Individualized model for predicting COVID-19 deterioration in patients with cancer: A multicenter retrospective study.

The 2019 novel coronavirus has spread rapidly around the world. Cancer patients seem to be more susceptible to infection and disease deterioration, but the factors affecting the deterioration remain unclear. We aimed to develop an individualized model for prediction of coronavirus disease (COVID-19) deterioration in cancer patients. The clinical data of 276 cancer patients diagnosed with COVID-19 in 33 designated hospitals of Hubei, China from December 21, 2019 to March 18, 2020, were collected and randomly divided into a training and a validation cohort by a ratio of 2:1. Cox stepwise regression analysis was carried out to select prognostic factors. The prediction model was developed in the training cohort. The predictive accuracy of the model was quantified by C-index and time-dependent area under the receiver operating characteristic curve (t-AUC). Internal validation was assessed by the validation cohort. Risk stratification based on the model was carried out. Decision curve analysis (DCA) were used to evaluate the clinical usefulness of the model. We found age, cancer type, computed tomography baseline image features (ground glass opacity and consolidation), laboratory findings (lymphocyte count, serum levels of C-reactive protein, aspartate aminotransferase, direct bilirubin, urea, and d-dimer) were significantly associated with symptomatic deterioration. The C-index of the model was 0.755 in the training cohort and 0.779 in the validation cohort. The t-AUC values were above 0.7 within 8 weeks both in the training and validation cohorts. Patients were divided into two risk groups based on the nomogram: low-risk (total points ≤ 9.98) and high-risk (total points > 9.98) group. The Kaplan-Meier deterioration-free survival of COVID-19 curves presented significant discrimination between the two risk groups in both training and validation cohorts. The model indicated good clinical applicability by DCA curves. This study presents an individualized nomogram model to individually predict the possibility of symptomatic deterioration of COVID-19 in patients with cancer.

Curcumin potentiates laryngeal squamous carcinoma radiosensitivity via NF-ΚB inhibition by suppressing IKKγ expression.

Context: Curcumin has shown efficacy in promoting radiosensitivity combined with radiotherapy. However, the role and mechanism of curcumin on radiosensitivity in laryngeal squamous cell cancer (LSCC) is largely unknown.Objective: The aim of our study is to explore the role of IKKγ-NF-κB signaling in curcumin enhancing LSCC cell radiosensitivity in vitro.Materials and methods: Curcumin and X-ray were used to induce cell DNA damage and apoptosis, or inhibit cell clone formation. IKKγ siRNA and plasmid were used to change IKKγ expression. The CCK8 assay was used to detect cell viability. Clone formation ability was analyzed using a clonogenic assay, cell apoptosis was examined using flow cytometry, an immunofluorescence assay was used to detect DNA damage, while mRNA and protein levels were assayed using real time PCR and western blotting, respectively.Results: Curcumin significantly enhanced irradiation-induced DNA damage and apoptosis, while weakening clone-forming abilities of LSCC cell line Hep2 and Hep2-max. Compared to Hep2 cells, Hep2-max cells are more sensitive to curcumin post-irradiation. Curcumin suppressed irradiation-induced NF-κB activation by suppressing IKKγ expression, but not IKKα and IKKß. Overexpression of IKKγ decreased irradiation-induced DNA damage and apoptosis, while promoting clone-forming abilities of Hep2 and Hep2-max cells. IKKγ overexpression further increased expression of NF-κB downstream genes, Bcl-XL, Bcl-2, and cyclin D1. Conversely, IKKγ silencing enhanced irradiation-induced DNA damage and apoptosis, but promoted clone formation in Hep2 and Hep2-max cells. Additionally, IKKγ silencing inhibited expression of Bcl-XL, Bcl-2, and cyclin D1.Conclusions: Curcumin enhances LSCC radiosensitivity via NF-ΚB inhibition by suppressing IKKγ expression.

Radiosensitisation of human glioma cells by inhibition of ß1,6-GlcNAc branched N-glycans.

Gliomas are the most prevalent type of primary brain tumors and are resistant to radiation therapy. ß1,6-GlcNAc branched N-glycans, which are encoded by N-acetylglucosaminyltransferase V (GnT-V), play important roles in glioma progression. However, the relationship between ß1,6-GlcNAc branched expression and radiosensitivity in glioma cells is still unknown. In this study, the expression of ß1,6-GlcNAc branched N-glycans in nonneoplastic brain and glioma samples was characterized by lectin histochemistry. The radiosensitivity of glioma cells was evaluated by colony formation assay. We found that ß1,6-GlcNAc branches were highly expressed in glioblastoma specimens, compared with diffuse astrocytomas and nonneoplastic brain. In addition, ß1,6-GlcNAc branched expression was negatively correlated with the radiosensitivity of glioblastoma cells. Furthermore, the inhibition of N-linked ß1,6-GlcNAc branches by GnT-V silencing in U251 cells could reduce the cell clonogenic survival after X-irradiation. Meanwhile, the G2/M checkpoint was impaired and there was an increase in the number of apoptotic cells. Tunicamycin, an inhibitor of N-glycan biosynthesis, was also able to enhance the radiosensitivity of U251 cells. Thus, our results suggest that development of therapeutic approaches targeting N-linked ß1,6-GlcNAc branches may be a promising strategy in glioblastoma treatment.

Overexpression of zinc finger DHHC-type containing 1 is associated with poor prognosis and cancer cell growth and metastasis in uterine corpus endometrial carcinoma.

The zinc finger DHHC-type containing 1 (ZDHHC1) gene is implicated in the pathogenesis and progression of various malignant tumors, but its precise involvement in uterine corpus endometrial carcinoma (UCEC) remains unknown. Thus, this study investigated ZDHHC1 expression in UCEC using publicly available TCGA and Xena databases and elucidated the functions and mechanisms of the ZDHHC1 gene in UCEC progression using bioinformatics and in vitro experiments. The correlation between ZDHHC1 expression and prognosis, clinical features, immune cells, and RNA modifications of UCEC was evaluated using nomograms, correlation, ROC, and survival analyses. The impacts of ZDHHC1 overexpression on UCEC progression and mechanisms were explored with bioinformatics and in vitro experiments. Our study revealed that ZDHHC1 expression was significantly downregulated in UCEC and correlated with poor prognosis, cancer diagnosis, clinical stage, age, weight, body mass index, histological subtypes, residual tumor, tumor grade, and tumor invasion. Notably, Cox regression analysis and constructed nomograms showed that downregulated ZDHHC1 expression was a prognostic factor associated with poor prognosis in patients with UCEC. Conversely, above-normal ZDHHC1 expression inhibited the cell growth, cell cycle transition, migration, and invasion of UCEC cells, which may be related to the cell cycle, DNA replication, PI3K-AKT, and other pathways that promote tumor progression. Altered ZDHHC1 expression in UCEC was significantly associated with RNA modifications and the changes in cancer immune cell populations, such as CD56 bright NK cells, eosinophils, Th2 cells, and cell markers. In conclusion, considerably reduced ZDHHC1 expression in UCEC is associated with cancer cell growth, metastasis, poor prognosis, immune infiltration, and RNA modifications, revealing the promising potential of ZDHHC1 as a prognostic marker for UCEC.

Lack of association between methylenetetrahydrofolate reductase gene A1298C polymorphism and breast cancer susceptibility.

Published data on the association between methylenetetrahydrofolate reductase gene (MTHFR) A1298C polymorphism and breast cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. Crude ORs with 95% CIs were used to assess the strength of association between the MTHFR A1298C polymorphism and breast cancer risk. The pooled ORs were performed for co-dominant model (AC vs. AA, CC vs. AA), dominant model (CC+AC vs. AA), and recessive model (CC vs. AC+AA), respectively. A total of 26 studies including 12,244 cases and 15,873 controls were involved in this meta-analysis. Overall, no significant associations were found between MTHFR A1298C polymorphism and breast cancer risk when all studies pooled into the meta-analysis (AC vs. AA: OR=0.99, 95% CI 0.94-1.05; CC vs. AA: OR 0.99, 95% CI 0.90-1.09; dominant model: OR=0.99, 95% CI 0.95-1.04; and recessive model: OR=0.98, 95% CI 0.90-1.08). In the subgroup analysis by ethnicity or study design, still no significant associations were found for all comparison models. In conclusion, this meta-analysis suggests that the MTHFR A1298C polymorphism may be not associated with breast cancer development. However, large sample and representative population-based studies with homogeneous breast cancer patients and well matched controls are warranted to confirm this finding.

Heterochronic triple primary malignancies with Epstein-Barr virus infection and tumor protein 53 gene mutation: A case report and review of literature.

BACKGROUND: The diagnosis and etiology of multiple primary malignant neoplasms (MPMNs) are difficult to establish. Here, we report a case of heterochronic triple primary malignancies with gastric cancer, nasopharyngeal squamous cell cancer, and then rectal cancer. CASE SUMMARY: The patient was first diagnosed with gastric cancer at the age of 33 in 2014 and underwent distal gastrectomy and gastrojejunostomy and six cycles of adjuvant chemotherapy. Three years later, he was diagnosed with nasopharyngeal cancer and treated with radical chemoradiotherapy in 2017. Recently, a mass in the middle of the rectum was resected and reported as ulcerative, moderately to poorly differentiated adenocarcinoma. Research on the etiology of MPMNs showed that Epstein-Barr virus (EBV) infection may be the cause of gastric cancer and nasopharyngeal squamous cell cancer since these two primary lesions were positive for transcripts of EBV-encoded ribonucleic acid using an in situ hybridization EBV-encoded ribonucleic acid probe in formalin-fixed, paraffin-embedded tissue. The cause of rectal cancer may be due to a somatic mutation of tumor protein 53 gene in exon 8 (c.844C>T, p.Arg282Trp) through high-throughput sequencing for the rectal cancer. Appropriate standard therapy for each primary cancer was administered, and the patient has no evidence of cancer disease to date. CONCLUSION: To our knowledge, this is the first report on heterochronic triple primary malignancies whose cause may be associated with EBV infection and tumor protein 53 genetic mutations. The etiological research may not only elucidate the cause of MPMN but also has implications in clinical management.

Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide.

BACKGROUND: Hypoxia-inducible factor-1α (HIF-1α), a critical transcription factor to reduced O2 availability, has been demonstrated to be extensively involved in tumor survival, aggressive progression, drug resistance and angiogenesis. Thus it has been considered as a potential anticancer target. Triptolide is the main principle responsible for the biological activities of the Traditional Chinese Medicine tripterygium wilfordii Hook F. Triptolide possesses great chemotherapy potential for cancer with its broad-spectrum anticancer, antiangiogenesis, and drug-resistance circumvention activities. Numerous biological molecules inhibited by triptolide have been viewed as its possible targets. However, the anticancer action mechanisms of triptolide remains to be further investigated. Here we used human ovarian SKOV-3 cancer cells as a model to probe the effect of triptolide on HIF-1α. RESULTS: Triptolide was observed to inhibit the proliferation of SKOV-3 cells, and meanwhile, to enhance the accumulation of HIF-1α protein in SKOV-3, A549 and DU145 cells under different conditions. Triptolide did not change the kinetics or nuclear localization of HIF-1α protein or the 26 S proteasome activity in SKOV-3 cells. However, triptolide was found to increase the levels of HIF-1α mRNA. Unexpectedly, the HIF-1α protein induced by triptolide appeared to lose its transcriptional activity, as evidenced by the decreased mRNA levels of its target genes including VEGF, BNIP3 and CAIX. The results were further strengthened by the lowered secretion of VEGF protein, the reduced sprout outgrowth from the rat aorta rings and the inhibitory expression of the hypoxia responsive element-driven luciferase reporter gene. Moreover, the silencing of HIF-1α partially prevented the cytotoxicity and apoptosis triggered by triptolide. CONCLUSIONS: The potent induction of HIF-1α protein involved in its cytotoxicity, together with the suppression of HIF-1 transcriptional activity, indicates the great therapeutic potential of triptolide as an anticancer drug. Meanwhile, our data further stress the possibility that HIF-1α functions in an unresolved nature or condition.

Telomere length inversely correlates with radiosensitivity in human carcinoma cells with the same tissue background.

A relationship between telomeres and radiosensitivity has been established by several studies based on non-mammalian model systems, mouse models, and few human genetic diseases. However, the relationship has not been proven in human carcinoma cells, which have more clinical significance than these other models. The present study aims to determine whether telomere length is related to radiosensitivity in human carcinoma cells, and to examine the influence of tissue or genetic background. Two HEp-2 larynx squamous carcinoma cell lines, eight hepatocellular carcinoma cell lines, and five breast cancer cell lines were used. Telomere length was determined by terminal restriction fragment (TRF) Southern blot analysis and cell survival was measured by a colony-forming assay. Our results indicated that there was a significant negative correlation of telomere length and radiosensitivity in the same tissue-derived cell lines, with or without the same genetic background. Thus, telomere length may be used as a promising tool to predict the radiosensitivity of human carcinomas.

Radio-activation of hTERT promoter in larynx squamous carcinoma cells: an 'indirected-activator' strategy in radio-gene-therapy.

The usefulness of human telomerase reverse transcriptase (hTERT) gene promoter has been proposed in cancer-targeted gene therapy. However, this promoter may not be strong enough to achieve therapeutic levels of transgene expression. In this study, we tested an 'indirected-activator' strategy that utilizes radiation to increase the activity of the hTERT gene promoter. We demonstrated that hTERT may participate in the process of DNA repair induced by irradiation. We found that Zidovudine (AZT, an hTERT inhibitor) can decrease the telomerase activity in human HEp-2 larynx squamous carcinoma cells and lower the survival fraction of HEp-2 cells exposed to radiation. In HEp-2 cells exposed to 6 Gy-radiation, the hTERT promoter showed 2.9-fold higher activity compared with unirradiated cells. Importantly, an increased expression of enzyme horseradish peroxidase (HRP) controlled by the hTERT promoter was found in the transfected cells after irradiation, which coincided with a higher killing rate for HEp-2 cells after prodrug indole-3-acetic acid (IAA; converted by HRP into a cytotoxin) incubation combined with irradiation or not. Our observations suggest that hTERT promoter-mediated gene therapy could be improved in combination with radiotherapy, which may be due to cellular DNA damage responses.

Loss of LINC01939 expression predicts progression and poor survival in gastric cancer.

As highly tissue-specific genes, it is increasingly recognized that long non-coding RNAs (lncRNAs) are considered as promising prognostic biomarkers for multiple human cancers. However, lack of tissue-specific lncRNAs in gastric cancer (GC) still exist. In this study, we identified a novel lncRNA LINC01939 which showed the largest fold change in GC than other human cancers from lnCAR database by bioinformatic analysis. Reverse transcription quantitative polymerase chain reaction (qPCR) assay confirmed that LINC01939 was significantly downregulated in GC tissues compared with matched normal tissues. Low expression of LINC01939 was positively associated with advanced TNM stage and lymphatic metastasis. Patients with low LINC01939 expression have remarkably shorter overall survival (OS) and progression-free survival (PFS) than those with high LINC01939 expression. Univariate and multivariate analysis showed that LINC01939 is an independent protective predictor of OS and PFS in GC patients. Therefore, our data suggest that the newly identified lncRNA LINC01939 might act as a potential prognostic biomarker for GC.

[Effective inhibition of hTERT expression by RNA interference on the radiosensitivity of human laryngeal cancer Hep-2 cell line].

OBJECTIVE: To construct an eukaryotic expression vector of human telomerase reverse transcriptase (hTERT) gene specific shRNA, and investigate the effect of pshRNA-hTERT combined with gamma-irradiation on cell survival and telomerase activity. METHODS: According to the coding sequence of hTERT mRNA, the target of RNAi was designed, and recombinant expression plasmid pshRNA-hTERT was constructed. The vector was transfected into Hep-2 cells. The radiosensitivity of Hep-2 cells was determined by clonogenic assay. Telomeric repeat amplification protocol (TRAP-PCR-ELISA) was used to observe the telomerase activity in each group. Results Recombinant expression vector pshRNA-hTERT was successfully transfected into Hep-2 cells. The hTERT expression inhibition rate reached 60. 8%. pshRNA-hTERT not only inhibited telomerase activity of Hep-2, but also inhibited the raise of telomerase activity induced by gamma-irradiation. Exposure of Hep-2 cells to pshRNA-hTERT for 24 hrs before irradiation resulted in a decrease in mean surviving fraction of Hep-2 cells compared with cells of group with irradiation alone (67. 7% vs 85. 7%, P <0. 05) . CONCLUSION: RNAi showed a significant inhibitory effect to the expression of hTERT. The results indicate that pshRNA-hTERT can effectively inhibit telomerase activity of Hep-2 cells treated or untreated with 2 Gy gamma-irradiation and significantly enhance the radiosensitivity of Hep-2 cells in vitro. The role of radiosensitization of pshRNA-hTERT may be related with the inhibition of telomerase activity.

Prognostic and predictive value of serum carcinoembryonic antigen levels in advanced non-small cell lung cancer patients with epidermal growth factor receptor sensitive mutations and receiving tyrosine kinase inhibitors.

BACKGROUND: Despite the widespread use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced or recurrent non-small cell lung cancer (NSCLC), no biomarkers for predicting the efficacy of EGFR-TKIs in patients with EGFR-sensitive mutations have yet been identified. The purpose of our study was to explore the effect of baseline serum tumor markers in stage IIIB/IV NSCLC patients treated with EGFR-TKIs. METHODS: One hundred and seventy-seven patients with stage IIIB/IV NSCLC who harbored EGFR-sensitive mutations and were treated with EGFR-TKIs were retrospectively reviewed. Their levels of CEA, CYFRA 21-1, NSE and CA199 were measured before treatment with EGFR-TKIs. RESULTS: The response rate for all patients was 54.8%, with a median progression-free survival of 6.6 months and overall survival of 14.8 months. In univariate analyses, patients with CEA levels below the cutoff point (10 ng/ml) had higher RR, better PFS, and better OS than those with CEA levels above 10 ng/mL (RR: 69.2% vs. 43.4%, p= 0.001; mPFS: 7.8 months vs. 5.3 months, p=0.029; mOS: 18.8 months vs. 11.8 months, p=0.000). The baseline serum CEA level was an independent factor for RR (odds ratio [OR] =0.322, p=0.001), PFS (hazard ratio [HR] =1.45, p=0.025), and OS (HR=2.133, p=0.000). CONCLUSION: Our study suggests that baseline serum CEA levels may play a role in predicting the efficacy of EGFR-TKIs in stage IIIB/IV NSCLC patients with EGFR-sensitive mutations who are treated with EGFR-TKIs.

Significant association between Let-7-KRAS rs712 G > T polymorphism and cancer risk in the Chinese population: a meta-analysis.

Association between let-7-KRAS rs712 polymorphism and cancer risk was inconsistent. We therefore conducted this meta-analysis to clarify the association between let-7-KRAS rs712 polymorphism and cancer risk with STATA 14.0 software. A systemic literature search in online databases (PubMed, Embase, CNKI and Wanfang database) was preformed to obtain relevant articles. A total of 13 case-control studies involving 3,453 patients and 4,470 controls were identified up to May 16, 2015. The pooled results indicated that significantly increased risk were observed in Chinese population in T vs. G (OR = 1.21, 95% CI = 1.03-1.42) and TT vs. GG + GT genetic models (OR = 1.69, 95% CI = 1.17-2.42). Sensitivity analysis was conducted and the result without heterogeneity showed significant associations in all five genetic models. Subgroup analyses of cancer type indicated a similar result in digestive cancer (for T vs. G: OR = 1.41, 95% CI = 1.26-1.57; GT vs. GG: OR = 1.24, 95% CI = 1.07-1.43; TT vs. GG: OR = 2.53, 95% CI = 1.86-3.44; GT + TT vs. GG: OR = 1.36, 95% CI = 1.19-1.56; TT vs. GG + GT: OR = 2.35, 95% CI = 1.73-3.19). In summary, these evidences demonstrate that let-7-KRAS rs712 G > T polymorphism might be associated with digestive system cancer risk in the Chinese population.

Significance of glucocorticoid receptor expression in patients with non-small cell lung cancer treated with pemetrexed-based chemotherapy.

BACKGROUND: Pemetrexed is the preferred chemotherapy agent in the management of non-squamous non-small cell lung cancer (non-sq-NSCLC), but lacks biomarkers predicting its efficacy. Dexamethasone, one of the premedications of pemetrexed, may downregulate p53 through the glucocorticoid receptor (GR). The purpose of our study was to explore the effect of GR in peripheral blood mononuclear cells (PBMC) and its role in predicting pemetrexed efficacy. METHODS: In all, 122 patients with stage IV non-sq-NSCLC who received first-line pemetrexed-containing chemotherapy were retrospectively reviewed. The expression of GR in PBMC was measured before treatment with pemetrexed using real-time PCR was used to detect the levels of GRα and GRß. RESULTS: The response rate for all patients was 38.5%, with a median progression-free survival (PFS) of 5.9 months and overall survival (OS) of 14.3 months. In univariate analyses, patients with a low GRα/GRß ratio in PBMC had higher RR, better PFS, and better OS than those with a high GRα/GRß ratio (RR: 48.2 vs. 30.3%, p = 0.043; mPFS: 6.9 vs. 4.0 months, p < 0.001; mOS: 18.7 vs. 12.2 months, p = 0.005). The baseline GRα/GRß ratio was an independent factor for RR (odds ratio [OR] = 0.451, 95% CI 0.208-0.978; p = 0.044), PFS (HR = 1.584, 95% CI 1.094-2.295; p = 0.015), and OS (HR = 1.761, 95% CI 1.195-2.595; p = 0.004). CONCLUSIONS: Baseline GRα/GRß ratio in PBMC may play a role in predicting the efficacy of first-line pemetrexed-containing chemotherapy in stage IV non-sq NSCLC patients.

Chinese medicine Angelica sinensis suppresses radiation-induced expression of TNF-alpha and TGF-beta1 in mice.

Radiotherapy of thoracic cancer often causes pulmonary inflammation leading to pneumonitis and fibrosis. We favor the hypothesis that cytokine-mediated multicellular interactions may result in the overexpression of proinflammatory cytokines such as TNF-alpha and TGF-beta1, which promotes progressive radiation-induced lung injury. The root of Angelica sinensis, known as 'Danggui' in Chinese medicine, is widely used to treat radiation-induced pneumonitis in humans and shows clinical efficacy and low/no toxicity with an unclear mechanism. Using quantitative RT-PCR and immunohistochemistry (IHC) methods, we investigated radiation-induced lung injury in a mouse model. C57BL/6 mice were assigned to 4 groups: no treatment (NT), Angelica Sinensis treatment only (AS), X-ray irradiation only (XRT, single fraction of 12 Gy irradiation to the thoraces) and AS treatment plus XRT (AS/XRT). Mice in NT and AS groups exhibited low TNF-alpha and TGF-beta1 mRNA levels and few positive cell counts for TNF-alpha (8-17 cells per field, x400 magnification) and TGF-beta1 (9-31 cells per field), respectively. In XRT mice, there were increased inflammatory cells positive for TNF-alpha and TGF-beta1 in lung tissue compared with NT mice (P<0.01). However, when XRT mice received AS treatment (AS/XRT), the number of inflammatory cells in lung tissue positive for both TNF-alpha and TGF-beta1 was decreased compared with XRT-only mice (P<0.01) accompanied by moderately decreased mRNA levels of TNF-alpha and TGF-beta1. We conclude that radiation induces expression of TNF-alpha and TGF-beta1 in the inflammatory cells of irradiated lung tissue during the pneumonic phase. The predominant localization of TNF-alpha and TGF-beta1 in inflammatory cell infiltrates suggests these cytokines' involvement in the process of radiation-induced pneumonitis. Moreover, effective down-regulation of TNF-alpha and TGF-beta1 in irradiated lung tissue by Angelica Sinensis is, at least in part, indicative of its clinical efficacy in treating radiation-induced pneumonitis.

Apoptosis induced by short hairpin RNA-mediated STAT6 gene silencing in human colon cancer cells.

BACKGROUND: The relationship between signal transduction and tumors has become one of the foci in cancer research. Signal transducer and activator of the transcription 6 (STAT6) signaling pathway is found to be activated in some cancer cells. But the function of the pathway in cancer cells is unknown. This study was undertaken to investigate the effect of the Stat6 signaling pathway on apoptosis in human colon cancer cells (HT-29 cells) and the possible mechanism of Stat6 by RNA interference techniques. METHODS: Four eukaryotic expression plasmid vectors of short hairpin RNA (shRNA) specific for the STAT6 gene were designed and generated by molecular biological technology. The plasmid vectors were transfected into HT-29 cells by cation liposomes to block the Stat6 signaling pathway. The expressions of STAT6 mRNA and phosph-Stat6 protein were detected by the reverse transcriptase polymerase chain reaction (RT-PCR) method and flow cytometry respectively to screen the most effective shRNA at 72 hours after transfection. The apoptosis condition of the cells in which the expression of the STAT6 gene had been interfered was analyzed by flow cytometry and confocal microscopy. Both mRNA and protein expression of B cell lymphoma-2 (Bcl-2) and Bax were detected by RT-PCR and western blotting. RESULTS: Two effective eukaryotic expression plasmid vectors of shRNA specific for the STAT6 gene were generated successfully. One can reduce the expression of the STAT6 gene by 82.4% and the other by 56.8% (P < 0.01). The apoptotic rate of colon cancer cells in which STAT6 gene expression had been interfered was significantly higher than that in controlled colon cancer cells (P < 0.01). In the cells in which the Stat6 signaling pathway was blocked, the levels of mRNA and protein Bcl-2 were significantly decreased, whereas those of Bax were significantly increased (P < 0.01). CONCLUSIONS: The Stat6 signaling pathway can inhibit apoptosis in human colon cancer cells. The subsequent disorder of Bcl-2/Bax expression may play an important part in that process. The STAT6 gene may serve as a potential target in cancer therapy.

CCND1 G870A polymorphism and colorectal cancer risk: An updated meta-analysis.

Molecular epidemiological studies have revealed a closer association between cyclin D1 (CCND1) polymorphism and the risk of colorectal cancer; however, the results were inconsistent. The aim of the present meta-analysis was to investigate the association between CCND1 G870A polymorphism and colorectal cancer risk. Online electronic databases (PubMed and Embase) were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the association between CCND1 G870A polymorphism and the risk of colorectal cancer. In addition, heterogeneity, publication bias and sensitivity analysis were performed to guarantee the statistical power. In total, 23 published case-control studies with 6,320 patients and 8,252 controls were selected. Significantly increased risks were observed in four genetic models (A vs. G: OR=1.09, 95% CI=1.00-1.18, I2=54.3%; GA vs. GG: OR=1.13, 95% CI=1.04-1.24, I2=18.2%; AA vs. GG, OR=1.17: 95% CI=1.00-1.38, I2=52.5%; GA+AA vs. GG: OR=1.14, 95% CI=1.05-1.24, I2=33.8%). Similarly, significant associations were also identified in the stratified analysis in the cancer subtype of sporadic colorectal cancer (GA vs. GG: OR=1.21, 95% CI=1.04-1.42, I2=24.1%; GA+AA vs. GG: OR=1.18, 95% CI=1.02-1.37, I2=35.0%), Caucasian population (GA vs. GG, OR=1.14, 95% CI=1.02-1.28, I2=19.8%; GA+AA vs. GG, OR=1.14, 95% CI=1.02-1.27, I2=37.5%) and other subgroups of control design and genotyping type. The present updated meta-analysis suggested that CCND1 G870A may present an increased risk for developing colorectal cancer, particularly in sporadic colorectal cancer and a Caucasian population.

Reversal effect of GnT-V on the radioresistance of human nasopharyngeal carcinoma cells by alteration ß1, 6-GlcNAc branched N-glycans.

Radiotherapy is the primary treatment for human nasopharyngeal carcinoma (NPC), yet radioresistance remains a major obstacle to successful treatment in many cases. N-acetylglucosaminyltransferase V (GnT-V), which synthesizes ß1, 6-GlcNAc branched N-glycans, is closely related to the radiosensitivity of NPC cells. However, a better understanding of the functional role of GnT-V in NPC radioresistance and the related mechanisms is urgently needed. In the present study, a radioresistant NPC cell line, CNE-2R, was established by repeated γ-irradiation. We found that GnT-V levels, as well as ß1, 6-GlcNAc branched N-glycans were significantly increased in the CNE-2R cells as compared with that in the parental cells. Meanwhile, knockdown of GnT-V in the CNE-2R cells enhanced cell radiosensitivity and inhibited the formation of ß1, 6-branched N-glycans. In addition, the regulated expression of GnT-V in the CNE-2R cells converted the heterogeneous N-glycosylated forms of CD147. Furthermore, swainsonine, an inhibitor of N-glycan biosynthesis, was also able to reverse the radioresistance of the CNE-2R cells. Taken together, the present study revealed a novel mechanism of GnT-V as a regulator of radioresistance in NPC cells, which may be useful for fully understanding the biological role of N-glycans in NPC radioresistance.

MMP1 rs1799750 single nucleotide polymorphism and lung cancer risk: a meta-analysis.

BACKGROUND: Numerous studies have investigated the association of matrix metalloproteinase 1 (MMP1) rs1799750 single nucleotide polymorphism with lung cancer susceptibility, but the findings are inconsistent. Therefore, we performed a meta-analysis to comprehensively evaluate any possible association. METHODS: We searched publications from MEDLINE, EMBASE and CNKI databases which assessed links between the MMP1 rs1799750 polymorphism and lung cancer risk. We calculated the pooled odds ratio (OR) and its 95% confidence interval (95%CI) using either fixed-effects or random-effects models. RESULTS: The meta-analysis was based on 9 publications encompassing 4,823 cases and 4,298 controls. The overall results suggested there was a significant association between the MMP1 rs1799750 polymorphism and lung cancer risk (1G vs. 2G: OR = 0.83, 95%CI = 0.73-0.94; 1G1G vs. 2G2G: OR = 0.73, 95%CI = 0.59-0.92; 1G1G vs. 1G2G/2G2G: OR = 0.87, 95%CI = 0.79-0.97; 1G1G/1G2G vs. 2G2G: OR = 0.78, 95%CI = 0.64-0.95). In the subgroup analysis by ethnicity, the association was still obvious in Asians (all P values < 0.05), but there was no association in Caucasians (all P values > 0.05). CONCLUSIONS: The MMP1 rs1799750 polymorphism is associated with decreased lung cancer risk, and a race-specific effect may exist in this association.

Advanced breast angiosarcoma completely responding to gemcitabine-containing chemotherapy.

BACKGROUND: For patients with anthracycline-resistant metastatic angiosarcoma, there is currently no available standard for second-line therapy, and a need exists for novel effective regimens to improve response rates. CASE REPORT: We report here on a case of a primary angiosarcoma of both breasts in a 34-year-old woman presenting with lung metastases. Upon completion of 3 cycles of the MAID regimen (mesna, adriamycin, ifosfamide, dacarbazine), computed tomography showed disease progression. Subsequently, a second-line chemotherapy was started using the GVP regimen (gemcitabine, vincristine, cisplatin). Complete response of the lung metastases was achieved after 6 cycles of treatment. CONCLUSION: In the absence of an effective therapy among patients with anthracycline-resistant metastatic breast angiosarcoma, a GVP chemotherapy regimen can be performed as a selective option.