPN was highly expressed in the specimens with capsular infiltration compared to those without (P < 0.05), and also was significantly related with portal vein invasion (P < 0.01) and lymph node invasion (P < 0.01). The mean disease-free survival (DFS) was only 13.55 ± 14.77 months when the HBV-related HCC specimens highly expressed OPN compared to 36.00 ± 18.68 months for those with low expression (P < 0.001). The overall survival (OS) of the patients was 18.63 ± 17.28 months when the HCC over-expressed OPN compared to 42.59 ± 16.85 months for HCC with the low expressed OPN (P < 0.001). Multivariate analysis showed that OPN over-expression was the strongest independent adverse prognostic factor for both DFS (P = 0.01) and OS (P = 0.014).ConclusionsOPN over-expression was closely related to capsular infiltration, venous invasion, lymph node metastasis, and also with worse prognosis, suggesting that OPN might be deemed as a useful molecular marker for predicting the prognosis of HCC.

•miR-218 is down-regulated in tumor endothelial cells.•Expression of miR-218 in endothelial cells correlated with micro vessel density of gastric cancer•miR-218 inhibits the tube formation, migration and sprouting ability of endothelial cells.•Down-regulation of ROBO1 partly recapitulates the inhibitory effects on endothelial cells miR-218 induces.•Local injection of mature miR-218 in xenografted tumor disrupts the vessel plexus and thus inhibits tumor growth.Aberrant expression of miRNAs is involved in several carcinogenic processes, including tumor growth, metastasis and angiogenesis. The aim of this study was to determine the role of miR-218 in gastric cancer angiogenesis. In situ hybridization was performed on a set of tissue microarray samples to assess the difference in miR-218 expression in vessels between tumor tissues and normal gastric mucosa. In vitro, ectopic expression of miR-218 disturbed the tubular structure and inhibited the migration of endothelial cells. Motility and tube formation were rescued when miR-218 was downregulated. Moreover, miR-218 suppressed endothelial cell sprouting in a fibrin bead sprouting assay. Subsequently, we identified ROBO1 as a target of miR-218 in endothelial cells and determined it was responsible for the effect of miR-218 on tumor angiogenesis. In vivo, local injection of mature miR-218 in xenografted tumors disrupted the vessel plexus and thus inhibited tumor growth. Taken together, our study demonstrated an anti-angiogenic role of miR-218 in gastric cancer and indicated that delivery of miR-218 may be a potential therapeutic strategy to inhibit tumor angiogenesis.

BackgroundLiver cirrhosis represents the end stage of chronic liver injury. Currently, liver transplantation provides the only definite cure but it is beset with many problems, including lack of donors and risk of rejection. Stem cell therapy is very attractive in this setting because it has the potential to help tissue regeneration. In this study, we aimed to investigate the therapeutic effect of peripheral blood monocyte cell (PBMC) transplantation in decompensated liver cirrhosis.MethodsA total of 40 subjects (31 men and nine females, age range 21–71 years) was recruited to two groups. Group 1 received granulocyte–colony-stimulating factor (G-CSF) mobilization, PBMC collection by leukapheresis and PBMC transplant therapy. Group 2 received G-CSF mobilization for 4 days. At baseline and 6 months after treatment, liver function of the two groups was monitored by blood examination and ultrasonagraphy.ResultsBoth groups gained significant improvement in liver synthetic function, such as serum albumin and prothrombin time, from baseline to 6 months after treatment (P < 0.01). However, there was no significant difference in alanine aminotransferase, aspartate aminotransferase and total bilirubin in both groups (P > 0.05). Compared with group 2, a significantly improved liver function was observed in group 1, including elevated serum albumin level and a decreased CTP score (P < 0.05). No major adverse effects were noted.DiscussionAutologous PBMC transplantation could be considered as a novel and alternative treatment for patients with decompensated liver cirrhosis.

Aim of the StudyCroton tiglium (Croton tiglium L., Euphorbiaceae) is widely used as a herb for treatment of gastrointestinal disturbances. Previous studies established its purgative and inflammational properties. The present study aimed to investigate the effects of Croton tiglium oil (CO) on intestinal transit in mice.Materials and MethodsGastrointestinal transit in mice and contractile characteristics of isolated intestinal strips from mice were evaluated. Intestinal inflammation was confirmed by histological examination.ResultsLow dose of CO increased the gastrointestinal transit of charcoal and barium meal as well as the production of fecal pellets in mice. In contrast, high dose exerted inhibitory effects. For normal colonic circular strips, both high and low dose of CO inhibited the contractile frequency. Low doses (0–20 μg/ml) of CO enhanced the phasic contractions, while high doses (>40 μg/ml) reduced them. Colonic longitudinal strips in CO-treated mice were less sensitive to electrical field stimulation than those in control mice. The contraction of colonic longitudinal, colonic and jejunal circular strips in CO-treated mice was more sensitive to atropine than that in control mice.ConclusionsCO might modulate gastrointestinal motility and induce intestinal inflammation related to immunological milieu and motor activity. Our findings may highlight the ethno-medical uses of Croton tiglium on intestinal disorders.