Patient-Controlled Subcutaneous Analgesia with Hydromorphone versus Oral Oxycontin for Opioid Titration of Cancer Pain: A Prospective Multicenter Randomized Trial.

Background: Studies have shown that oral oxycontin tablets can be used for opioid titration. The European Society for Medical Oncology (ESMO) guidelines for adult cancer pain recommend opioid titration through the parenteral route, usually the intravenous or subcutaneous route. Patient-controlled subcutaneous analgesia (PCSA) with hydromorphone needs further evaluation for opioid titration. This prospective multicenter study was designed to compare the efficacy and safety of hydromorphone PCSA with oral oxycontin tablets for opioid titration of cancer pain. Patients and Methods: Eligible patients with cancer pain were randomly assigned in a 1:1 ratio to the PCSA group or the oxycontin group for dose titration. Different titration methods were given in both groups depending on whether the patient had an opioid tolerance. The primary endpoint of this study was time to successful titration (TST). Results: A total of 256 patients completed this study. The PCSA group had a significantly lower TST compared with the oxycontin group (median [95% confidence interval (CI)], 5.5[95% CI:2.5-11.5] hours vs.16.0 [95% CI:11.5-22.5] hours; p<0.001). The frequency (median; interquartile) of breakthrough pain (Btp) over 24 hours was significantly lower in the PCSA group (2.5;2.0-3.5) than in the oxycontin group.(3.0; 2.5-4.5) (p=0.04). The pain was evaluated by numeric rating scale (NRS) score at 12 hours after the start of titration. The pain score (median; interquartile) was significantly lower in the PCSA versus the oxycontin group (2.5;1.5-3.0) vs 4.5;3.0-6.0) (p=0.02). The equivalent dose of oral morphine (EDOM) for a successful titration was similar in both groups (p=0.29), but there was a significant improvement in quality of life (QoL) in both groups (p=0.03). No between-group difference in the incidence of opioid-related adverse effects was observed (p=0.32). Conclusion: Compared with oral oxycontin tablet, the use of PCSA with hydromorphone achieved a shorter titration duration for patients with cancer pain (p<0.001), without significantly increasing adverse events (p=0.32).

A novel mechanism for C1GALT1 in the regulation of gastric cancer progression.

BACKGROUND: Gastric cancer (GC) is a highly aggressive and lethal disease around the world. High expression of core 1 ß 1, 3-galactosyltransferase 1 (C1GALT1), the primary enzyme responsible for protein O-glycosylation, plays a critical role in gastric carcinogenesis. However, proteins that can be O-glycosylated by C1GALT1 in GC have not been completely elucidated. Also, the mechanism leading to its upregulation in GC is currently unknown. RESULTS: Using public databases and our patient samples, we confirmed that C1GALT1 expression was upregulated at both the mRNA and protein levels in GC tissues. Elevated expression of C1GALT1 protein was closely associated with advanced TNM stage, lymph node metastasis, tumor recurrence, and poor overall survival. With gain- and loss-of-function approaches, we demonstrated that C1GALT1 promoted GC cell proliferation, migration, and invasion. By employing lectin pull-down assay and mass spectrometry, integrin α5 was identified as a new downstream target of C1GALT1 in GC. C1GALT1 was able to modify O-linked glycosylation on integrin α5 and thereby modulate the activation of the PI3K/AKT pathway. Functional experiments indicated that integrin α5 inhibition could reverse C1GALT1-mediated tumor growth and metastasis both in vitro and in vivo. Moreover, transcription factor SP1 was found to bind to the C1GALT1 promoter region and activated its expression. Further investigation proved that miR-152 negatively regulated C1GALT1 expression by directly binding to its 3' -UTR. CONCLUSIONS: Our findings uncover a novel mechanism for C1GALT1 in the regulation of GC progression. Thus, C1GALT1 may serve as a promising target for the diagnosis and treatment of GC.

Long non-coding RNA FOXD3-AS1 silencing exerts tumor suppressive effects in nasopharyngeal carcinoma by downregulating FOXD3 expression via microRNA-185-3p upregulation.

Emerging evidence indicates that the incidence of nasopharyngeal carcinoma (NPC) remains high in endemic regions despite changing environmental factors, suggesting that genetic traits contribute to its development. Recently, long non-coding RNA-microRNA-messenger RNA (lncRNA-miRNA-mRNA) axis has been reported to be implicated in the pathophysiological processes of malignancies. Moreover, initial bioinformatic analysis revealed a highly expressed lncRNA Forkhead box D3 antisense RNA1 (FOXD3-AS1) for mechanistic network underlying NPC in this present study. Therefore, this study aims to delineate the ability of lncRNA FOXD3-AS1 to influence the NPC progression. The relationship among lncRNA FOXD3-AS1, miR-185-3p, and FOXD3 was identified with bioinformatics prediction, dual-luciferase reporter gene assays, RNA-binding protein immunoprecipitation, and RNA pull-down assays. Furthermore, effects of lncRNA FOXD3-AS1 on malignant phenotypes in vitro, alongside tumor formation in vivo, of transfected NPC stem-like cells were examined with gain- and loss-of-function experiments. Our findings revealed that lncRNA FOXD3-AS1 and FOXD3 exhibited increased expression levels, while miR-185-3p exhibited diminished levels in NPC. The levels of lncRNA FOXD3-AS1 and FOXD3 were further correlated with tumor node metastasis stage and pathological type of patients with NPC. LncRNA FOXD3-AS1 was also confirmed to negatively regulate the miR-185-3p expression, which further targeted the downstream gene FOXD3. In addition, lncRNA FOXD3-AS1 knockdown repressed cell stemness, colony formation, viability, invasion, migration, and in vivo tumor growth, and accelerated cell apoptosis. Moreover, FOXD3 silencing or miR-185-3p overexpression reversed the effects of lncRNA FOXD3-AS1. Our findings provide evidence indicating that lncRNA FOXD3-AS1 could bind to miR-185-3p to upregulate the FOXD3 expression, thereby promoting the development of NPC.

Curcumin Inhibits the Migration and Invasion of Non-Small-Cell Lung Cancer Cells Through Radiation-Induced Suppression of Epithelial-Mesenchymal Transition and Soluble E-Cadherin Expression.

Radiotherapy has been reported to cause cancer metastasis. Thus, a new strategy for radiotherapy must be developed to avoid this side effect. A549 cells were exposed to radiation to induce an epithelial-mesenchymal transition (EMT) cell model. Real-time PCR and western blotting were used to detect mRNA and protein expression levels, and Transwell invasion and wound healing assays were used to detect cell migration and invasion. ELISA was used to detect soluble E-cadherin (sE-cad) secretion. siRNA was used to silence MMP9 expression. The results show that A549R cells exhibited an EMT phenotype with increased E-cadherin, N-cadherin, Snail, Slug, vimentin and Twist expression and decreased pan-keratin expression. sE-cad levels were increased in A549R cells and in the serum of NSCLC patients with distant metastasis. Exogenous sE-cad treatment and sE-cad overexpression promoted A549R and A549 cell migration and invasion. In contrast, blocking sE-cad attenuated A549 cell migration and invasion. Curcumin inhibited sE-cad expression and reversed EMT induced by radiation. Furthermore, curcumin suppressed sE-cad-enhanced A549 and A549R cell migration and invasion. Curcumin inhibited MMP9 expression, and silencing MMP9 suppressed sE-cad expression. Taken together, we found a nonclassic EMT phenomenon induced by radiation. Curcumin inhibits NSCLC migration and invasion by suppressing radiation-induced EMT and sE-cad expression by decreasing MMP9 expression.

Association between the pri-miR-26a-1 rs7372209 C>T polymorphism and cancer susceptibility: multivariate analysis and trial sequential analysis.

MiR-26 has been suggested to play a tumor-suppressive role in cancer development, which could be influenced by the mutate pri-miR-26ª-1. Molecular epidemiological studies have demonstrated some inconsistent associations between pri-miR-26ª-1 rs7372209 C>T polymorphism and cancer risk. We therefore performed this meta-analysis with multivariate statistic method to comprehensively evaluate the associations between rs7372209 C>T polymorphism and cancer risk. Eleven publications involving 6,709 patients and 6,514 controls were identified. Multivariate analysis indicated that the over-dominant genetic model was most likely. Pooled results indicated no significant association in the overall population (CC+TT vs. CT: OR=1.08, 95%CI=0.96-1.22, P=0.20, I2=54.4%), as well as the subgroup analysis according to ethnicity, control source, tumor locations, and HWE status of controls. In addition, heterogeneity, accumulative, sensitivity analysis, publication bias and trial sequential analysis (TSA) were conducted to test the statistical power. Overall, our results indicated that the pri-miR-26a-1 rs7372209 C>T polymorphism may not be a potential risk for cancer development.

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.

Altered O-glycosylation is associated with inherent radioresistance and malignancy of human laryngeal carcinoma.

Radioresistance (inherent or acquired) remains a major obstacle affecting the clinical outcome of radiotherapy for laryngeal carcinoma. Results from our laboratory and other groups suggest that aberrant glycosylation contributes to cancer acquired radioresistance. However, the role of glycosylation in inherent radioresistance of laryngeal carcinoma has not been fully uncovered. In this study, we investigated the glycan profiling of the inherent radioresistant (Hep-2max) and radiosensitive (Hep-2min) cell lines using lectin microarray analysis. The results revealed that the radioresistant cell line Hep-2max presented higher core 1-type O-glycans than the sensitive one. Further analysis of the O-glycan regulation by benzyl-α-GalNAc application in Hep-2max cells showed partial inhibition of the O-glycan biosynthesis and increased radiosensitivity. In addition, core 1 ß1, 3-galactosyltransferase (C1GALT1) overexpression in Hep-2min cells enhanced cell migration, invasion, and radioresistance. Conversely, knockdown of C1GALT1 in Hep-2max cells was able to suppress these malignant phenotypes. Moreover, mechanistic investigations showed that C1GALT1 modified the O-glycans on integrin ß1 and regulated its activity. The glycosylation-mediated radioresistance was further inhibited by anti-integrin ß1 blocking antibody. Importantly, we also observed that core 1-type O-glycans expression was correlated with advanced tumor stage, metastasis, and poor survival of laryngeal carcinoma patients. These findings suggest that altered O-glycosylation can lead to the inherent radioresistance and progression, and therefore may be important for enhancing the efficacy of radiotherapy in laryngeal carcinoma.

Prognostic value of DNA repair genes based on stratification of glioblastomas.

Abnormal expression of DNA repair genes is frequently associated with cancerogenesis of many tumors, however, the role DNA repair genes play in the progression of glioblastoma remains unclear. In this study, taking advantage of large scale of RNA-seq data, as well as clinical data, the function and prognosis value of key DNA repair genes in glioblastoma were analyzed by systematically bioinformatic approaches. Clustering was performed to screen potentially abnormal DNA repair genes related to the prognosis of glioblastoma, followed by unsupervised clustering to identify molecular subtypes of glioblastomas. Characteristics and prognosis differences were analyzed among these molecular subtypes, and modular driver genes in molecular subtypes were identified based on changes in expression correlation. Multifactor Cox proportional hazard analysis was used to find the independent prognostic factor. A total of 15 key genes, which were significantly related to prognosis, were identified and four molecular subtypes of disease were obtained through unsupervised clustering, based on these 15 genes. By analyzing the clinical features of these 4 molecular subtypes, Cluster 4 was found to be different from others in terms of age and prognosis level. A total of 5 key DNA repair genes, CDK7, DDB2, RNH1, RFC2 and FAH, were screened to be significantly related to the prognosis of glioblastomas (p = 9.74e-05). In summary, the DNA repair genes which can predict the prognosis of patients with Glioblastoma multiforme (GBM) were identified and validated. The expression level of DNA repair genes shows the potential of predicting the prognosis and therapy design in targeting GBM.

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.

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.

Postoperative brachytherapy and electron beam irradiation for keloids: A single institution retrospective analysis.

The aim of the present study was to perform a retrospective analysis of the control rate and toxicity of postoperative brachytherapy and electron beam irradiation for keloids. A retrospective review was performed of 116 keloid patients who underwent postoperative brachytherapy and electron beam irradiation between January 1, 2002 and June 30, 2012. Several different radiotherapy techniques and fractionation schedules were performed in the analysis, including high-dose rate (HDR) irradiation with 192Ir at 8 Gy/1 fraction (F)+9 Gy/3F or 20 Gy/4F; HDR brachytherapy with 60Co at 20 Gy/4F or 18 Gy/6F; or external beam electron therapy at 26 Gy/13F or 30 Gy/15F. The endpoints of the study were analysis of the control rate and toxicity. The median observation period was 46.5 months (range, 10.0-120.0 months) for all patients. In total, 18 of the 116 patients relapsed, and 16.7 months (range, 10.0-30.0 months) was the median time to recurrence for these patients. The control rates for the patients who received hypofractionation (>2 Gy per fraction) and conventional fraction (2 Gy per fraction) were 88.5 and 76.3%, respectively (P=0.043). The control rates for the patients whose calculated biological effective doses (BED) were >30 Gy and <30 Gy were 89.7 and 79.3%, respectively (P=0.104). There were no grade 2 or higher adverse effects based on the Common Terminology Criteria for Adverse Events v3.0 in the late phase. No evidence was identified for a link between radiotherapy and the subsequent occurrence of cancer. The results of the present study indicate that hypofractionated radiotherapy played an important role as an adjuvant therapy following surgical excision of keloids. A BED of >30 Gy appears to be sufficient. No definitive evidence was found for an association between radiotherapy and the occurrence of cancer during the follow-up, however, more cases and longer follow-up periods are required.

Chitooligosaccharides inhibit ethanol-induced oxidative stress via activation of Nrf2 and reduction of MAPK phosphorylation.

Chitooligosaccharides (COS) are hydrolyzed products of chitosan and have been proven to exhibit various biological functions. The aims of this study were to investigate the mechanisms underlying the hepatoprotective effects of COS against ethanol-induced oxidative stress in vitro. Human L02 normal liver cells were pretreated with COS (0.25, 0.5 and 1.0 mg/ml) and then hepatotoxicity was stimulated by the addition of ethanol (80 mM). Pretreatment with COS protected L02 cells from ethanol-induced cell cytotoxicity through inhibition of reactive oxygen species generation. Furthermore, ethanol-induced lipid peroxidation and glutathione depletion was inhibited by COS. The antioxidant potential of COS was correlated with the induction of antioxidant genes including HO-1, NQO1 and SOD via the transcriptional activation of nuclear factor erythroid-2­related factor-2 (Nrf2). Additionally, the protective effects of COS against ethanol were blocked by Nrf2 knockdown. Moreover, signal transduction studies showed that COS was able to suppress the ethanol-induced phosphorylation of p38 MAPK, JNK and ERK. In conclusion, the COS-mediated activation of Nrf2 and reduction of MAPK phosphorylation may be important for its hepatoprotective action.

Downregulation of CD147 by chitooligosaccharide inhibits MMP-2 expression and suppresses the metastatic potential of human gastric cancer.

Metastasis is considered to be the major cause of mortality in patients with cancer, and gastric cancer is a highly metastatic cancer. In the present study, the anti-metastatic activity of chitooligosaccharide (COS) in human gastric cancer cells and its underlying mechanism were investigated. It was found that COS significantly inhibited SGC-7901 cell proliferation and metastasis in a dose-dependent manner, as observed by MTT, wound-healing and Transwell assays. Quantitative real-time polymerase chain reaction and western blot analysis indicated that COS could decrease the expression of cluster of differentiation 147 (CD147) and subsequently reduce matrix metalloproteinase-2 (MMP-2) expression. A clear dose-dependent inhibition of MMP-2 activity was also observed in SGC-7901 cells following treatment with COS in gelatin zymography experiments. Furthermore, overexpression of CD147 (when transfected with pEGFP-C1 plasmid) in SGC-7901 cells partially protected against COS-induced inhibition of MMP-2. The results of the present study demonstrated the potential of COS in suppressing gastric cancer metastasis, and that the CD147/MMP-2 pathway may be involved as the key mechanism of its anti-metastatic effect.

Fenbendazole as a potential anticancer drug.

BACKGROUND/AIMS: To evaluate the anticancer activity of fenbendazole, a widely used antihelminth with mechanisms of action that overlap with those of the hypoxia-selective nitroheterocyclic cytotoxins/radiosensitizers and the taxanes. MATERIALS AND METHODS: We used EMT6 mouse mammary tumor cells in cell culture and as solid tumors in mice to examine the cytotoxic and antitumor effects of fenbendazole as a single agent and in combination regimens. RESULTS: Intensive treatments with fenbendazole were toxic to EMT6 cells in vitro; toxicity increased with incubation time and under conditions of severe hypoxia. Fenbendazole did not alter the dose-response curves for radiation or docetaxel; instead, the agents produced additive cytotoxicities. Febendazole in maximally-intensive regimens did not alter the growth of EMT6 tumors, or increase the antineoplastic effects of radiation. CONCLUSION: These studies provided no evidence that fenbendazole would have value in cancer therapy, but suggested that this general class of compounds merits further investigation.

Use of fenbendazole-containing therapeutic diets for mice in experimental cancer therapy studies.

Pinworm infection (oxyuriasis) is a common problem in rodent colonies. Facility-wide prophylactic treatment of all mice with a diet containing therapeutic levels of fenbendazole for several weeks is often used to control pinworm outbreaks. We examined the effect of feeding a therapeutic diet containing 150 ppm fenbendazole on the growth of EMT6 mouse mammary tumors implanted into BALB/c Rw mice. Mice were randomized to receive either a fenbendazole-containing or control diet for 1 wk before tumor cells were injected intradermally in the flanks and throughout tumor growth. Tumor growth was monitored by serial measurements of tumor diameters from the time tumors became palpable until they reached 1000 mm3. The medicated diet did not alter tumor growth, invasion, or metastasis. When tumors reached volumes of approximately 100 mm3, some were irradiated locally with 10 Gy of X-rays. Irradiation significantly delayed tumor growth; fenbendazole did not alter the radiation-induced growth delay. However, cell culture studies showed that fenbendazole concentrations not far above those expected in the tissues of mice on this diet altered the growth of the tumor cells in culture. Recent data from other laboratories also have demonstrated effects of fenbendazole that could complicate experiments. Care should therefore be exercised in deciding whether chow containing fenbendazole should be administered to mouse colonies being used in cancer research.