The prognostic value of the ratio of standard uptake value of lymph node to primary tumor before treatment of locally advanced nasopharyngeal carcinoma.

BACKGROUND: To evaluate the prognostic value of the ratio of the standard uptake value of the lymph node and primary tumor before the treatment of locally advanced nasopharyngeal carcinoma and examine the prognostic value of the tumor metabolic parameters (SUVmax, MTV, and TLG) of the lymph node and primary tumor of locally advanced nasopharyngeal carcinoma. METHODS: A total of 180 patients with locally advanced nasopharyngeal carcinoma diagnosed pathologically from January 1, 2016 to December 31, 2018 were selected, and the MEDEX system was used to automatically delineate the SUVmax, MTV, and TLG of the lymph node metastases and nasopharyngeal carcinoma primary tumor. In addition, the ratio of LN-SUVmax (SUVmax of the lymph node metastases) to T-SUVmax (SUVmax of the nasopharyngeal carcinoma primary tumor) was calculated, and a ROC curve was drawn to obtain the best cut-off value. Kaplan-Meier and Cox regression models were used for survival and multivariate analyses, respectively. RESULTS: The median follow-up period for participants was 32 (4-62) months. Univariate analysis showed that age (P = 0.013), LN-SUVmax (P = 0.001), LN-TLG (P = 0.007) and NTR (P = 0.001) were factors influencing the overall survival (OS). Factors affecting local progression-free survival (LPFS) were LN-SUVmax (P = 0.005), LN-TLG (P = 0.003) and NTR (P = 0.020), while clinical stage (P = 0.023), LN-SUVmax (P = 0.007), LN-TLG (P = 0.006), and NTR (P = 0.032) were factors affecting distant metastasis-free survival (DMFS). Multivariate analysis showed that NTR was an independent influencing factor of OS (HR 3.00, 95% CI 1.06-8.4, P = 0.038), LPFS (HR 3.08, 95% CI 1.27-7.50, P = 0.013), and DMFS (HR 1.84, 95% CI 0.99-3.42, P = 0.054). Taking OS as the main observation point, the best cut-off point of NTR was 0.95. Kaplan-Meier results showed that the 3-year OS (97.0% vs 85.4%, χ2 = 11.25, P = 0.001), 3-year LPFS (91.3% vs 82.1%, χ2 = 4.035, P = 0.045), and 3-year DMFS (92.3% vs 87.9%, χ2 = 4.576, P = 0.032) of patients with NTR < 0.95 were higher than those with NTR > 0.95. CONCLUSIONS: High NTR before treatment indicates a poor prognosis for patients with nasopharyngeal carcinoma. This can serve as a reference value for the reasonable treatment and prognosis monitoring of such patients.

Bioinformatics screening the novel and promising targets of curcumin in hepatocellular carcinoma chemotherapy and prognosis.

BACKGROUND: The aim of present study was to screen the novel and promising targets of curcumin in hepatocellular carcinoma diagnosis and chemotherapy. METHODS: Potential targets of curcumin were screened from SwissTargetPrediction, ParmMapper and drugbank databases. Potential aberrant genes of hepatocellular carcinoma were screened from Genecards databases. Fifty paired hepatocellular carcinoma patients' gene expression profiles from the GEO database were used to test potential targets of curcumin. Besides, GO analysis, KEGG pathway enrichment analysis and PPI network construction were used to explore the underlying mechanism of candidate hub genes. ROC analysis and Kaplan-Meier analysis were used to evaluate the diagnostic and prognostic value of candidate hub genes, respectively. Real-time PCR was used to verify the results of bioinformatics analysis. RESULTS: Bioinformatics analysis results suggested that AURKA, CDK1, CCNB1, TOP2A, CYP2B6, CYP2C9, and CYP3A4 genes served as candidate hub genes. AURKA, CDK1, CCNB1 and TOP2A were significantly upregulated and correlated with poor prognosis in hepatocellular carcinoma, AUC values of which were 95.7, 96.9, 98.1 and 96.1% respectively. There was not significant correlation between the expression of CYP2B6 and prognosis of hepatocellular carcinoma, while CYP2C9 and CYP3A4 genes were significantly downregulated and correlated with poor prognosis in hepatocellular carcinoma. AUC values of CYP2B6, CYP2C9, and CYP3A4 were 96.0, 97.0 and 88.0% respectively. In vitro, we further confirmed that curcumin significantly downregulated the expression of AURKA, CDK1, and TOP2A genes, while significantly upregulated the expression of CYP2B6, CYP2C9, and CYP3A4 genes. CONCLUSIONS: Our results provided a novel panel of AURKA, CDK1, TOP2A, CYP2C9, and CYP3A4 candidate genes for curcumin related chemotherapy of hepatocellular carcinoma.

Indocyanine green near-infrared imaging-guided lymph node dissection during oesophageal cancer surgery: A single-centre experience.

Objective: This study aimed to investigate the feasibility of using indocyanine green (ICG) near-infrared (NIR) imaging during lymphadenectomy for oesophageal cancer. Methods: Eighty-seven patients with primary oesophageal cancer were enrolled in this study. All the enrolled patients received an endoscopic injection of ICG between 40 min and 23 h before surgery. Nodal dissection during surgery was performed under fluorescence imaging visualisation, with the NIR signal shown in purple. ICG+ or ICG- nodes were recorded station by station and were microscopically evaluated. Results: Endoscopic peritumoral ICG injection was successfully performed in all patients. Major post-surgery complications included wound infection, pleural effusion, dysphonia, pneumonia and anastomotic fistula. No patients experienced ICG-related adverse events. A total of 2,584 lymph nodes were removed, and the mean number of lymph nodes for each patient was 29.70 ± 9.24. Most of the removed nodes (97.83%) were ICG+, and 3.32% of the ICG+ nodes were metastatic. No metastatic nodes were ICG- or belonged to an ICG- lymph node station. The time from ICG injection to surgery did not affect the number of harvested lymph nodes. Conclusions: The use of ICG-NIR imaging during oesophageal cancer surgery can enhance the visualisation of lymph nodes during surgery. It is a feasible, safe and helpful technique for lymphadenectomy.

Predictive Value of Pretreatment Lymphocyte-to-Monocyte Ratio and Platelet-to-Lymphocyte Ratio in the Survival of Nasopharyngeal Carcinoma Patients.

OBJECTIVE: The present study aimed to investigate the predictive value of some indexes, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory response index (SIRI), and systemic immune-inflammatory index (SII) in the survival of nasopharyngeal carcinoma (NPC) and provide reference for the treatment. METHODS: A retrospective analysis was performed on 216 patients from 2016 to 2018. The cutoff values of these indexes were determined by the receiver operating characteristic (ROC) curve. The prognostic value of the indexes was evaluated according to the rate of overall survival (OS), regional recurrence-free survival (RRFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS). RESULTS: The survival analysis showed that NLR ≤2.695 (P = 0.017) and PLR ≤140.065 (P = 0.041) were associated with poor OS; however, the LMR and SIRI showed no significant statistical significance. NLR ≤2.045 (P = 0.018) and PLR ≤125.605 (P = 0.003) were associated with poor RRFS, LMR ≤2.535 (P = 0.027) and PLR ≤140.065 (P = 0.009) were associated with poor DMFS, NLR ≤2.125 (P = 0.018) and PLR ≤132.645 (P = 0.026) were associated with poor LRRFS, respectively. Logistic regression analysis showed that low LMR (≤2.535) was significantly inferior in OS (HR 23.085, 95% CI 3.425-155.622, P = 0.001) and DMFS (HR 22.839, 95% CI 4.096-127.343, P < 0.001). Moreover, low PLR (≤140.065) remained significantly related to worse OS (HR 11.908, 95% CI 1.295-109.517, P = 0.029) and DMFS (HR 9.556, 95% CI 1.448-63.088, P = 0.019). CONCLUSION: The index LMR and PLR can be used for predicting survival in NPC patients.

miR-22-3p Suppresses Endothelial Progenitor Cell Proliferation and Migration via Inhibiting Onecut 1 (OC1)/Vascular Endothelial Growth Factor A (VEGFA) Signaling Pathway and Its Clinical Significance in Venous Thrombosis.

BACKGROUND Proliferation and migration play crucial roles in various physiological processes, especially in injured endothelial repair. Endothelial progenitor cells (EPCs), as the precursors of endothelial cell, are involved in the regeneration of the endothelial lining of blood vessels. Furthermore, EPCs were found to be a potential choice for venous thrombosis (VT) treatment. MATERIAL AND METHODS EPCs were isolated from human peripheral blood of healthy adults and VT patients. Differently expressed micro(mi)RNAs were examined by quantitative real-time polymerase chain reaction, after which proliferative capacity and migration effect were tested by Cell-Counting Kit 8, scratch wound assay, and transwell assays. Bioinformatic analysis was applied to investigate the potential target messenger ribonucleic acid and a dual-luciferase reporting system was utilized to confirm the binding of miR-22-3p to its target gene. Western blot was carried out to detect candidate protein expression level. Finally, miR-22-3p expression was monitored in VT patients during follow-up to assess its correlation with prognosis of VT. RESULTS Our data revealed that miR-22-3p was upregulated in EPCs derived from deep VT (DVT) individuals and suppression of miR-22-3p contributed to proliferation and migration of EPCs. In addition, miR-22-3p/onecut 1 (OC1)/vascular endothelial growth factor A (VEGFA) signaling pathway was involved in regulating EPC migration and proliferation. In addition, lower expression of miR-22-3p in DVT patients indicated decreased risk of VT recurrence. CONCLUSIONS Our results suggest that miR-22-3p regulates OC1/VEGFA signaling and is involved in regulating EPC proliferation and migration. The expression level of miR-22-3p could be monitored to predict DVT patients' prognosis.

Study on the yielding behaviors of ferrofluids: a very shear thinning phenomenon.

The yielding behaviors of the ferrofluids are vital for many applications. However, previous studies have mainly focused on the magnetoviscous effect under relatively high shear rates and rarely involved the yielding process of ferrofluids under very low shear rates. In this study, ferrofluid samples of different particle volume concentrations were prepared and their shear thinning behaviors within a wide shear stress range were systematically studied under various magnetic field strengths and temperatures. The very shear thinning phenomenon of ferrofluids was first observed and its microscopic mechanism was analyzed. A precipitous fall-off stage as the mark of yielding appeared between the low shear and high shear plateaus in the viscosity curves of ferrofluids. The precipitous fall-off stage in the viscosity curves became steeper with the increase of the magnetic field strength or decrease in the temperature. For ferrofluids with relatively low particle volume concentrations, the high viscosity limit under the low shear region disappeared when temperature exceeded a certain value and was interpreted as the disappearance of the equilibrium columnar structures under high Brownian thermal interaction level. A composite Ellis model was proved to be suitable for the fitting of different types of yield stresses and a structural number, Sn was proposed for the dimensionless analysis of the shear thinning behaviors of ferrofluids. The findings in this study contribute to a better understanding of the microscopic mechanism of yielding behaviors of ferrofluids and also provide guidance for many practical applications.

Depletion of Ars2 inhibits cell proliferation and leukemogenesis in acute myeloid leukemia by modulating the miR-6734-3p/p27 axis.

Ars2 is a component of the nuclear cap-binding complex (CBC) that contributes to microRNA biogenesis and is required for cellular proliferation. Little is known regarding the functional role of Ars2 in cell proliferation and leukemogenesis of acute myeloid leukemia. Here, we show that the elevated expression of Ars2 was observed in acute myeloid leukemia (AML) cell lines and bone marrow samples from AML patients and was correlated with poorer overall survival. Overexpression of Ars2 promoted cell proliferation and colony formation in AML cells, whereas depletion of Ars2 inhibited cell proliferation and colony formation. Mechanistic studies reveal that depletion of Ars2 suppressed the interaction of Ars2 with CBC and led to alterations in miRNA processing. Furthermore, Ars2 depletion reduced the levels of miR-6734-3p, resulting in upregulation of p27 and culminating in cell cycle arrest at the G1 phase. In vivo studies indicate that depletion of Ars2 significantly reduced leukemic cell burden and prolonged the survival time of the leukemia-bearing mice. These findings indicate that Ars2 may not only play a crucial role in the regulation of cell proliferation and leukemogenesis, but could also be identified as a critical therapeutic target for treatment of AML.

Demethylzeylasteral inhibits glioma growth by regulating the miR-30e-5p/MYBL2 axis.

Glioma is the most common and malignant form of primary brain tumour, and is characterised by high proliferation and extensive invasion and neurological destruction. Demethylzeylasteral (T-96), which is extracted from Tripterygium wilfordii, is considered to have immunosuppressive, anti-inflammatory and anti-angiogenic effects. Here, the anti-tumour effect of T-96 on glioma was evaluated. Our results demonstrated that T-96 significantly inhibited glioma cell growth and induced cell cycle arrest in G1 phase but did not induce apoptosis. Cell invasion and migration were dramatically suppressed after treatment with T-96. Almost all genes related to cell cycle and DNA replication were downregulated after treatment with T-96. Our results showed that miR-30e-5p was noticeably upregulated after T-96 treatment, and MYBL2, which is involved in cell cycle progression and is a target gene of miR-30e-5p, was significantly reduced in synchrony. Overexpression of MYBL2 partially rescued the T-96-induced inhibition of cell growth and proliferation. Moreover, a miR-30e-5p antagomir significantly reduced the upregulation of miR-30e-5p expression induced by T-96, leading to recovery of MYBL2 expression, and partially rescued the T-96-induced inhibition of cell growth and proliferation. More important, T-96 effectively upregulated miR-30e-5p expression and downregulated MYBL2 expression, thus inhibiting LN-229 cell tumour growth in a mouse model. These results indicated that T-96 might inhibit glioma cell growth by regulating the miR-30e-5p/MYBL2 axis. Our study demonstrated that T-96 might act as a promising agent for malignant glioma therapy.

Ars2 promotes cell proliferation and tumorigenicity in glioblastoma through regulating miR-6798-3p.

Arsenic resistance protein 2 (Ars2) is a component of the nuclear RNA cap-binding complex (CBC) that is important for some microRNA biogenesis and it is critical for cell proliferation and tumorigenicity. However, mechanism of Ars2-regulated cellular proliferation and tumorigenicity in glioblastoma has not been fully understood. Western blotting was used to detect the expressions of Ars2, p53, p21, and cleavage/activation of caspases-3 (C-Caspase 3). Microarray and Quantitative Real-time PCR (qRT-PCR) were performed to identify the Ars2-regulated microRNAs. Apoptosis assessed by flow cytometry analysis was used to evaluate the role of Ars2 in cells proliferation. The lentivirus-mediated gene knockdown approach was conducted to determine the function of Ars2. The orthotopic glioblastoma xenograft was used to demonstrate the role of Ars2 in glioblastoma growth in vivo. The high expression of Ars2 was observed in several glioblastoma cell lines and was significantly associated with poorer overall survival. Importantly, the overexpression of Ars2 promoted cell proliferation and colony formation in glioblastoma cells, whereas the depletion of Ars2 inhibited cell proliferation, colony formation, and tumor growth. Mechanistic study revealed that knockdown of Ars2 reduced the expression levels of miR-6798-3p, which was responsible for the up-regulation of p53 and p21, leading to apoptosis. Furthermore, the knockdown of Ars2 suppressed tumor growth in orthotopic glioblastoma xenograft model and significantly prolonged the survival time of the tumor-bearing mice. These findings identify a critical role for Ars2 in regulation of proliferation and tumorigenicity in glioblastoma and suggest that Ars2 could be a critical therapeutic target for glioblastoma intervention.

Study of the thixotropic behaviors of ferrofluids.

The thixotropic behaviors of ferrofluid samples of different particle concentration were studied using different measurement methods, including the three interval thixotropic test and the hysteresis loop test. The experimental results demonstrated that ferrofluids exhibit significant thixotropic behaviors and the microstructural evolution in ferrofluids behind the macroscopic rheological mechanics is discussed. The influence of magnetic field strength, particle concentration and temperature on the thixotropy of ferrofluids was also analyzed. Microscopic ferrofluid theory was adopted to study the thixotropic behaviors of ferrofluids under different shearing conditions, indicating that different thixotropic behaviors of ferrofluids can be induced by the presence and evolution of different kinds of microstructures, such as linear chain-like and dense drop-like structures. Furthermore, a phenomenal thixotropic model was employed to analyze the experimental results, indicating that a more specific model for ferrofluids is needed. These findings contribute to a better understanding of the microscopic mechanism of the complex rheological behaviors of ferrofluids.

Cancer-testis specific gene OIP5: a downstream gene of E2F1 that promotes tumorigenesis and metastasis in glioblastoma by stabilizing E2F1 signaling.

Background: The cancer-testis specific gene Opa interacting protein 5 (OIP5) is reactivated in many human cancers, but its functions in glioblastoma remain unclear. Here, we assessed the significance of OIP5 in the tumorigenesis and metastasis of glioblastoma for the first time. Methods: An immunohistochemistry assay was performed to detect OIP5 expression changes in glioblastoma patients. Overall survival analysis was performed to evaluate the prognostic significance of OIP5. Growth curve, colony formation, and transwell assays were used to analyze cell proliferation and metastasis. Tumorigenicity potential was investigated in orthotopic tumor models, and immunoprecipitation, chromatin immunoprecipitation, and luciferase assays were employed to explore the mechanisms underlying the activation of OIP5 expression by E2F transcription factor 1 (E2F1) to stabilize and maintain E2F1 signaling. Results: OIP5 was found to be upregulated in glioblastoma patients and to impair patient survival, and the increased expression of OIP5 was positively correlated with tumor stage. Compared with short hairpin green fluorescent protein cells, cells in which OIP5 was knocked down exhibited significantly reduced proliferation, metastasis, colony formation, and tumorigenicity abilities, whereas OIP5 recovery enhanced these abilities. OIP5 was highly correlated with cell cycle progression but had no obvious effects on apoptosis. Notably, we demonstrated a feedback loop in which E2F1 activates the expression of OIP5 to stabilize and maintain E2F1 signaling and promote the E2F1-regulated gene expression that is required for aggressive tumor biology. Conclusions: Collectively, our findings demonstrate that OIP5 promotes glioblastoma progression and metastasis, suggesting that OIP5 is a potential target for anticancer therapy.

Dephosphorylation and mitochondrial translocation of cofilin sensitizes human leukemia cells to cerulenin-induced apoptosis via the ROCK1/Akt/JNK signaling pathway.

In this study, we determined that cerulenin, a natural product inhibitor of fatty acid synthase, induces mitochondrial injury and apoptosis in human leukemia cells through the mitochondrial translocation of cofilin. Only dephosphorylated cofilin could translocate to mitochondria during cerulenin-induced apoptosis. Disruption of the ROCK1/Akt/JNK signaling pathway plays a critical role in the cerulenin-mediated dephosphorylation and mitochondrial translocation of cofilin and apoptosis. In vivo studies demonstrated that cerulenin-mediated inhibition of tumor growth in a mouse xenograft model of leukemia was associated with mitochondrial translocation of cofilin and apoptosis. These data are consistent with a hierarchical model in which induction of apoptosis by cerulenin primarily results from activation of ROCK1, inactivation of Akt, and activation of JNK. This leads to the dephosphorylation and mitochondrial translocation of cofilin and culminates with cytochrome c release, caspase activation, and apoptosis. Our study has revealed a novel role of cofilin in the regulation of mitochondrial injury and apoptosis and suggests that cerulenin is a potential drug for the treatment of leukemia.

Tanshinone IIA inhibits HIF-1α and VEGF expression in breast cancer cells via mTOR/p70S6K/RPS6/4E-BP1 signaling pathway.

Hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) play important roles in angiogenesis and tumor growth. Tanshinone IIA (T2A) is a novel antiangiogenic agent with promising antitumor effects; however, the molecular mechanism underlying the antiangiogenic effects of T2A remains unclear. In the present study, we provided evidence showing that T2A inhibited angiogenesis and breast cancer growth by down-regulating VEGF expression. Specifically, T2A repressed HIF-1α expression at the translational level and inhibited the transcriptional activity of HIF-1α, which led to the down-regulation of VEGF expression. Suppression of HIF-1α synthesis by T2A correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway regulating HIF-1α expression at the translational level. In addition, we also found that T2A inhibited the angiogenesis and growth of human breast cancer xenografts in nude mice through suppression of HIF-1α and VEGF. Our study provides novel perspectives and potential targets for the treatment of human breast cancer.

Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis.

Cofilin is a member of the actin-depolymerizing factor (ADF) family protein, which plays an essential role in regulation of the mitochondrial apoptosis. It remains unclear how cofilin regulates the mitochondrial apoptosis. Here, we report for the first time that natural compound 4-methylthiobutyl isothiocyanate (erucin) found in consumable cruciferous vegetables induces mitochondrial fission and apoptosis in human breast cancer cells through the mitochondrial translocation of cofilin. Importantly, cofilin regulates erucin-induced mitochondrial fission by interacting with dynamin-related protein (Drp1). Knockdown of cofilin or Drp1 markedly reduced erucin-mediated mitochondrial translocation and interaction of cofilin and Drp1, mitochondrial fission, and apoptosis. Only dephosphorylated cofilin (Ser 3) and Drp1 (Ser 637) are translocated to the mitochondria. Cofilin S3E and Drp1 S637D mutants, which mimick the phosphorylated forms, suppressed mitochondrial translocation, fission, and apoptosis. Moreover, both dephosphorylation and mitochondrial translocation of cofilin and Drp1 are dependent on ROCK1 activation. In vivo findings confirmed that erucin-mediated inhibition of tumor growth in a breast cancer cell xenograft mouse model is associated with the mitochondrial translocation of cofilin and Drp1, fission and apoptosis. Our study reveals a novel role of cofilin in regulation of mitochondrial fission and suggests erucin as a potential drug for treatment of breast cancer.

A novel granulocyte-specific α integrin is essential for cellular immunity in the silkworm Bombyx mori.

Haemocytes play crucial roles in immune responses and survival in insects. Specific cell markers have proven effective in clarifying the function and haematopoiesis of haemocytes. The silkworm Bombyx mori is a good model for studying insect haemocytes; however, little is known about haemocyte-specific markers or their functions in silkworm. In this study, we identified the α subunit of integrin, BmintegrinαPS3, as being specifically and highly expressed in silkworm haemocytes. Immunofluorescence analysis validated the specificity of BmintegrinαPS3 in larval granulocytes. Further analyses indicated that haemocytes dispersed from haematopoietic organs (HPOs) into the circulating haemolymph could differentiate into granulocytes. In addition, the processes of encapsulation and phagocytosis were controlled by larval granulocytes. Our work demonstrated that BmintegrinαPS3 could be used as a specific marker for granulocytes and could be applied to future molecular cell biology studies.

Bax is essential for death receptor-mediated apoptosis in human colon cancer cells.

To demonstrate the role of Bax in death receptor-induced apoptosis in the human colon cancer HCT116 cells. We treated HCT116 cells and HCT116 with p53(-/-) (KO) by 0.1 µg/mL TRAIL for 24 hours, which indicated that HCT116 parental cells are sensitive to p53-independent death receptor-induced apoptosis. Although the p53 signaling pathway is totally intact in this system, the down-regulation of Bax in HCT116 cells is dramatically resistant to TRAIL and failed to undergo apoptosis. However, the over-expression of Bax can rescue the sensitivity of apoptosis induced by the death receptor. Our study has revealed an essential role for Bax in death receptor-induced apoptosis in the human colon cancer HCT116 cells. It may aid in a molecular understanding of possible defects in signal transduction and a regulation of the death receptor-induced apoptotic process.