TH-4000, a hypoxia-activated pan-HER inhibitor, shows excellent preclinical efficacy for the treatment of HER2+ breast cancer.

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer is correlated with poor prognosis, the current treatment of which is still based on surgery and adjuvant targeted therapy with monoclonal antibody. Problems of drug resistance hinder the use of monoclonal antibodies. Subsequently, tyrosine kinase inhibitors (TKIs) have been noticed, TKIs have the advantages of multi-targets and reduced drug resistance. However, TKIs that target HER family proteins often cause adverse effects such as liver damage and diarrhea. Thus, TKIs with high selectivity are being developed. TH-4000, a prodrug that generated an active form TH-4000Effector (TH-4000E) under hypoxic condition, was evaluated in this research. We found that TH-4000E ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium) (1-1000 nM) had potent and highly selective toxic effects on HER2+ breast cancer cells and inhibited the phosphorylation of HER family kinases at lower doses than that of Lapatinib and Tucatinib. TH-4000E activated Caspase-3 and induced apoptosis through a reactive oxygen species (ROS)-dependent pathway. The prodrug TH-4000 ([(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide) (50 mg/kg) effectively suppressed the tumor growth with less liver damage in mouse tumor models. This hypoxia-targeted strategy has possessed advantage in avoiding drug-induced liver damage, TH-4000 could be a promising drug candidate for the treatment of HER2+ breast cancer.

Preoperative Hepatic and Regional Arterial Chemotherapy in Patients Who Underwent Curative Colorectal Cancer Resection: A Prospective, Multi-center, Randomized Controlled Trial.

OBJECTIVE: To evaluate the effects of the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis of stage II and III colorectal cancer (CRC) in a multicenter setting. SUMMARY OF BACKGROUND DATA: Our previous single-center pilot trial suggested that PHRAC in combination with surgical resection could reduce the occurrence of liver metastasis (LM) and improve survival in CRC patients. METHODS: A prospective multi-center randomized controlled trial was conducted from December 2008 to December 2012 at 5 hospitals in China. Eligible patients with clinical stage II or III CRC who underwent curative resection were randomized to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary endpoint was DFS. Secondary endpoints were cumulative LM rates, overall survival (OS), and safety (NCT00643877). RESULTS: A total of 688 patients from 5 centers in China were randomly assigned (1:1) to each arm. The five-year DFS rate was 77% in the PHRAC arm and 65% in the control arm (HR = 0.61, 95% CI 0.46-0.81; P = 0.001). The 5-year LM rates were 7% and 16% in the PHRAC and control arms, respectively (HR = 0.37, 95% CI 0.22-0.63; P < 0.001). The 5-year OS rate was 84% in the PHRAC arm and 76% in the control arm (HR = 0.61, 95% CI 0.43-0.86; P = 0.005). There were no significant differences regarding treatment related morbidity or mortality between the two arms. CONCLUSIONS: The addition of PHRAC could improve DFS in patients with stage II and III CRC. It reduced the incidence of LM and improved OS without compromising patient safety. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00643877.

A novel long non-coding RNA TONSL-AS1 regulates progression of gastric cancer via activating TONSL.

Long non-coding RNAs (lncRNAs) are reported to play a significant role in various malignant tumors, yet their potential functions in gastric cancer are not clear. In this study, we found a novel lncRNA, named TONSL-AS1, was downregulated in gastric cancer tissues and cell lines compared with the normal. TONSL-AS1 inhibited cell migration, invasion and proliferation in SGC-7901, MGC-803 cells. Furthermore, TONSL-AS1 could suppress cell tumorigenesis in vivo. Mechanistically, TONSL-AS1's genomic neighboring gene TONSL, which was reported as a tumor suppress gene, was upregulated by TONSL. Additionally, the TONSL-AS1 was positively associated with TONSL in cancer tissues. Our study revealed that the tumor-inhibiting effect of TONSL-AS1 in gastric cancer cells was associated with TONSL. In general, our results indicated that TONSL-AS1 works as a tumor suppressor lncRNA, which may be a new therapeutic target for gastric cancer.

HOXC13-AS promotes breast cancer cell growth through regulating miR-497-5p/PTEN axis.

Dysregulated long noncoding RNAs (lncRNAs) remains to be explored in tumorigenesis. LncRNA HOXC13 antisense RNA (HOXC13-AS) has been found as an oncogene in many cancers; however, the role of HOXC13-AS in breast cancer still elusive. In this study, the HOXC13-AS levels and its role in cell proliferation was first measured by real-time quantitative polymerase chain reaction, Cell Counting Kit-8 assay, and colony formation assay. It showed that HOXC13-AS was increased in breast cancer tissues compared with the adjacent normal tissues and upregulated HOXC13-AS promoted the growth of breast cancer cells. Then, we found that the miR-497-5p levels were downregulated in cancer tissues compared with the adjacent tissues and miR-497-5p suppressed breast cancer cell proliferation. Further study showed that HOXC13-AS could function as a "sponge" for miR-497-5p then suppress miR-497-5p expression. Moreover, we next identified that Phosphatase and Tensin homolog (PTEN) is the target of miR-497-5p. Overexpression of miR-497-5p by chemical mimics decreased the expression of PTEN, while downregulation of miR-497-5p by HOXC13-AS rescued the expression of PTEN. Finally, we showed that HOXC13-AS promoted the proliferation of breast cancer cells and tumor growth through miR-497-5p/PTEN axis in vitro and in vivo. Hence, we conclude that HOXC13-AS, which is significantly upregulated in breast cancers, promoted cell proliferation through the suppressed miR-497-5p and further upregulated PTEN.

Involvement of miR-143 in cisplatin resistance of gastric cancer cells via targeting IGF1R and BCL2.

We investigated the possible role of miR-143 in the development of cisplatin resistance in human gastric cancer cell line. miR-143 was detected by quantitative real-time PCR. Cisplatin resistance changes of cells was tested via MTT assay. Target genes of miR-143 were verified by dual-luciferase activity assay. Immunohistochemistry, immunofluorescence staining, Western blot, cell proliferation, and clonogenic and apoptosis assay were used to elucidate the mechanism of miR-143 in cisplatin resistance formation. miR-143 was downregulated in gastric cancer tissues and cell lines. It was also downregulated in cisplatin-resistant gastric cancer cell line SGC7901/cisplatin (DDP), which was concurrent with the upregulation of IGF1R and BCL2, compared with the parental SGC7901 cell line, respectively. Overexpressed miR-143 sensitized SGC7901/DDP cells to cisplatin. The luciferase activity suggested that IGF1R and BCL2 were both target genes of miR-143. Enforced miR-143 reduced its target proteins, inhibited SGC7901/DDP cells proliferation, and sensitized SGC7901/DDP cells to DDP-induced apoptosis. Our findings suggested that hsa-miR-143 could modulate cisplatin resistance of human gastric cancer cell line at least in part by targeting IGF1R and BCL2.

A human serum albumin-indocyanine green complex offers improved tumor identification in fluorescence-guided surgery.

Background: Complete tumor removal is critical for achieving a good prognosis in patients but remains challenging for surgeons. Near-infrared fluorescence-guided surgery (NIRFGS) enables surgeons to accurately localize tumors in real time and facilitates accurate resection. Indocyanine green (ICG) has been approved by the U.S. Food and Drug Administration and the National Medical Products Administration for many years. Although the application of ICG has progressed for a variety of surgeries, there are inherent limitations to ICG, including poor water solubility and photostability, short blood half-life, and aggregation in blood, resulting in poor imaging performance. We found that mixing ICG with human serum albumin (HSA) preoperatively and then injecting it can improve the imaging performance. Methods: We prepared fluorescent probes by combining ICG with HSA and identified their optimal ratio via in vitro absorption measurement and emission spectrum characterization of ICG-HSA complex with different mixing ratios and concentration gradients. Subsequently, under the optimal ratio and clinical simulated concentration, we conducted dynamic change analysis of the fluorescence spectral properties after mixing. We then compared the uptake of ICG-HSA in vitro for two different cell types and the imaging performance of different molar ratios of ICG and HSA in mouse models. Results: Through in vitro absorption and emission spectrum characterization of ICG-HSA mixtures with different mixing ratios and concentration gradients, the optimal ratio of the mixture was obtained (ICG:HSA =4:5). Using this ratio, clinical simulated concentration, and mixing, we completed the dynamic change analysis of the fluorescence spectrum properties. The results verified that HSA can improve the dispersion and stability of ICG in aqueous solution, reduce the proportion of free-state ICG, and thus improve the biodistribution. Moreover, the fluorescence performance of ICG was improved. ICG-HSA and ICG uptake in MDA-MB-231 cells and imaging in vivo showed that HSA increased the enrichment of ICG in tumor compared to ICG alone (ICG-HSAfluorescence intensity =237.3±10.7 vs. ICGfluorescence intensity =127.1±10.7). Compared with ICG alone, ICG-HSA provided a clearer tumor boundary and higher tumor-to-background ratio (TBR) (ICG-HSATBRmax 3.49±0.56 vs. ICGTBRmax 1.94±0.23). Conclusions: This study suggests that ICG-HSA can achieve higher tumor-to-background contrast with shorter time and can provide an overall superior imaging performance compared to ICG alone, thus exhibiting considerable potential for clinical application.

First-line camrelizumab (a PD-1 inhibitor) plus apatinib (an VEGFR-2 inhibitor) and chemotherapy for advanced gastric cancer (SPACE): a phase 1 study.

Patients with advanced gastric cancer typically face a grim prognosis. This phase 1a (dose escalation) and phase 1b (dose expansion) study investigated safety and efficacy of first-line camrelizumab plus apatinib and chemotherapy for advanced gastric or gastroesophageal junction adenocarcinoma. The primary endpoints included maximum tolerated dose (MTD) in phase 1a and objective response rate (ORR) across phase 1a and 1b. Phase 1a tested three dose regimens of camrelizumab, apatinib, oxaliplatin, and S-1. Dose regimen 1: camrelizumab 200 mg on day 1, apatinib 250 mg every other day, oxaliplatin 100 mg/m² on day 1, and S-1 40 mg twice a day on days 1-14. Dose regimen 2: same as dose regimen 1, but oxaliplatin 130 mg/m². Dose regimen 3: same as dose regimen 2, but apatinib 250 mg daily. Thirty-four patients were included (9 in phase 1a, 25 in phase 1b). No dose-limiting toxicities occurred so no MTD was identified. Dose 3 was set for the recommended phase 2 doses and administered in phase 1b. The confirmed ORR was 76.5% (95% CI 58.8-89.3). The median progression-free survival was 8.4 months (95% CI 5.9-not evaluable [NE]), and the median overall survival (OS) was not mature (11.6-NE). Ten patients underwent surgery after treatment and the multidisciplinary team evaluation. Among 24 patients without surgery, the median OS was 19.6 months (7.8-NE). Eighteen patients (52.9%) developed grade ≥ 3 treatment-emergent adverse events. Camrelizumab plus apatinib and chemotherapy showed favorable clinical outcomes and manageable safety for untreated advanced gastric cancer (ChiCTR2000034109).

Icariin potentiates the antitumor activity of gemcitabine in gallbladder cancer by suppressing NF-κB.

AIM: Gemcitabine has been increasingly prescribed for the treatment of gallbladder cancer. However, the response rate is low. The aim of this study is to determine whether icariin, a flavonoid isolated from Epimedi herba, could potentiate the antitumor activity of gemcitabine in gallbladder cancer. METHODS: Human gallbladder carcinoma cell lines GBC-SD and SGC-996 were tested. Cell proliferation and apoptosis were analyzed using MTT assay and flow cytometry, respectively. The expression of apoptosis- and proliferation-related molecules was detected with Western blotting. Caspase-3 activity was analyzed using colorimetric assay, and NF-κB activity was measured with ELISA. A gallbladder cancer xenograft model was established in female BALB/c (nu/nu) mice. The mice were intraperitoneally administered gemcitabine (125 mg/kg) in combination with icariin (40 mg/kg) for 2 weeks. RESULTS: Icariin (40-160 µg/mL) dose-dependently suppressed cell proliferation and induced apoptosis in both GBC-SD and SGC-996 cells, with SGC-996 cells being less sensitive to the drug. Icariin (40 µg/mL) significantly enhanced the antitumor activity of gemcitabine (0.5 µmol/L) in both GBC-SD and SGC-996 cells. The mice bearing gallbladder cancer xenograft treated with gemcitabine in combination with icariin exhibited significantly smaller tumor size than the mice treated with either drug alone. In GBC-SD cells, icariin significantly inhibited both the constitutive and gemcitabine-induced NF-κB activity, enhanced caspase-3 activity, induced G(0)-G(1) phase arrest, and suppressed the expression of Bcl-2, Bcl-xL and surviving proteins. CONCLUSION: Icariin, by suppressing NF-κB activity, exerts antitumor activity, and potentiates the antitumor activity of gemcitabine in gallbladder cancer. Combined administration of gemcitabine and icariin may offer a better therapeutic option for the patients with gallbladder cancer.

SMYD3 regulates gastric cancer progression and macrophage polarization through EZH2 methylation.

SET and MYND domain-containing protein 3 (SMYD3), a known histone methyltransferase, was reported to regulate cancer pathogenesis. However, its role in gastric development and progression remains unclear. EZH2 methylation had been associated with cancer metastasis, but the EZH2 methylation status in gastric cancer (GC) is unknown. Here, we report that EZH2 K421 methylation was responsible for gastric cancer cell soft agar colony formation, in vivo metastasis, and macrophage polarization. Mechanically, we identified SMYD3 as the methyltransferase of EZH2 at K421 residue which accelerates EZH2 Ubiquitin proteasome degradation. Cell harboring non-methylated EZH2 mutants promotes gastric cancer cell metastasis. Taken together, our results showed that SMYD3-EZH2 axis restricts gastric cancer metastasis via integrating epigenetic signaling.

Unintended consequences of curtailment cap policies on power system decarbonization.

As countries pursue power system decarbonization, a well-intentioned strategy being pursued in jurisdictions like China is the strict integration target, often in the form of a curtailment cap. The effects of these curtailment caps have not been systematically studied. Here, we evaluate the effects of these caps on the decarbonization of one provincial power system using a capacity expansion model. Results reveal that curtailment caps yield deleterious effects that do not align with the stated goals of these policies. Capping curtailment significantly increases storage capacity (+43% with a 5% curtailment cap) and reduces renewable capacity (-17%). Even with the increase in flexible storage capacity, the policy still jeopardizes power system reliability by increasing occurrences of over or under generation. It also suppresses power generation from hydropower and reduces energy storage utilization while increasing fossil fuel utilization. Capping curtailment increases economic costs (+6% with a 5% curtailment cap) and CO2 emissions (+7%).

Identification of lysine-lactylated substrates in gastric cancer cells.

Cancer cells tend to utilize aerobic glycolysis to generate energy and metabolites; the end product of aerobic glycolysis is lactate, which promotes lysine lactylation (Kla). Kla is a newly discovered histone post-translational modification (PTM) that plays important roles in regulating gene expression. However, Kla in non-histone mammalian proteins is unclear. Here, a comprehensive analysis of lactylated proteins in gastric cancer AGS cells was conducted. There were 2375 Kla sites found in 1014 proteins. Interestingly, KEGG pathway analysis showed that these proteins were significantly enriched in spliceosome function. In addition, Kla was more abundant in gastric tumors than in adjacent tissues, and high levels of Kla in gastric tumors were associated with poor prognosis. These results suggest that Kla could be a prognostic marker in gastric cancer. This lysine lactylome analysis in gastric cancer cells, the first of its kind, provides a valuable foundation for further studies of Kla.

A pilot study of near-infrared fluorescence guided surgery for primary tumor localization and lymph node mapping in colorectal cancer.

BACKGROUND: This pilot study aimed to evaluate the feasibility of near-infrared fluorescence imaging for primary tumor localization, lymph node mapping, and metastatic lymph node detection in colorectal cancer (CRC) using indocyanine green (ICG). METHODS: A total of 11 patients with CRC were prospectively enrolled. ICG (25 mg dissolved in 30 mL sterile water) was intravenously injected preoperatively, and the fluorescence intensity of the primary tumor, lymph nodes, and normal tissues, as well as the signal-to-background ratio (SBR) and contrast-to-noise ratio (CNR) were measured at 0.5, 1, 2, 4, and 24 h after ICG injection. RESULTS: The primary tumor could be located intraoperatively, and the tumor boundary was clear at 2-4 h. There was good contrast in the fluorescence intensity between tumor and normal tissues (SBR =2.11±0.36, CNR =8.74±0.35). The lymph node detection rate was 95% (38/40), and the SBR threshold of lymph nodes was 1.13. CONCLUSIONS: This pilot study showed that primary tumor localization and lymph node mapping in CRC is feasible using near-infrared fluorescence imaging technology, though metastatic lymph nodes cannot be discriminated from benign ones. In addition, cancer nodules missed by both white light mode and palpation by the surgeon were unexpectedly found, resulting in a change in the surgical prognosis in 9.1% (1/11) of patients.

Study on Efficacy and Safety of Low-Dose Apatinib Combined with Camrelizumab and SOX Regimen as First-Line Treatment of Locally Advanced and Unresectable Gastric/Gastroesophageal Junction Cancer: A Protocol for an Open-Label, Dose Escalation and Extension Phase Ib Clinical Trial.

BACKGROUND: The standard treatment for advanced gastric/gastroesophageal junction cancer (AGC/GEJC) is palliative chemotherapy combined with targeted therapy. The SOX regimen (S-1 plus oxaliplatin) is recommended as neoadjuvant or palliative first-line chemotherapy in Asian patients. Apatinib, an oral VEGFR tyrosine kinase inhibitor, is associated with additional survival benefit as third- or subsequent-line therapy. However, the median overall survival time of AGC/GEJC is only 8-11 months in the West and 13-17 months in East Asia/Japan, even with the application of anti-angiogenic agents. Hence, the multimodal and individual management of patients is challenging standards to improve prognosis, including the preferential use of low-dose anti-angiogenic drugs and immunotherapy, as well as the application of multi-disciplinary treatment (MDT)-directed conversion therapy. METHODS/DESIGN: This single-center study was designed to combine low-dose apatinib with camrelizumab plus the SOX regimen in diagnosed potentially resectable and initially unresectable AGC/GEJC. This a prospective, open-label, single-arm, dose escalation and extension phase Ib clinical trial, conducted in Jiangsu Province Hospital, beginning from June 2020. All patients will first receive this combined regimen (3 weeks/cycle) for at most eight cycles, then apatinib and camrelizumab in maintenance therapy until disease progression, intolerable toxicity, death, a maximum 2 years of treatment or discontinuation for any reason. Follow-up and evaluation will be carried out regularly. If surgery is allowed by MDT discussions, oral apatinib will be discontinued during the last preoperative cycle. The primary endpoints are the objective response rate and maximum tolerated dose according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) and the Common Terminology Criteria for Adverse Events (CTCAE) criteria (version 5.0). DISCUSSION: This study will assess the response and side effects of AGC/GEJC patients in the use of low-dose apatinib combined with camrelizumab and the SOX regimen, and this combined therapy is expected to be a feasible and optimized first-line treatment option. In addition, this study will provide robust evidence and novel ideas for conversion therapy. TRIAL REGISTRATION: ChiCTR.gov.cn: ChiCTR2000034109.

Short hairpin RNA targeting beta-catenin suppresses cell proliferation and induces apoptosis in human gastric carcinoma cells.

OBJECTIVE: Aberrant activation of Wnt/beta-catenin signaling is involved in various cancers, including human gastric cancer. Here we investigate the role of Wnt/beta-catenin signaling in regulating gastric cancer cell apoptosis. MATERIAL AND METHODS: Expression of beta-catenin was investigated after transfection with beta-catenin short hairpin RNA (shRNA) in gastric cancer cells by Western blotting and immunofluorescence analysis. beta-catenin/T-cell factor transcriptional activity was also investigated by using a luciferase reporter assay. Next, the effects of beta-catenin shRNA on cell proliferation and apoptosis were evaluated by the 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide assay and flow cytometric analysis. To investigate the precise mechanism of these effects, a comprehensive analysis was performed using a cDNA microarray. RESULTS: shRNA targeting beta-catenin resulted in a significant decrease in beta-catenin expression, and its nuclear localization and cell proliferation. Meanwhile, increased cell apoptosis was confirmed. The comprehensive analysis showed that shRNA targeting beta-catenin upregulated 26 apoptosis-related genes (including PERP, TRAF3, PDCD2, TNFRSF25, AKT2 and YWHAZ) and downregulated 48 apoptosis-related genes (including MALT1, IRAK1, TNFAIP3, PPP1R13L, TRIP and YWHAB) in gastric cancer cells. Pathway analysis suggested that the nuclear factor-kappaB pathway was involved in beta-catenin knockdown-induced apoptosis. CONCLUSIONS: Attenuation of beta-catenin by shRNA resulted in suppressed cell proliferation and apparent apoptosis, suggesting that beta-catenin may be a target for therapy of gastric cancer.

RNA-binding protein RBM38 acts as a tumor suppressor in gastric cancer.

OBJECTIVES: The aim of this study was to evaluate the expression of RBM38 protein in gastric cancer patients and to explore its association with clinical pathological characteristics and prognosis. MATERIALS AND METHODS: A total of 120 pairs of gastric cancer tissues and non-cancerous gastric mucosa from 120 patients who underwent gastrectomy for gastric cancer were included in the current study. RBM38 protein expression levels were detected in all tissue specimens by immunohistochemistry staining. The positive rate of RBM38 was compared between cancer tissue and normal tissue, and its association with the clinical pathological characteristics and prognosis was elucidated. RESULTS: RBM38 protein was predominantly expressed in the cytoplasm of epithelial cells. The percentage of tissues with high RBM38 protein expression level was significantly lower (χ2=28.972, P<0.001) in gastric cancer tissues compared with adjacent non-cancerous gastric mucosal tissues. The expression level of RBM38 protein was associated with tumor size (P=0.028), depth of invasion (P<0.001), lymph node metastasis (P<0.001), TNM stage (P<0.001) and Lauren classification of the tumor (P=0.001), whereas it was not associated with gender (P=0.066) and age (P=0.6) of patients. Moreover, we noticed that the low expression level of RBM38 protein was also associated with poor prognosis in gastric cancer patients (log rank =5.325; P=0.021). CONCLUSION: Overall, our findings indicated that RBM38 may play a vital role as a tumor suppressor, which may be a potential marker in the diagnosis and prognosis of gastric cancer.

An online debris sensor system with vibration resistance for lubrication analysis.

The health condition of the lubricated systems can be directly indicated by the concentration and material type of the abrasive particles, which may provide very early warnings of faults/failures and benefit the condition based maintenance. Oil debris particle detecting techniques are thus important for machinery condition monitoring and fault diagnosis. This work proposes a new structure of online debris sensor (ODS), which applies the radial magnetic field, different from the traditional axial magnetic field. The designed ODS can effectively reduce the interferences of the background noise and the vibration of the machine in operation. Moreover, in order to optimally determine the number of turns of an inductive coil and the current of the drive coils, two methods are developed respectively in this work which can ensure sensitivity and anti-vibration features of the ODS. The instrumentation circuit system for detecting debris particles and sensing signals has been also designed to extract and to record the signatures of particles. The designed ODS device is then applied to analyze micro debris particles in the lubricating system on a test rig. Experimental results have demonstrated that ODS can successfully detect the 120 µm(H) ferrous particles and 500 µm(H) non-ferrous particles under vibration conditions.

Diagnostic value of circulating miR-21 for colorectal cancer: a meta-analysis.

BACKGROUND: MicroRNA-21 (miR-21) is highly expressed in the plasma of colorectal cancer (CRC) patients. Thus, miR-21 may be a useful novel diagnostic biomarker for CRC. This meta-analysis aims to verify the diagnostic value of circulating miR-21 in CRC patients. METHODS: A literature search was conducted for publications that evaluated the diagnostic value of miR-21 for CRC. The quality of each study was scored with the Quality Assessment of Diagnostic Accuracy Studies. The bivariate meta-analysis model was employed to summarize the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). Receiver operating characteristic curves were used to check the overall test performance. RESULTS: Five publications with six studies involving 579 patients and 266 controls were included in this meta-analysis. The pooled sensitivity was 77.4% [95% confidence interval (CI): 67.2%-85.1%], specificity was 84.6% (95% CI: 79.7%-88.5%), PLR was 5.02 (95% CI: 3.73-6.75), NLR was 0.27 (95% CI: 0.18-0.40), and DOR was 18.77 (95% CI: 10.41-33.83). The area under the summary ROC curve was 0.86. In addition, the results became prominent in the CRC group when a study that explored the advanced adenoma was excluded. CONCLUSION: Circulating miR-21 may be a suitable diagnostic biomarker for CRC with moderate sensitivity and specificity. Further studies should evaluate the diagnostic value of miR-21 for CRC in the future.

Hypermethylation of Syk gene in promoter region associated with oncogenesis and metastasis of gastric carcinoma.

AIM: To investigate the relationship between methylation of Syk (spleen tyrosine kinase) gene in promoter region and oncogenesis, metastasis of gastric carcinoma. The relation between silencing of the Syk gene and methylation of Syk promoter region was also studied. METHODS: By using methylation-specific PCR (MSP) technique, the methylation of Syk promoter region in specimens from 61 gastric cancer patients (tumor tissues and adjacent normal tissues) was detected. Meanwhile, RT-PCR was used to analyse syk expression exclusively. RESULTS: The expression of the Syk gene was detected in all normal gastric tissues. Syk expression in gastric carcinoma was lower in 14 out of 61 gastric cancer samples than in adjacent normal tissues (chi(2)=72.3, P<0.05). No methylation of Syk promoter was found in adjacent normal tissues. hypermethylation of Syk gene in promoter was detected 21 cases in 61 gastric carcinoma patients. The rate of methylation of Syk promoter in gastric carcinoma was higher than that in adjacent normal tissues (chi(2)=25.1, P<0.05). In 31 patients with lymph node metastasis, 17 were found with Syk promoter methylation. A significant difference was noted between two groups (chi(2)=11.4,P<0.05). CONCLUSION: Hypermethylation leads to silencing of the Syk gene in human gastric carcinoma. Methylation of Syk promoter is correlated to oncogenesis and metastasis of gastric carcinoma. Syk is considered to be a potential tumor suppressor and anti-metastasis gene in human gastric cancer.

Correlation of tumor-positive ratio and number of perigastric lymph nodes with prognosis of patients with surgically-removed gastric carcinoma.

AIM: To evaluate the tumor-positive ratio and number of perigastric lymph nodes as prognostic factors of gastric carcinoma in surgically-treated patients. METHODS: The postoperative survival of 169 patients with gastric cancer who were performed D2 curative gastrectomy was analyzed with regard to its lymph node metastasis ratio and number. Meanwhile correlation of tumor-positive ratio and number of perigastric lymph nodes with pathological parameters of these patients was studied. RESULTS: The overall 5-year survival rate of all the patients studied was 29.6%. The 5-year cumulative survival rate in patients with 1%-20% and more than 20% of tumor-positive lymph nodes was 70.6% and 12.0% respectively, and 46.6% and 17.4% in those with 1-5 and more than 5 of tumor-positive lymph nodes respectively, which were significantly decreased with the increment of involved lymph nodes assessed by either numbers or ratio (P<0.05). Multiple stepwise regression analysis showed that both the positive ratio and number of tumor-involved lymph nodes were sensitive prognostic factors in these surgically-treated patients, which were also significantly correlated with tumor size and depth of submucosal invasion (P<0.05). CONCLUSION: Tumor-positive ratio and number of perigastric lymph nodes are associated with cancer progression and five-year survival rate, and may serve as valuable prognostic factors of gastric cancer in surgically-treated patients.

Association of VCAM-1 overexpression with oncogenesis, tumor angiogenesis and metastasis of gastric carcinoma.

AIM: To investigate the relationship between the expression of vascular cell adhesion molecule-1 (VCAM-1) and oncogenesis, tumor angiogenesis and metastasis in gastric carcinoma, and to evaluate the clinical significance of serum VCAM-1 levels in gastric cancer. METHODS: Specimens from 41 patients with gastric cancer, 8 patients with benign gastric ulcer, and 10 healthy subjects were detected for the expression of VCAM-1 by immunohistochemistry. Microvessel density (MVD) was measured by counting the endothelial cells immunostained with the monoclonal antibody CD34 at x200 magnification. Serum VCAM-1 concentrations were measured by an enzyme linked immunosorbent assay in the 41 gastric cancer patients before surgery, and at 7 days after surgery as well as in 25 healthy controls. The association between preoperative serum VCAM-1 levels and clinicopathological features, and their changes following surgery was evaluated. In addition, serum carcinoembryonic antigen (CEA) was also examined. RESULTS: Of the 41 gastric cancer tissues, 31 (75.6 %) were VCAM-1 positive. The VCAM-1 positive gastric cancers were more invasive and classified in the more advanced stage than the VCAM-1 negative ones. The VCAM-1 positive cancers were associated with more lymph node metastases than VCAM-1-negative ones (P<0.05). The expression of VCAM-1 was detected in tissues of two of the eight patients with gastric ulcer and two of the 10 healthy controls. The expression of VCAM-1 in gastric cancer patients was significantly more frequent than that in the healthy controls and ulcer group (both P<0.05). MVD in VCAM-1 expressing tissues was higher than that in VCAM-1 negative tissues (t=2.13,P<0.05). Serum VCAM-1 levels in gastric cancer patients were significantly higher than those in controls (t=3.4, P<0.05). There was a significant association between serum VCAM-1 levels and disease stage, as well as invasion depth of the tumor and the presence of distant metastases. The concentrations of serum CEA in gastric cancer were higher than normal controls. Both serum VCAM-1 and CEA levels decreased significantly after radical resection of the primary tumor (P<0.05). Furthermore, the serum levels of VCAM-1 were positively correlated with the expression of VCAM-1 in the tumor tissue (r=0.85, P<0.05). CONCLUSION: The expression of VCAM-1 is closely related to oncogenesis, tumor angiogenesis and metastasis in gastric carcinoma. Serum VCAM-1 level in gastric cancer patients is significantly increased compared with normal controls, which decreases significantly after radical resection of the primary tumor. The serum concentration of VCAM-1 may be considered as an effective marker of tumor burden of gastric cancer. Moreover, overexpression of VCAM-1 in gastric cancer tissue is likely a major source of serum VCAM-1.