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Supplementary Table 1 from Characterization of the Methylation Patterns in Human Papillomavirus Type 16 Viral DNA in Head and Neck Cancers

EGF receptor (EGFR)–targeted monoclonal antibodies (mAb), such as cetuximab, execute their antitumor effect in vivo via blockade of receptor–ligand interactions and engagement of Fcγ receptors on immune effector cells that trigger antibody-dependent cell-mediated cytotoxicity (ADCC). We show that tumors counteract the in vivo antitumor activity of anti-EGFR mAbs by increasing tumor cell-autonomous expression of TGF-β. We show that TGF-β suppresses the expression of key molecular effectors of immune cell–mediated cytotoxicity, including Apo2L/TRAIL, CD95L/FasL, granzyme B, and IFN-γ. In addition to exerting an extrinsic inhibition of the cytotoxic function of immune effectors, TGF-β–mediated activation of AKT provides an intrinsic EGFR-independent survival signal that protects tumor cells from immune cell–mediated apoptosis. Treatment of mice-bearing xenografts of human head and neck squamous cell carcinoma with cetuximab resulted in emergence of resistant tumor cells that expressed relatively higher levels of TGF-β compared with untreated tumor-bearing mice. Although treatment with cetuximab alone forced the natural selection of TGF-β–overexpressing tumor cells in nonregressing tumors, combinatorial treatment with cetuximab and a TGF-β–blocking antibody prevented the emergence of such resistant tumor cells and induced complete tumor regression. Therefore, elevated levels of TGF-β in the tumor microenvironment enable tumor cells to evade ADCC and resist the antitumor activity of cetuximab in vivo. Our results show that TGF-β is a key molecular determinant of the de novo and acquired resistance of cancers to EGFR-targeted mAbs, and provide a rationale for combinatorial targeting of TGF-β to improve anti-EGFR–specific antibody therapy of EGFR-expressing cancers. Mol Cancer Ther; 11(11); 2429–39. ©2012 AACR.

PDF file - 256K, Clinical characteristics of patients with HNSCC

Supplementary Table 3 from Characterization of the Methylation Patterns in Human Papillomavirus Type 16 Viral DNA in Head and Neck Cancers

Supplementary Table 2 from Characterization of the Methylation Patterns in Human Papillomavirus Type 16 Viral DNA in Head and Neck Cancers

PDF file - 70K, A, Serum levels of the indicated cytokines in patients with HNSCC and pleomorphic adenoma (non-cancer control). B, Comparison of serum TGF-beta1 levels in non-cancer controls and patients with HNSCC at the time of new diagnosis and at the time of recurrence. C, Comparison of serum levels of TGF-beta1 in patients with HPV-negative HNSCC at the time of diagnosis, and at two time points after the completion of treatment

Supplementary Figure 2 from Characterization of the Methylation Patterns in Human Papillomavirus Type 16 Viral DNA in Head and Neck Cancers

Supplementary Figure 1 from Characterization of the Methylation Patterns in Human Papillomavirus Type 16 Viral DNA in Head and Neck Cancers

Supplementary Figures S1-S2 from A Promoter Methylation Pattern in the N-Methyl-d-Aspartate Receptor 2B Gene Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma

Purpose: To investigate whether the promoter methylation pattern in N-methyl-d-aspartate receptor 2B (NMDAR2B) is correlated with clinical features of human esophageal squamous cell carcinoma (ESCC), the methylation status of the gene was examined at three different sites (P1, P2, and P3) where two CpG islands reside within 1 kb upstream of the transcription start site.Experimental Design: Three independent modalities for methylation analysis (bisulfite sequencing, combined bisulfite restriction analysis, and TaqMan methylation-specific PCR) were done to analyze total 67 ESCC tissues that included 43 primary tumors with well-characterized clinicopathologic variables including patient outcome.Results: Using an optimized cutoff value based on quantitative methylation-specific PCR, we found that patients with higher NMDAR2B methylation ratio in the proximal region (P1) showed a worse 5-year disease-specific survival rate than those without NMDAR2B methylation (P < 0.006). A significant correlation was also seen between NMDAR2B promoter methylation and the presence of vascular permeation (P = 0.03).Conclusion: NMDAR2B promoter methylation could be a clinically applicable marker in ESCC.

Supplementary Data 1-9 from Overexpression of Glycosylphosphatidylinositol (GPI) Transamidase Subunits Phosphatidylinositol Glycan Class T and/or GPI Anchor Attachment 1 Induces Tumorigenesis and Contributes to Invasion in Human Breast Cancer

PDF file - 2120KB, FAK activity is significantly higher in erlotinib-resistant cells from lung and H and N origin. Total cell lysates were extracted from two pairs of lung (H358/H1703 and Calu3/Calu6) and two pairs of H and N (SCC-S/SCC-R and JHU011/JHU028) cancer cell lines and were subjected to immunoblot analysis with antibodies specific for phosphorylated and total FAK. Beta-actin was used a loading control.

Supplementary Data 1 from LOXL1 and LOXL4 Are Epigenetically Silenced and Can Inhibit Ras/Extracellular Signal-Regulated Kinase Signaling Pathway in Human Bladder Cancer

PDF file - 197KB

Promoter hypermethylation is one of the common mechanisms leading to gene silencing in various human cancers. Using a combination of pharmacologic unmasking and microarray techniques, we identified 59 candidate hypermethylated genes, including LOXL1, a lysyl oxidase-like gene, in human bladder cancer cells. We further showed that LOXL1 and LOXL4 are commonly silenced genes in human bladder cancer cells, and this silence is predominantly related to promoter methylation. We also found LOXL1 and LOXL4 gene methylation and loss of expression in primary bladder tumors. In addition, somatic mutations were identified in LOXL4, but not in LOXL1 in bladder cancer. Moreover, reintroduction of LOXL1 and LOXL4 genes into human bladder cancer cells leads to a decrease of colony formation ability. Further studies indicated that the overexpression of LOXL1 and LOXL4 could antagonize Ras in activating the extracellular signal-regulated kinase (ERK) signaling pathway. Thus, our current study suggests for the first time that lysyl oxidase-like genes can act as tumor suppressor genes and exert their functions through the inhibition of the Ras/ERK signaling pathway in human bladder cancer. [Cancer Res 2007;67(9):4123–9]

Supplementary Figure and Table Legends from Identification of Hypermethylated Genes Associated with Cisplatin Resistance in Human Cancers

PDF file - 127KB, Levels of Mig6 protein in the panel of 25 human cancer cell lines with known erlotinib resistance was identified by immunoblot analysis followed by densitometric quantification. The expression level of Mig6 was plotted against IC50 of corresponding cell line.

PDF file - 108KB, TGFbeta induces EMT-associated kinase switch promotes erlotinib-resistance of tumor cells. A. Erlotinib sensitive cell lines H292 and SCC-S were treated with TGFβ1 (4 ng/ml) for 21 days and immunoblot analysis was performed with indicated antibodies. B. Parental and TGFbeta-induced H358 and SCC-S cells were treated with erlotinib for 72 hours and cell viability was assayed. Values were set at 100% for untreated controls. C. Protein lysates were extracted from H358 and SCC-S cells treated or untreated with TGFbeta for 21 days and immunoblot analysis was performed with antibodies against indicated phospho RTKs. Beta-actin was used as a loading control.

PDF file - 2202KB, Summary of EGFR, KRAS, NRAS and P53 mutation status in 18 human NSCLCs and 27 pancreatic directly xenografted low passage tumors.

Based on the oncogenic role of phosphatidylinositol glycan (PIG) class U in human tumors, we explored the role of two additional subunits of the glycosylphosphatidylinositol (GPI) transamidase complex in human breast cancer. We found that PIG class T (PIG-T) and GPI anchor attachment 1 (GPAA1) were overexpressed in breast cancer cell lines and primary tumors. Forced expression of PIG-T and GPAA1 transformed NIH3T3 cells in vitro and increased tumorigenicity and invasion of these cells in vivo. Suppression of PIG-T expression in breast cancer cell lines led to inhibition of anchorage-independent growth. Moreover, we found that PIG-T and GPAA1 expression levels positively correlated with paxillin phosphorylation in invasive breast cancer cell lines. Furthermore, suppression of PIG-T and GPAA1 expression led to a decrease in paxillin phosphorylation with a concomitant decrease in invasion ability. These results suggest that the GPI transamidase complex is composed of a group of proto-oncogenes that individually or as a group contribute to breast cancer growth. This aberrant growth is mediated, at least partially, by phosphorylation of paxillin, contributing to invasion and progression of breast cancer. (Cancer Res 2006; 66(22): 9829-36) (Cancer Res 2006; 66(20): 9829-36)

Supplementary Table 1 from Identification of Hypermethylated Genes Associated with Cisplatin Resistance in Human Cancers

Supplementary Figures 1-3, Table 1 from Identification of Hypermethylated Genes Associated with Cisplatin Resistance in Human Cancers

PDF file - 199KB, RNA was extracted from 18 human NSCLCs and 27 pancreatic directly xenografted low passage tumors. Levels of miR200c were measured by quantitative RT-PCR and mRNA levels of Mig6 and EGFR were determined by Affymetrix expression array. Expression levels of A. miR200c, B. Mig6 mRNA or C. EGFR mRNA transcripts were plotted against erlotinib responsiveness.

Supplementary Table 1, Figures 1-10, Methods from An EGFR-ERK-SOX9 Signaling Cascade Links Urothelial Development and Regeneration to Cancer

Purpose: To study the radio-sanitization effect of paclitaxel liposomes on breast cancer cells, SK-BR-3.Methods: Breast cancer cell line SK-BR-3 was cultured and made into a cell suspension. Four groups of cells were used: control and radiotherapy groups, paclitaxel group, and paclitaxel liposome + radiotherapy group (combination group). The growth inhibitory effects of the different treatments on SKBR-3 cells were determined with CCK-8 method. Apoptosis in each group was evaluated with flow cytometry, while Western blotting was employed to assay Bcl-2, Caspase-3 and Bax protein levels.Results: There were marked inhibitory effect on growth of SK-BR-3 cells in drug, radiotherapy and combination groups, relative to control, while apoptosis was greater in combination group than in drug and radiotherapy groups (p < 0.05). The Bcl-2 protein level was higher in radiotherapy, drug and combination groups than in control group, while Caspase-3 and Bax proteins were markedly higher thancontrol values (p < 0.05).Conclusion: Paclitaxel liposomes exert radio-sensitization effect on SK-BR-3 by regulating the levels of apoptotic proteins. This provides a basis for research and development of new drugs. Keywords: Paclitaxel liposomes, Apoptotic proteins, Breast cancer, SK-BR-3, Radiotherapy, Sensitization, Bcl-2, Caspase-3, Bax

With the rapid development of industrial applications based on modular multilevel converter(MMC), the operation reliability is receiving more and more attention. This paper concentrates on open-circuit fault detection and location(FDL) of sub-modules(SMs), and proposes a new strategy based on machine learning(ML) classifier. According to the analyzation the open-circuit fault characteristics, the proposed strategy selects the voltages of SMs as original features for FDL. In order to construct the dataset as well as reduce the amount of calculation, 9 time-domain features are extracted as the new inputs. A ML model based on random forest is then trained and tested with the dataset, considering FDL as classification. To prove the effectiveness of the proposed strategy, the MMC models are built both in the simulations and experiments.

The unknown disturbances and the changing uncertainties bring difficulties for designing a stable attitude controller for UAV. In this paper, a novel adaptive fault-tolerant attitude control approach is designed based on the long short-term memory (LSTM) network for the fixed-wing UAV subject to the high dynamic disturbances and actuator faults. Firstly, the high dynamic disturbances can be compensated by the adaptive laws. Meanwhile, the actuator faults can be handled by the proposed adaptive fault-tolerant control (AFTC) scheme. Moreover, the LSTM network is introduced to approximate the unknown and time-accumulating nonlinearities. With the introduction of the one-to-one nonlinear mapping (NM), the output constraints in the control system can be guaranteed. Additionally, it can be demonstrated that the boundness of all the signals can be assured. At last, numerical simulation results are provided to illustrate the effectiveness of the proposed method.

Nowadays, the practical tasks of UAVs are becoming more and more complicated and diversified. In the practical flight process, the large-scale changes of the flight environment, the modeling errors, and the external disturbances may induce the instability of the UAV flight system. Meanwhile, the constraints of the UAV attitudes also have to be guaranteed during the flight process. However, most existing control methods still have limitations in handling the constraints and the multisource disturbances simultaneously. To address this problem, in this paper, we focus on the actual output tracking control for the UAV systems with full-state constraints and multisource disturbances. Firstly, a high-order tan-type barrier Lyapunov function (HOBLF) has been constructed for the UAV to maintain the full-state constraints. Secondly, by combining the adaptive backstepping technique and the fuzzy logic systems, the modeling errors and the unknown nonlinearities of the UAV attitude control system can be handled. Moreover, by properly constructing several adaptive laws, the time-varying disturbances existing in the UAV attitude control system can be suppressed. Finally, the full-state-constrained antidisturbance controller is formed, ensuring that the tracking error approaches arbitrarily to small neighborhood and does not violate the given constraints. The simulation results illustrate the feasibility and the advantages of the proposed method.