Expression of c-MET, EGFR and HER-2 in gastric adenocarcinoma tissue and its relationship with clinicopathological characteristics.

OBJECTIVE: To determine the expression of tyrosine protein kinase Met (c-MET), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER-2) in cases with gastric adenocarcinoma (GA). METHODS: The positive rates of the c-MET, EGFR, and HER-2 proteins between cancerous tissues and normal tissues sampled from 87 patients with GA were compared. The patients were assigned to different subgroups according to their clinicopathological characteristics and analyzed. Then the relationship between the above three indexes and the positive expression of Ki-67 were analyzed. In addition, the patients were assigned to positive and negative groups based on the situation of c-MET, EGFR and HER-2 proteins, and followed up for three years. These groups were compared in terms of recurrence-free survival, overall survival, and risks factors of prognosis. RESULTS: The positive rates of c-MET, EGFR and HER-2 proteins in GA tissues were all higher than those in corresponding non-tumor tissues (all P<0.001), and the positive rates of them were greatly different in subgroups with different differentiation, invasion depth, TNM stage, lymph node metastasis (LNM), distant metastasis and presence of tumor thrombus (all P<0.05) and were positively correlated with the expression of Ki-67 protein (P<0.05). Moreover, the survival analysis results revealed lower recurrence-free survival and overall survival rates in groups with negative expression of c-MET, EGFR, and HER-2 than those in groups with positive expression of them (both P<0.001). Furthermore, the positive EGFR was an independent prognostic factor affecting the survival of patients with GA. CONCLUSION: The expression of c-MET, EGFR and HER-2 proteins is correlated with clinical characteristics of patients with GA, and patients with positive expression of them face a higher recurrence rate. Additionally, EGFR protein may affect patients' survival.

Clinical Significance of the Interleukin 24 mRNA Level in Head and Neck Squamous Cell Carcinoma and Its Subgroups: An In Silico Investigation.

IL24 mRNA is known to have an apoptotic effect on cancer cells but not on noncancer cells. However, the expression level of the IL24 mRNA in head and neck squamous cell carcinoma (HNSCC) and its subgroups is rarely studied. In this study, the clinical implication of IL24 mRNA was evaluated in the common subgroups of HNSCC, including oral squamous cell carcinoma (OSCC), nasopharyngeal carcinoma (NPC), and laryngeal squamous cell carcinoma (LSCC) for analysis. Substantial IL24 mRNA expression data were calculated from several databases, such as the Gene Expression Omnibus (GEO), ArrayExpress, Sequence Read Archive (SRA), ONCOMINE, and The Cancer Genome Atlas (TCGA) databases. We ultimately collected a total of 41 microarrays and RNA-seq including 1,564 HNSCC and 603 noncancer tissue samples. IL24 mRNA was highly expressed in OSCC, LSCC, and NPC as shown by the separated standard mean difference (SMD), as well as HNSCC as a whole part (SMD = 1.47, 95% confdence interval (CI) = 1.24-1.70, P < 0.0001). In all subgroups, the IL24 mRNA upregulation had the ability to distinguish cancer from noncancer tissue with area under the curves (AUCs) of the summary receiver operating characteristic (sROC) higher than 0.85. In conclusion, IL24 mRNA may be used as a potential marker for cancer screening, and its clinical diagnostic value needs to be further studied. It also provides a new idea for the treatment of the IL24 gene in HNSCC and its subgroups in the future.

Prognostic alternative splicing signature in cervical squamous cell carcinoma.

Basing on alternative splicing events (ASEs) databases, the authors herein aim to explore potential prognostic biomarkers for cervical squamous cell carcinoma (CESC). mRNA expression profiles and relevant clinical data of 223 patients with CESC were obtained from The Cancer Genome Atlas (TCGA). Correlated genes, ASEs and percent-splice-in (PSI) were downloaded from SpliceSeq, respectively. The PSI values of survival-associated alternative splicing events (SASEs) were used to construct the basis of a prognostic index (PI). A protein-protein interaction (PPI) network of genes related to SASEs was generated by STRING and analysed with Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Consequently, 41,776 ASEs were discovered in 19,724 genes, 2596 of which linked with 3669 SASEs. The PPI network of SASEs related genes revealed that TP53 and UBA52 were core genes. The low-risk group had a longer survival period than high-risk counterparts, both groups being defined according to PI constructed upon the top 20 splicing events or PI on the overall splicing events. The AUC value of ROC reached up to 0.88, demonstrating the prognostic potential of PI in CESC. These findings suggested that ASEs involve in the pathogenesis of CESC and may serve as promising prognostic biomarkers for this female malignancy.

12-O-tetradecanoylphorbol-13-acetate (TPA) increases murine intestinal crypt stem cell survival following radiation injury.

Radiation enteropathy is a common complication in cancer patients following radiation therapy. Thus, there is a need for agents that can protect the intestinal epithelium against radiation. 12-O-tetradecanoylphorbol-13-acetate (TPA) has been shown to induce differentiation and/or apoptosis in multiple cell lines and primary cells. In the current report, we studied the function of TPA in radiation induced enteropathy in cultured rat intestinal epithelial cell line IEC-6 after ionizing radiation (IR) and in mice after high dose total-body gamma-IR (TBI). In IEC-6 cells, there were reduced apoptosis and cell cycle arrest in TPA treated cells after IR. We detected a four-fold increase in crypt cell survival and a two-fold increase in animal survival post TBI in TPA treated mice. The beneficial effects of TPA were accompanied by upregulation of stem cells markers and higher level of proteins that are involved in PKC signaling pathway. In addition, TPA also decreased the TBI-augmented levels of the DNA damage indicators. The effects were only observed when TPA was given before irradiation. These results suggest that TPA has the ability to modulate intestinal crypt stem cells survival and this may represent a promising countermeasure against radiation induced enteropathy.

[Research Progress on Relationship between CD58 Molecule and ALL and Lymphoma -Review].

Lymphocyte function-associated antigen-3 (LFA-3/CD58) is a cell-surface glycoprotein, it can bind to CD2 and activate the costimulation pathways of T lymphocytes and natural killer (NK) cells, maximizing the cytolysis of target cells by cytotoxic T lymphocytes (CTL) and NK cells. Some studies have demonstrated that in acute lymphoblastic leukemia(ALL) and lymphomas, lack of CD58 on the tumor cells may fail to activate the T lymphocytes and NK cells, resulting in feeble cytotoxic effect and subsequently escape from immune surveillance, making the disease become more complicated and liable to relapse. Therefore, this article aims to review the structure, biological characteristics of CD58 on the tumor cells and its relationship with ALL and lymphomas.

CREB1 directly activates the transcription of ribonucleotide reductase small subunit M2 and promotes the aggressiveness of human colorectal cancer.

As the small subunit of Ribonucleotide reductase (RR), RRM2 displays a very important role in various critical cellular processes such as cell proliferation, DNA repair, and senescence, etc. Importantly, RRM2 functions like a tumor driver in most types of cancer but little is known about the regulatory mechanism of RRM2 in cancer development. In this study, we found that the cAMP responsive element binding protein 1 (CREB1) acted as a transcription factor of RRM2 gene in human colorectal cancer (CRC). CREB1 directly bound to the promoter of RRM2 gene and induced its transcriptional activation. Knockdown of CREB1 decreased the expression of RRM2 at both mRNA and protein levels. Moreover, knockdown of RRM2 attenuated CREB1-induced aggressive phenotypes of CRC cells in vitro and in vivo. Analysis of the data from TCGA database and clinical CRC specimens with immunohistochemical staining also demonstrated a strong correlation between the co-expression of CREB1 and RRM2. Decreased disease survivals were observed in CRC patients with high expression levels of CREB1 or RRM2. Our results indicate CREB1 as a critical transcription factor of RRM2 which promotes tumor aggressiveness, and imply a significant correlation between CREB1 and RRM2 in CRC specimens. These may provide the possibility that CREB1 and RRM2 could be used as biomarkers or targets for CRC diagnosis and treatment.

[Comparison of Clinical Outcomes between P190 and P210 Trans-cripts in Adult Ph Chromosome Positive Acute Lymphoblastic Leukemia in the New Era of TKI].

OBJECTIVE: To explore the differences of clinical characteristics and outcome between p190 and p210 transcripts in adult Ph chromosome positive acute lymphoblastic leukemia patients in the new era with tyrosine kinase inhibitor (TKI) treatment, so as to provide an insight for improving the prognostic stratification and individualized treatment of the Ph(+) ALL patients. METHODS: The clinical data of 65 patients were analysed retrospectively, these patients were diagnosed as Ph(+) ALL and treated with conventional chemotherapy plus TKI treatment with or without hematopoietic stem cell transplantation (HSCT) from January 2005 to December 2014 in our hospital, then the differences of clinical features and prognosis were compared between the p190 (n = 41) and the p210 group (n = 24). RESULTS: The p190 group had lower platelet count than the p210 group (46.3 × 10(9)/L vs 65 × 10(9)/L) (P = 0.084); the leukemic blast cells in bone marrow at diagnosis was slightly higher in p190 group than that in p210 group (88.4% vs 76.8%) (P = 0.096); the other clinical features, such as sex, age, white blood cells, hemoglobin, leukemic blast cells in peripheral blood, and BCR-ABL/ABL expression level were not significantly different between these two groups. As to the response to treatment, the complete remission rate (CR) after induction therapy was 80% (32/40) and 87% (20/23) respectively in the p190 and p210 group, no significant difference was seen (P = 0.732). The time from induction to the first complete remission (CR1) was not significantly different either (28 days vs 29 days) (P = 0.922). The recurrence rate was 61% (20/33) in the p190 group and 43% (9/21) in the p210 group, but the difference was not significantly different (P = 0.202). However, the duration of remission in p190 group was shorter than that in p210 group, whether from the time of initial diagnosis to relapse (212 days vs 274 days) (P = 0.077) or from the time of CR1 to relapse (146 days vs 242 days) (P = 0.084). For the prognosis, the p190 group presented with a shorter 5 year-survival rate (P = 0.016) as well as event-free survival rate (P = 0.085). CONCLUSION: The p190 group tends to have lower peripheral blood platelet count and higher percentage of leukemic blasts in bone marrow at diagnosis; while the CR rate and the time from induction to CR1 are not significantly different; however, the p190 group is more likely to relapse at a relatively early stage, and the 5 year-survival rate and event-free survival rate are lower in p190 group than that in p210 group, indicating that the patients carrying p190 transcript are probably necessary to receive more intensive therapy such as HSCT as early as possible after achieving CR1, which can promisingly improve the overall prognosis of the Ph(+) ALL patients.

Ribonucleotide reductase large subunit M1 plays a different role in the invasion and metastasis of papillary thyroid carcinoma and undifferentiated thyroid carcinoma.

Ribonucleotide reductase (RR) has been reported to be associated with several types of cancer while the expression and role of RR in thyroid carcinoma (TC) has not been investigated. Here, we first examined the expression level of three RR subunit proteins (RRM1, RRM2, and RRM2B) in papillary thyroid carcinoma (PTC) and undifferentiated thyroid carcinoma (UTC) patient samples by immunohistochemistry. The results showed that RRM1 was higher expressed in 95.2 % cancer tissues compared with their adjacent normal tissues in 146 PTC samples. The expression level of RRM1 was positively correlated with T stage, lymph node metastasis (LNM), extrathyroidal invasion (ETI), and TNM stage in PTC patients. However, in 12 UTC samples, RRM1 expression was negatively expressed in six cases. To further determine the biological role of RRM1 in TC, ectopic expression or siRNA-mediated knockdown of RRM1 were carried out in the high-differentiated thyroid carcinoma cell line TPC-1 and the poor-differentiated thyroid carcinoma cell line SW579, respectively. In TPC-1 and SW579 cells, overexpression and siRNA knockdown of RRM1 demonstrated that RRM1 promoted DNA synthesis and proliferation in both cell lines as shown by EdU incorporation and cell viability assays. However, RRM1 enhanced cell migration and invasion in TPC-1 cells but inhibited that in SW579 cells as shown by wound healing and transwell assays. Moreover, we also found that RRM1 promoted PTEN expression and reduced Akt phosphorylation in a RR-activity-independent manner in the low-differentiated TC cells but not in the high-differentiated TC cells. In contrast, RRM2 expression was higher expressed in both PTC and UTC patient samples, consisting with its oncogenic role in other cancers. Therefore, we suggest that RRM1 promotes thyroid carcinoma proliferation as a component of RR but may play a different role in the invasion and metastasis of differently differentiated thyroid carcinomas through a non-RR pathway, which could be meaningful to precision treatment of thyroid carcinoma with RR inhibitors.

E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2.

As the ribonucleotide reductase small subunit, the high expression of ribonucleotide reductase small subunit M2 (RRM2) induces cancer and contributes to tumor growth and invasion. In several colorectal cancer (CRC) cell lines, we found that the expression levels of RRM2 were closely related to the transcription factor E2F1. Mechanistic studies were conducted to determine the molecular basis. Ectopic overexpression of E2F1 promoted RRM2 transactivation while knockdown of E2F1 reduced the levels of RRM2 mRNA and protein. To further investigate the roles of RRM2 which was activated by E2F1 in CRC, CCK-8 assay and EdU incorporation assay were performed. Overexpression of E2F1 promoted cell proliferation in CRC cells, which was blocked by RRM2 knockdown attenuation. In the migration and invasion tests, overexpression of E2F1 enhanced the migration and invasion of CRC cells which was abrogated by silencing RRM2. Besides, overexpression of RRM2 reversed the effects of E2F1 knockdown partially in CRC cells. Examination of clinical CRC specimens demonstrated that both RRM2 and E2F1 were elevated in most cancer tissues compared to the paired normal tissues. Further analysis showed that the protein expression levels of E2F1 and RRM2 were parallel with each other and positively correlated with lymph node metastasis (LNM), TNM stage and distant metastasis. Consistently, the patients with low E2F1 and RRM2 levels have a better prognosis than those with high levels. Therefore, we suggest that E2F1 can promote CRC proliferation, migration, invasion and metastasis by regulating RRM2 transactivation. Understanding the role of E2F1 in activating RRM2 transcription will help to explain the relationship between E2F1 and RRM2 in CRC and provide a novel predictive marker for diagnosis and prognosis of the disease.

Label-free silver nanoparticles for the naked eye detection of entecavir.

A simple, rapid, field-portable colorimetric method for the detection of entecavir was proposed based on the color change caused by the aggregation of silver nanoparticles. Neutralization of the electrostatic repulsion from each silver nanoparticle resulted in the aggregation of AgNPs and a consequent color change of AgNPs from yellow to wine-red, which provided a platform for rapid and field-portable colorimetric detection of entecavir. The concentration of entecavir could be determined with naked eye or UV-vis spectrometer. The proposed method can be used to detect entecavir in human urine with a detection limit of 1.51µg mL(-1), within 25min by naked eye observation without the aid of any advanced instrument or complex pretreatment. Results from UV-vis spectra showed that the absorption ratio was linear with the concentration of entecavir in the range of 5.04-25.2µg mL(-1) and 1.01-5.04µg mL(-1) with linear coefficients of 0.9907 and 0.9955, respectively. The selectivity of AgNPs detection system for entecavir is excellent comparing with other ions and analytes. Due to its rapid, visible color changes, and excellent selectivity, the AgNPs synthesized in this study are suitable to be applied to on-site screening of entecavir in human urine.

[Adsorption and release behavior of epirubicin hydrochloride on carboxylated single-walled carbon nanotubes].

In this study, the adsorption behavior of epirubicin hydrochloride (EPI) on carboxylated single-walled carbon nanotubes (c-SWNTs) obtained by mixture acid treatment was investigated. The results indicated that the dispersion of c-SWNTs in water was obviously improved. The absorption of EPI on c-SWNTs came to equilibrium after 240 min and could be explained by pseudo-second-order model. Moreover, there were heterogeneous distribution of active sites onto c-SWNTs surface and the Freundlich isotherm model was better fit to describe the absorption precess of EPI on c-SWNTs. The absorption capacity of EPI on c-SWNTs increased obviously with the increasing pH and decreasing temperature. Compared with multi-walled carbon nanotubes, carboxylated multi-walled carbon nanotubes, SWNTs, c-SWNTs possessed higher absorption capacity for EPI. The controlled, targeted and sustained release of EPI from c-SWNTs-EPI could be instructive for the development of nano-carrier.