Neoalbaconol inhibits angiogenesis and tumor growth by suppressing EGFR-mediated VEGF production.

Neoalbaconol, derived from Albatrellus confluens, shows anti-cancer activities in the previously study, but its role in angiogenesis is unknown. Here, we determined whether neoalbaconol could attenuate angiogenesis and how does it occur. Data demonstrated that neoalbaconol could inhibit the proliferation of breast cancer cells and induce apoptosis. Also, neoalbaconol suppressed vascular endothelial growth factor (VEGF)-induced human umbilical vascular endothelial cells (HUVECs) proliferation, migration, invasion, and capillary-like tube formation in vitro and reduced tumor angiogenesis in vivo. VEGF receptor activation and the downstream signal transduction cascades activation were inhibited by neoalbaconol. Additionally, neoalbaconol blocked EGFR-mediated VEGF production. EGFR overexpression reversed the neoalbaconol-induced VEGF reduction, confirming the importance of the EGFR inhibition in anti-angiogenesis of neoalbaconol. Furthermore, neoalbaconol inhibited tumor growth and tumor angiogenesis in a breast cancer xenograft model in vivo. Taken together, these results indicate that neoalbaconol could inhibit tumor angiogenesis and growth through direct suppression effects on vascular endothelial cells and reduction of proangiogenic factors in cancer cells.

Real-world hospital costs for nonchemotherapy drugs and nondrug care associated with platinum-based doublets in the first-line setting for advanced nonsquamous non-small-cell lung cancer in Chinese patients: a retrospective cohort study.

OBJECTIVE: The objective of this study was to compare hospital costs per treatment cycle (HCTC) for nonchemotherapy drugs and nondrug care associated with platinum-based doublets in the first-line setting for advanced nonsquamous non-small-cell lung cancer (AdvNS-NSCLC) in Chinese patients. METHODS: Patients receiving platinum-based doublets in the first-line setting for AdvNS-NSCLC from 2010 to 2012 in two Chinese tertiary hospitals were identified to create the retrospective study cohort. Propensity score methods were used to create matched treatment groups for head-to-head comparisons on HCTC between pemetrexed-platinum and other platinum-based doublets. Multiple linear regression analyses were performed to rank studied platinum-based doublets for their associations with the log10 scale of HCTC for nonchemotherapy drugs and nondrug care. RESULTS: Propensity score methods created matched treatment groups for pemetrexed-platinum versus docetaxel-platinum (61 pairs), paclitaxel-platinum (39 pairs), gemcitabine-platinum (93 pairs), and vinorelbine-platinum (73 pairs), respectively. Even though the log10 scale of HCTC for nonchemotherapy drugs and nondrug care associated with pemetrexed-platinum was ranked lowest in all patients (coefficient -0.174, P=0.015), which included patients experiencing any hematological adverse events (coefficient -0.199, P=0.013), neutropenia (coefficient -0.426, P=0.021), or leukopenia (coefficient -0.406, P=0.001), pemetrexed-platinum had the highest total HCTC (median difference from RMB 1,692 to RMB 7,400, P<0.001) among platinum-based doublets because of its higher drug acquisition costs (median difference from RMB 4,636 to RMB 7,332, P<0.001). CONCLUSION: Among Chinese patients receiving platinum-based doublets in the first-line setting for AdvNS-NSCLC, the higher acquisition costs for nonplatinum cytotoxic drugs associated with pemetrexed-platinum could be partially offset by its significantly lower hospital costs for nonchemotherapy drugs and nondrug care.

Field Emission of Wet Transferred Suspended Graphene Fabricated on Interdigitated Electrodes.

Suspended graphene (SG) membranes could enable strain-engineering of ballistic Dirac fermion transport and eliminate the extrinsic bulk disorder by annealing. When freely suspended without contact to any substrates, graphene could be considered as the ultimate two-dimensional (2D) morphology, leading to special field characteristics with the 2D geometrical effect and effectively utilized as an outstanding structure to explore the fundamental electronic or optoelectronic mechanism. In this paper, we report field emission characterization on an individual suspended few-layer graphene. A controllable wet transfer method is used to obtain the continuous and suspended graphene membrane on interdigitated gold electrodes. This suspended structure displays an overall field emission from the entirely surface, except for the variation in the emitting positions, acquiring a better enhancement than the exfoliated graphene on the conventional flat substrate. We also observe the transition process from space charge flow at low bias to the Fowler-Nordheim theory at high current emission regime. It could enable theoretical and experimental investigation of the typical electron emission properties of the 2D regime. Numerical simulations are also carried out to study the electrical properties of the suspended structure. Further improvement on the fabrication would realize low disorder, high quality, and large-scale suspended graphene devices.

Multiple functions of the first EGF domain in matrilin-3: Secretion and endoplasmic reticulum stress.

Mutations in matrilin-3 are associated with common skeletal diseases, such as hand osteoarthritis (HOA), as well as rare chondrodysplasias, such as multiple epiphyseal dysplasia (MED) and spondyloepimetaphyseal dysplasia (SEMD). In the present study, we constructed the mutations R116W [at the von Willebrand factor, type A (vWFA) domain], T298M [at the first epidermal growth factor (EGF) domain] and C299S (at the first EGF domain), according to the mouse sequence, which are associated with human MED, HOA and SEMD, respectively, by overlap extension PCR and inserted them into an expression vector (pcDNA3.1/v5-His). We transfected these contructs into the COS-1 or MCT cells, and the results revealed that the HOA-related matrilin-3 mutation (T298M) leads to a high expression level of growth arrest DNA damage-inducible gene 153 (GADD153, also known as CHOP; an endoplasmic reticulum stress marker), as shown by western blot analysis and does not significantly affect protein secretion, as shown by immunofluorescence staining; however, osteochondroplasia, i.e., MED-related (R116W) and SEMD-related (C299S) mutations lead to both high levels of GADD153 expression and protein trafficking into the cytoplasm and form multiple vacuoles in cells, which in turn leads to insufficient protein secretion.

Supportive Care Costs Associated with Second-Line Chemotherapy in Chinese Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: A Retrospective Cohort Study.

PURPOSE: To compare supportive care costs associated with second-line chemotherapy for advanced non-squamous non-small cell lung cancer (advNS-NSCLC) in Chinese patients. METHODS: This retrospective cohort study included patients receiving pemetrexed or docetaxel-based second-line chemotherapy for advNS-NSCLC in four Chinese hospitals from 2007 to 2012. The best matched pairs between pemetrexed and other regimens were identified using propensity score methods for head-to-head comparisons of supportive care costs per treatment cycle. Linear regression analyses were performed to rank log10 scale of supportive care costs per treatment cycle associated with chemotherapy by tumor response and hematologic toxicity. RESULTS: 384 patients were included to create propensity score-matched treatment groups for pemetrexed singlet versus docetaxel singlet, platinum/pemetrexed, and platinum/docetaxel, respectively. Pemetrexed singlet was associated with significantly less supportive care costs per treatment cycle than the two doublets (platinum/pemetrexed: median difference -RMB 9,877, p = 0.003; platinum/docetaxel: median difference -RMB 8,370, p = 0.009; 1 RMB = 0.16 USD) but not docetaxel singlet in matched patients. Of the four studied chemotherapy regimens, pemetrexed singlet was associated with the lowest log10 scale of supportive care costs per treatment cycle in patients with tumor control (coefficient relative to docetaxel singlet -1.049, p < 0.001) or leukopenia (coefficient relative to docetaxel singlet -0.991, p = 0.034). CONCLUSION: Pemetrexed singlet cost significantly less for supportive care than pemetrexed or docetaxel-based doublets when treating Chinese patients with AdvNS-NSCLC in the second-line setting. Pemetrexed singlet was also associated with significantly less supportive care costs per treatment cycle than docetaxel singlet in patients with tumor control or leukopenia.

Clinical effectiveness and clinical toxicity associated with platinum-based doublets in the first-line setting for advanced non-squamous non-small cell lung cancer in Chinese patients: a retrospective cohort study.

BACKGROUND: Real-world evidence lacks for clinical effectiveness and clinical toxicity associated with platinum-based doublets in the first-line setting for advanced non-squamous non-small cell lung cancer (advNS-NSCLC) in Chinese patients. METHODS: Patients receiving first-line chemotherapy for advNS-NSCLC in four Chinese tertiary care hospitals from 2007 to 2012 were retrospectively identified for chart review. Propensity score methods created best matched pairs for platinum/pemetrexed versus other platinum-based doublets for head-to-head comparisons of early treatment discontinuation (completed treatment cycles <4), treatment failure (progressive disease or early treatment discontinuation), and adverse events (AE). Conventional multiple logistic regression analyses were also performed to confirm the impact of the studied platinum-based doublets on early treatment discontinuation, treatment failure, and hematological AE using vinorelbine/platinum as reference. RESULTS: 1,846 patients were included to create propensity score matched treatment groups for platinum/pemetrexed versus docetaxel (95 pairs), paclitaxel (118 pairs), gemcitabine (199 pairs), and vinorelbine (72 pairs)-contained doublet, respectively. Platinum/pemetrexed was associated with significantly lower risks of early treatment discontinuation (odds ratio (OR) ranged from 0.239, p = 0.001 relative to platinum/docetaxel to 0.389, p = 0.003 relative to platinum/paclitaxel) and treatment failure (OR ranged from 0.257, p < 0.001 relative to platinum/paclitaxel to 0.381, p < 0.001 relative to platinum/gemcitabine) than the other four studied doublets. Platinum/pemetrexed was also associated with several significantly lower hematological AE rates, such as versus platinum/paclitaxel (any hematological AE: OR 0.508, p = 0.032), platinum/gemcitabine (i.e., any hematological AE: OR 0.383, p < 0.001; anemia: OR 0.357, p < 0.001; thrombocytopenia: OR 0.345, p < 0.001) or platinum/vinorelbine (i.e., neutropenia: OR 0.360, p = 0.046; anemia: OR 0.181, p = 0.014) in matched patients. Further conventional logistic regression analyses indicated that pemetrexed/platinum was ranked lowest for the risks of early treatment discontinuation (OR 0.326, p < 0.001), treatment failure (OR 0.460, p < 0.001), and any hematological AE (OR 0.329, p < 0.001). CONCLUSIONS: Pemetrexed plus platinum had significantly superior clinical effectiveness as compared to the other platinum-based doublets with third-generation cytotoxic agents and was also associated with several lower hematological toxicity rates than gemcitabine or vinorelbine-based doublet in the first-line setting for advNS-NSCLC in Chinese patients.

Angiopoietin-like protein 2 negatively regulated by microRNA-25 contributes to the malignant progression of colorectal cancer.

Angiopoietin-like protein 2 (ANGPTL2) is associated with tumor progression while dysregulation of its expression has been observed in various types of cancer. However, the expression and role of ANGPTL2 remain exclusive in colorectal cancer (CRC). In the present study, we determined the expression levels of ANGPTL2 in CRC tissues and cells. The roles of ANGPTL2 and miR-25 in the migration and invasion of CRC SW620 and HCT-116 cells were also investigated using transwell assays or scratch wound assays. The results showed that ANGPTL2 increased with metastatic progression. Increased ANGPTL2 and decreased microRNA-25 (miR-25) expression were found to coexist in CRC. The functional studies revealed that knockdown of ANGPTL2 reduced colony formation, and the invasive and migratory abilities of human CRC SW620 and HCT-116 cells. Similarly, overexpression of miR-25 resulted in reduced colony formation, invasion and migration in both cell lines. The overexpression of miR-25 led to a decreased ANGPTL2 mRNA and protein expression, whereas the downregulation of miR-25 resulted in increased ANGPTL2 mRNA and protein expression, in SW620 and HCT-116 cells. miR-25 directly targeted ANGPTL2 by binding to its 3'­UTR, as determined by the dual luciferase reporter assay. To the best of our know-ledge, the results of this study suggest for the first time that the abnormal upregulation of ANGPTL2 in CRC is associated with miR-25 downregulation. Additionally, miR-25­mediated ANGPTL2 promoted the malignant progression of CRC. The present study provides evidence supporting ANGPTL2 and miR-25 as diagnostic or therapeutic targets for CRC.

Tumor response and clinical toxicity associated with second-line chemotherapy regimens for advanced non-squamous non-small cell lung cancer: A retrospective cohort study.

BACKGROUND: Previously reported superior tumor response of pemetrexed in the second-line setting for advanced non-squamous non-small cell lung cancer (advNS-NSCLC) has never been confirmed in real-world studies. Platinum-based doublet is frequently used in the second-line setting for advanced NSCLC in China. METHODS: A retrospective cohort study was conducted including patients receiving pemetrexed or docetaxel-based chemotherapy in the second-line setting for advNS-NSCLC in four Chinese tertiary care hospitals. Propensity score matched treatment groups were created for head-to-head comparisons on best tumor response and clinical toxicity. Multiple regression analyses were performed to rank the impact of the four regimens on the risks of tumor progression and hematological adverse events. RESULTS: Three hundred and eighty-four patients were included for creating matched treatment groups for pemetrexed versus platinum/pemetrexed (33 pairs), docetaxel (17 pairs), and platinum/docetaxel (29 pairs), respectively. No significant differences were identified for best tumor response between pemetrexed and the other three regimens. However, pemetrexed was associated with significantly fewer patients experiencing anemia (39.4% vs. 69.7%, P = 0.004) and neutropenia (6.1% vs. 30.3%, P = 0.021) than platinum/pemetrexed. Multiple regression analyses indicated that pemetrexed was associated with significantly slower tumor progression (hazard ratio 0.628, P = 0.040) and a significantly lower risk of neutropenia (odds ratio 0.132, P = 0.019) than docetaxel. CONCLUSIONS: Pemetrexed was associated with significantly postponed tumor progression and significantly less hematological toxicity than docetaxel in the real-world second-line setting for advNS-NSCLC in Chinese patients. Pemetrexed monotherapy had comparable tumor response, but significantly less hematological toxicity than pemetrexed-based doublet.

Downregulation of miR-124 promotes the growth and invasiveness of glioblastoma cells involving upregulation of PPP1R13L.

microRNA-124 (miR-124) plays an important role in regulating growth, invasiveness, stem-like traits, differentiation and apoptosis of glioblastoma cells. PPP1R3L, an inhibitory member of the apoptosis-stimulating protein of p53 family (IASPP), is also able to affect growth, cell cycle progression, metastasis and apoptosis of various types of cancer. To investigate the regulation of PPP1R13L expression by miR-124 and their effects on proliferation, cell cycle transition and invasion in glioblastoma cells, U251 and U373 glioblastoma cells were transfected with miR-124 mimics, its negative control (NC) or an inhibitor. We found that miR-124 was downregulated in glioblastoma tissues, and inversely regulated PPP1R13L expression in U251 and U373 glioblastoma cells. PPP1R13L was found to be a direct target of miR-124 in glioblastoma cells. Overexpression of miR-124 inhibited proliferation, G1/S transition and invasiveness in glioblastoma cells. miR-124 downregulation-mediated malignant progression of glioblastoma was partly attributed to increased PPP1R13L expression. Consequently, our findings provide a molecular basis for the role of miR-124/PPP1R13L in the progression of human glioblastoma and suggest a novel target for the treatment of glioblastoma.