bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of TGF‐β1 on OPG/RANKL Expression of Cementoblasts and Osteoblasts Are Similar without Stress but Different with Mechanical Compressive Stress
Authors: Yang Xianrui , Wang Yanmin , Han Xianglong , Shu Rui , Chen Tian , Zeng Huan , Xu Xin , Huang Lan , Ren Aishu , Song Jinlin , Cao Li , Bai Ding
Published: January 2015

Introduction. This study aimed to explore the effects of TGF‐β1 on regulating activities of cementoblasts and osteoblasts with or without stress. Material and Methods. Human recombinant TGF‐β1 was added with different doses. Immunohistochemical test of osteoprotegerin (OPG)/receptor activator of nuclear factor‐kappaB ligand (RANKL) and Alizarin Red‐S staining were conducted. Mechanical compressive stress was obtained by increasing the pressure of gaseous phase. OPG/RANKL expression was detected in both cells through quantitative real‐time PCR. Results. Similar significant differences (P < 0.05) existed in OPG/RANKL change with increasing concentration of TGF‐β1 without mechanical stress for cementoblasts and osteoblasts. However, under 3 h stress, OPG increased and RANKL decreased significantly (P < 0.01) but with similar OPG/RANKL change. Moreover, under 24 h stress, OPG change exhibited no difference (P > 0.05), but RANKL decreased significantly (P < 0.01) at 10 and 100 ng/mL TGF‐β1 in cementoblasts. In osteoblasts, OPG increased significantly (P < 0.01) at 10 and 100 ng/mL, whereas RANKL decreased with statistical difference (P < 0.05) at 1 and 10 ng/mL. Conclusions. The effects of TGF‐β1 on OPG/RANKL expression of cementoblasts and osteoblasts are similar even without mechanical stress. However, these effects are different under mechanical compressive stress.
A Novel Cost Based Model for Energy Consumption in Cloud Computing
Authors: Horri A. , Dastghaibyfard Gh.
Published: January 2015

Cloud data centers consume enormous amounts of electrical energy. To support green cloud computing, providers also need to minimize cloud infrastructure energy consumption while conducting the QoS. In this study, for cloud environments an energy consumption model is proposed for time‐shared policy in virtualization layer. The cost and energy usage of time‐shared policy were modeled in the CloudSim simulator based upon the results obtained from the real system and then proposed model was evaluated by different scenarios. In the proposed model, the cache interference costs were considered. These costs were based upon the size of data. The proposed model was implemented in the CloudSim simulator and the related simulation results indicate that the energy consumption may be considerable and that it can vary with different parameters such as the quantum parameter, data size, and the number of VMs on a host. Measured results validate the model and demonstrate that there is a tradeoff between energy consumption and QoS in the cloud environment. Also, measured results validate the model and demonstrate that there is a tradeoff between energy consumption and QoS in the cloud environment.
Circulating miR-765 and miR-149: Potential Noninvasive Diagnostic Biomarkers for Geriatric Coronary Artery Disease Patients
Authors: Ali Sheikh Md Sayed , Xia Ke , Li Fei , Deng Xu , Salma Umme , Deng Hai , Wei Wei Liu , Yang Tian-Lun , Peng Jun
Published: January 2015

The purpose of this study was to evaluate the diagnostic value of circulating miR-765 and miR-149 as noninvasive early biomarkers for geriatric coronary artery disease (CAD) patients. A total of 69 angiographically documented CAD patients including 37 stable CAD (72.9 ± 4.2 years) and 32 unstable CAD (72.03 ± 4.3 years) and 20 healthy subjects (71.7 ± 5.2 years), matched for age, sex, smoking habit, hypertension, and diabetes, were enrolled in this study. Compared with healthy subjects, circulating miR-765 levels were increased by 2.9-fold in stable CAD and 5.8-fold in unstable CAD patients, respectively, while circulating miR-149 levels were downregulated by 3.5-fold in stable CAD and 4.2-fold in unstable CAD patients, respectively. Furthermore, plasma levels of miR-765 were found to be positively correlated with ages within control, stable, and unstable groups. The ROC curves of miR-765 and miR-149 represented significant diagnostic values with an area under curve (AUC) of 0.959, 0.972 and 0.938, 0.977 in stable CAD patients and unstable CAD patients as compared with healthy subjects, respectively. Plasma levels of miR-765 and miR-149 might be used as noninvasive biomarkers for the diagnosis of CAD in geriatric people.
Nontrivial Solutions for Periodic Schrödinger Equations with Sign-Changing Nonlinearities
Authors: Chen Shaowei , Lin Lishan , Xiao Liqin
Published: January 2015

We prove a new infinite-dimensional linking theorem. Using this theorem, we obtain nontrivial solutions for strongly indefinite periodic Schrödinger equations with sign-changing nonlinearities.
Joint Multichannel Motion Compensation Method for MIMO SAR 3D Imaging
Authors: Yang Ze-min , Xing Meng-dao , Sun Guang-cai , Bao Zheng
Published: January 2015

The multiple-input-multiple-output (MIMO) synthetic aperture radar (SAR) system with a linear antenna array can obtain 3D resolution. In practice, it suffers from both the translational motion errors and the rotational motion errors. Conventional single-channel motion compensation methods could be used to compensate the motion errors channel by channel. However, this method might not be accurate enough for all the channels. What is more, the single-channel compensation may break the coherence among channels, which would cause defocusing and false targets. In this paper, both the translational motion errors and the rotational motion errors are discussed, and a joint multichannel motion compensation method is proposed for MIMO SAR 3D imaging. It is demonstrated through simulations that the proposed method exceeds the conventional methods in accuracy. And the final MIMO SAR 3D imaging simulation confirms the validity of the proposed algorithm.
Study on the Usefulness of APR Scores from the Viewpoint of Proinflammatory Cytokines
Authors: Nakamura T. , Hatanaka D. , Yoshioka T. , Yamada S. , Goto H.
Published: January 2015

Background. Delayed diagnosis and treatment of newborn infection adversely impact outcomes. Clinical laboratory parameters have aimed to obtain the most correct and prompt diagnosis and treatment of this disease. This study simultaneously observed changes over time in APR as well as proinflammatory cytokines and anti-proinflammatory cytokines and aims to clarify usefulness of APR scores.Methods. We evaluated the usefulness of acute phase reactants (APR) in 46 newborns whose serum up to age 7 days had been stored, with comparison of three types (Group I: infection 15, Group F: fetal inflammatory response syndrome 17, and Group C: control 14) of APR-based scores, those of C-reactive protein (CRP), alpha1-acid glycoprotein (AGP), and haptoglobin (Hp), with proinflammatory cytokine levels. APR scores for CRP, AGP, and Hp and the levels of the proinflammatory cytokines IL-1β, IL-6, IL-8, IL-10, and TNFαwere determined.Results. The cytokine levels started to increase from age 0 days and then decreased rapidly. The three APR scores, CRP, AG, and Hp, were elevated at age 0 days and then gradually decreased in infection (Group I) and fetal inflammatory response syndrome (Group F). The duration of antibiotic administration according to APR scores was significantly shorter in Group F than in Group I.Conclusion. This study demonstrated APR scores to be more useful for deciding whether antibiotics should be discontinued than proinflammatory cytokine levels.
Translationally Controlled Tumor Protein in Prostatic Adenocarcinoma: Correlation with Tumor Grading and Treatment-Related Changes
Authors: Rocca Bruno Jim , Ginori Alessandro , Barone Aurora , Calandra Calogera , Crivelli Filippo , De Falco Giulia , Gazaneo Sara , Tripodi Sergio , Cevenini Gabriele , del Vecchio Maria Teresa , Ambrosio Maria Raffaella , Tosi Piero
Published: January 2015

Prostate cancer is the second leading cause of cancer-related death. The androgen deprivation therapy is the standard treatment for advanced stages. Unfortunately, virtually all tumors become resistant to androgen withdrawal. The progression to castration-resistance is not fully understood, although a recent paper has suggested translationally controlled tumor protein to be implicated in the process. The present study was designed to investigate the role of this protein in prostate cancer, focusing on the correlation between its expression level with tumor differentiation and response to treatment. We retrieved 292 prostatic cancer specimens; of these 153 had been treated only by radical prostatectomy and 139 had undergone radical prostatectomy after neoadjuvant treatment with combined androgen blockade therapy. Non-neoplastic controls were represented by 102 prostatic peripheral zone specimens. In untreated patients, the expression of the protein, evaluated by RT-qPCR and immunohistochemistry, was significantly higher in tumor specimens than in non-neoplastic control, increasing as Gleason pattern and score progressed. In treated prostates, the staining was correlated with the response to treatment. An association between protein expression and the main clinicopathological factors involved in prostate cancer aggressiveness was identified. These findings suggest that the protein may be a promising prognostic factor and a target for therapy.
CTLA4Polymorphisms and De Novo Malignancy Risk after Renal Transplantation in Chinese Recipients
Authors: Guo Yi-feng , Qiu Jian-xin , Guo Fang , Liu Yong , Shang Ming-hua
Published: January 2015

Genetic polymorphisms in cytotoxic T lymphocyte-associated antigen 4 (CTLA4) play an influential role in graft rejection and the long-term clinical outcome of organ transplantation. We investigated the association of fiveCTLA4single-nucleotide polymorphisms (SNPs) (rs733618 C/T, rs4553808 A/G, rs5742909 C/T, rs231775 A/G, and rs3087243 G/A) with de novo malignancy in 1463 Chinese renal transplantation (RT) recipients who underwent a 192-month follow-up. Multivariate analyses revealed that recipient rs231775 genotype is significantly associated with tumorigenesis (P=0.012). Multiplicative interaction between rs231775 AA and possible risk factors of malignancy revealed two significant results: rs231775 AA × primary diseases and rs231775 AA × number of HLA-mismatch. The frequency of haplotype TACAG was significantly higher in the tumor group (17.07%) than that in the nontumor group (1.53%). In addition, aristolochic acid nephropathy (P=0.003) and the time of discovery of tumor (P=0.000) also were independently associated with tumorigenesis. Our data show that theCTLA4genotype rs231775 AA may be one of risk factors for the development of malignancy and haplotype TACAG was susceptible haplotype in Chinese kidney transplant recipients.
Breast Cancer Risk in Metabolically Healthy but Overweight Postmenopausal Women
Authors: Gunter Marc J. , Xie Xianhong , Xue Xiaonan , Kabat Geoffrey C. , Rohan Thomas E. , Wassertheil-Smoller Sylvia , Ho Gloria Y.F. , Wylie-Rosett Judith , Greco Theresa , Yu Herbert , Beasley Jeannette , Strickler Howard D.
Published: January 2015

Adiposity is an established risk factor for postmenopausal breast cancer. Recent data suggest that high insulin levels in overweight women may play a major role in this relationship, due to insulin's mitogenic/antiapoptotic activity. However, whether overweight women who are metabolically healthy (i.e., normal insulin sensitivity) have elevated risk of breast cancer is unknown. We investigated whether overweight women with normal insulin sensitivity [i.e., homeostasis model assessment of insulin resistance (HOMA-IR) index, or fasting insulin level, within the lowest quartile (q1)] have increased breast cancer risk. Subjects were incident breast cancer cases (N = 497) and a subcohort (N = 2,830) of Women's Health Initiative (WHI) participants with available fasting insulin and glucose levels. In multivariate Cox models, metabolically healthy overweight women, defined using HOMA-IR, were not at elevated risk of breast cancer compared with metabolically healthy normal weight women [HRHOMA-IR, 0.96; 95% confidence interval (CI), 0.64–1.42]. In contrast, the risk among women with high (q3-4) HOMA-IRs was elevated whether they were overweight (HRHOMA-IR, 1.76; 95% CI, 1.19-2.60) or normal weight (HRHOMA-IR, 1.80; 95% CI, 0.88–3.70). Similarly, using fasting insulin to define metabolic health, metabolically unhealthy women (insulin q3-4) were at higher risk of breast cancer regardless of whether they were normal weight (HRinsulin, 2.06; 95% CI, 1.01–4.22) or overweight (HRinsulin, 2.01; 95% CI, 1.35–2.99), whereas metabolically healthy overweight women did not have significantly increased risk of breast cancer (HRinsulin, 0.96; 95% CI, 0.64–1.42) relative to metabolically healthy normal weight women. Metabolic health (e.g., HOMA-IR or fasting insulin) may be more biologically relevant and more useful for breast cancer risk stratification than adiposity per se. Cancer Res; 75(2); 270–4. ©2014 AACR.
Th9 Cells: A Novel CD4 T-cell Subset in the Immune War against Cancer
Authors: Végran Frédérique , Apetoh Lionel , Ghiringhelli François
Published: January 2015

CD4 T cells are key components of the immune system that shape the anticancer immune response in animal models and in humans. The biology of CD4 T cells is complex because naïve T cells can differentiate into various subpopulations with various functions. Recently, a new population called Th9 cells was described. These cells are characterized by their ability to produce IL9 and IL21. They were first described in the context of parasite infections and allergic processes. However, some reports described their presence in the tumor bed in mice and humans. Their high secretion of IL9 and IL21 in the tumor bed contributes to their anticancer functions. Indeed, these cytokines trigger the activation of dendritic cells, mast cells, natural killer cells, and CD8 T cells to mount an antitumor immune response, thus explaining the remarkable ability of Th9 cells to control tumor growth. This review summarizes the latest advances in the Th9 field in cancer and focuses on their potential role as new tool for cell therapy. Cancer Res; 75(3); 475–9. ©2014 AACR.
Targeting the eIF4F Translation Initiation Complex: A Critical Nexus for Cancer Development
Authors: Pelletier Jerry , Graff Jeremy , Ruggero Davide , Sonenberg Nahum
Published: January 2015

Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic initiation factor 4F (eIF4F), the key regulator of the mRNA–ribosome recruitment phase of translation initiation. In many cellular and preclinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes, such as cell growth and proliferation, enhanced cell survival and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion, and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g., Ras, PI3K/AKT/TOR, and MYC), eIF4F serves as a direct link between important steps in cancer development and translation initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation initiation as antineoplastic agents. Cancer Res; 75(2); 250–63. ©2014 AACR.
Cross-Species Antibody Microarray Interrogation Identifies a 3-Protein Panel of Plasma Biomarkers for Early Diagnosis of Pancreas Cancer
Authors: Mirus Justin E. , Zhang Yuzheng , Li Christopher I. , Lokshin Anna E. , Prentice Ross L. , Hingorani Sunil R. , Lampe Paul D.
Published: January 2015

Purpose: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States, and its incidence is on the rise. Advanced disease is nearly uniformly lethal, emphasizing the need to identify PDA at its earliest stages. To discover early biomarkers of PDA, we evaluated the circulating proteome in murine preinvasive and invasive plasma samples and human prediagnostic and diagnostic samples.

Experimental Design: Using a customized antibody microarray platform containing >4,000 features, we interrogated plasma samples spanning preinvasive and invasive disease from a highly faithful mouse model of PDA. In parallel, we mined prediagnostic plasma from women in the Women's Health Initiative (WHI) who would later succumb to PDA together with matched, cancer-free control samples. Samples collected after an establishing diagnosis of PDA were also interrogated to further validate markers.

Results: We identified ERBB2 and TNC in our cross-species analyses, and multiple antibodies identified ESR1 in prediagnostic plasma from people that succumb to PDA. This 3-marker panel had an AUC of 0.86 (95% confidence interval [CI], 0.76–0.96) for the diagnostic cohort that increased to 0.97 (95% CI, 0.92–1.0) with CA19-9 included. The 3-marker panel also had an AUC of 0.68 (95% CI, 0.58–0.77) for the prediagnostic cohort.

Conclusions: We identified potential disease detection markers in plasma up to 4 years before death from PDA with superior performance to CA19-9. These markers might be especially useful in high-risk cohorts to diagnose early, resectable disease, particularly in patients that do not produce CA19-9. Clin Cancer Res; 21(7); 1764–71. ©2015 AACR.
Genomic Analysis of Metastatic Cutaneous Squamous Cell Carcinoma
Authors: Li Yvonne Y. , Hanna Glenn J. , Laga Alvaro C. , Haddad Robert I. , Lorch Jochen H. , Hammerman Peter S.
Published: January 2015

Purpose: A rare 5% of cutaneous squamous cell carcinomas (cSCC) metastasize, lack FDA-approved therapies, and carry a poor prognosis. Our aim was to identify recurrent genomic alterations in this little-studied population of metastatic cSCCs.

Experimental Design: We performed targeted sequencing of 504 cancer-associated genes on lymph node metastases in 29 patients with cSCC and identified mutations and somatic copy-number alterations associated with metastatic cSCC. We determined significantly mutated, deleted, and amplified genes and associated genomic alterations with clinical variables.

Results: The cSCC genome is heterogeneous with widely varying numbers of genomic alterations and does not appear to be associated with human papillomavirus. We found previously identified recurrently altered genes (TP53, CDKN2A, NOTCH1/2) but also a wide spectrum of oncogenic mutations affecting RAS/RTK/PI3K, squamous differentiation, cell cycle, and chromatin remodeling pathway genes. Specific mutations in known oncogenic drivers and pathways were correlated with inferior patient outcomes. Our results suggest potential therapeutic targets in metastatic cSCC, including PIK3CA, FGFR3, BRAF, and EGFR, similar to those reported in SCCs of the lung and head and neck, suggesting that clinical trials could be developed to accrue patients with SCCs from multiple sites of origin.

Conclusions: We have genomically characterized a rare cohort of 29 metastatic cSCCs and identified a diverse array of oncogenic alterations that can guide future studies of this disease. Clin Cancer Res; 21(6); 1447–56. ©2015 AACR.
Gain of HIF-1α under Normoxia in Cancer Mediates Immune Adaptation through the AKT/ERK and VEGFA Axes
Authors: Lee Young-Ho , Bae Hyun Cheol , Noh Kyung Hee , Song Kwon-Ho , Ye Sang-kyu , Mao Chih-Ping , Lee Kyung-Mi , Wu T.-C. , Kim Tae Woo
Published: January 2015

Purpose: Adaptation to host immune surveillance is now recognized as a hallmark of cancer onset and progression, and represents an early, indispensable event in cancer evolution. This process of evolution is first instigated by an immune selection pressure imposed by natural host surveillance mechanisms and may then be propagated by vaccination or other types of immunotherapy.

Experimental Design: We developed a system to simulate cancer evolution in a live host and to dissect the mechanisms responsible for adaptation to immune selection. Here, we show that the oxygen-sensitive α subunit of hypoxia-inducible factor 1 (HIF-1α) plays a central role in cancer immune adaptation under conditions of normal oxygen tension.

Results: We found that tumor cells gain HIF-1α in the course of immune selection under normoxia and that HIF-1α renders tumor cells resistant to lysis by tumor-specific cytotoxic T lymphocytes (CTL) in culture and in mice. The effects of HIF-1α on immune adaptation were mediated through VEGFA-dependent activation of the AKT and ERK signaling pathways, which induced an antiapoptotic gene expression network in tumor cells.

Conclusions: Our study therefore establishes a link between immune selection, overexpression of HIF-1α, and cancer immune adaptation under normoxia, providing new opportunities for molecular intervention in patients with cancer. Clin Cancer Res; 21(6); 1438–46. ©2015 AACR.
Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer
Authors: Zhang Liang , Wang Xiaoen , Bullock Andrea J. , Callea Marcella , Shah Harleen , Song Jiaxi , Moreno Kelli , Visentin Barbara , Deutschman Douglas , Alsop David C. , Atkins Michael B. , Mier James W. , Signoretti Sabina , Bhasin Manoj , Sabbadini Roger A. , Bhatt Rupal S.
Published: January 2015

Purpose: VEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic renal cell carcinoma (RCC). However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for patients with TKI-naïve or -resistant RCC.

Experimental Design: In this study, we performed transcriptome analysis of VEGFR TKI-resistant tumors in a murine model and discovered that the SPHK–S1P pathway is upregulated at the time of resistance. We tested sphingosine-1-phosphate (S1P) pathway inhibition using an anti-S1P mAb (sphingomab), in two mouse xenograft models of RCC, and assessed tumor SPHK expression and S1P plasma levels in patients with metastatic RCC.

Results: Resistant tumors expressed several hypoxia-regulated genes. The SPHK1 pathway was among the most highly upregulated pathways that accompanied resistance to VEGFR TKI therapy. SPHK1 was expressed in human RCC, and the product of SPHK1 activity, S1P, was elevated in patients with metastatic RCC, suggesting that human RCC behavior could, in part, be due to overproduction of S1P. Sphingomab neutralization of extracellular S1P slowed tumor growth in both mouse models. Mice bearing tumors that had developed resistance to sunitinib treatment also exhibited tumor growth suppression with sphingomab. Sphingomab treatment led to a reduction in tumor blood flow as measured by MRI.

Conclusions: Our findings suggest that S1P inhibition may be a novel therapeutic strategy in patients with treatment-naïve RCC and also in the setting of resistance to VEGFR TKI therapy. Clin Cancer Res; 21(8); 1925–34. ©2015 AACR.
Identification of Biological Relevant Minor Histocompatibility Antigens within the B-lymphocyte–Derived HLA-Ligandome Using a Reverse Immunology Approach
Authors: Hombrink Pleun , Hassan Chopie , Kester Michel G.D. , Jahn Lorenz , Pont Margot J. , de Ru Arnoud H. , van Bergen Cornelis A.M. , Griffioen Marieke , Falkenburg J.H. Frederik , van Veelen Peter A. , Heemskerk Mirjam H.M.
Published: January 2015

Purpose: T-cell recognition of minor histocompatibility antigens (MiHA) not only plays an important role in the beneficial graft-versus-leukemia (GVL) effect of allogeneic stem cell transplantation (allo-SCT) but also mediates serious GVH complications associated with allo-SCT. Using a reverse immunology approach, we aim to develop a method enabling the identification of T-cell responses directed against predefined antigens, with the goal to select those MiHAs that can be used clinically in combination with allo-SCT.

Experimental Design: In this study, we used a recently developed MiHA selection algorithm to select candidate MiHAs within the HLA-presented ligandome of transformed B cells. From the HLA-presented ligandome that predominantly consisted of monomorphic peptides, 25 polymorphic peptides with a clinically relevant allele frequency were selected. By high-throughput screening, the availability of high-avidity T cells specific for these MiHA candidates in different healthy donors was analyzed.

Results: With the use of MHC multimer enrichment, analyses of expanded T cells by combinatorial coding MHC multimer flow cytometry, and subsequent single-cell cloning, positive T-cell clones directed to two new MiHA: LB-CLYBL-1Y and LB-TEP1-1S could be demonstrated, indicating the immunogenicity of these two MiHAs.

Conclusions: The biologic relevance of MiHA LB-CLYBL-1Y was demonstrated by the detection of LB-CLYBL-1Y–specific T cells in a patient suffering from acute myeloid leukemia (AML) that experienced an anti-leukemic response after treatment with allo-SCT. Clin Cancer Res; 21(9); 2177–86. ©2015 AACR.
The BRAF and MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and CTLA-4
Authors: Liu Li , Mayes Patrick A. , Eastman Stephen , Shi Hong , Yadavilli Sapna , Zhang Tianqian , Yang Jingsong , Seestaller-Wehr Laura , Zhang Shu-Yun , Hopson Chris , Tsvetkov Lyuben , Jing Junping , Zhang Shu , Smothers James , Hoos Axel
Published: January 2015

Purpose: To assess the immunologic effects of dabrafenib and trametinib in vitro and to test whether trametinib potentiates or antagonizes the activity of immunomodulatory antibodies in vivo.

Experimental Design: Immune effects of dabrafenib and trametinib were evaluated in human CD4+ and CD8+ T cells from healthy volunteers, a panel of human tumor cell lines, and in vivo using a CT26 mouse model.

Results: Dabrafenib enhanced pERK expression levels and did not suppress human CD4+ or CD8+ T-cell function. Trametinib reduced pERK levels, and resulted in partial/transient inhibition of T-cell proliferation/expression of a cytokine and immunomodulatory gene subset, which is context dependent. Trametinib effects were partially offset by adding dabrafenib. Dabrafenib and trametinib in BRAF V600E/K, and trametinib in BRAF wild-type tumor cells induced apoptosis markers, upregulated HLA molecule expression, and downregulated certain immunosuppressive factors such as PD-L1, IL1, IL8, NT5E, and VEGFA. PD-L1 expression in tumor cells was upregulated after acquiring resistance to BRAF inhibition in vitro. Combinations of trametinib with immunomodulators targeting PD-1, PD-L1, or CTLA-4 in a CT26 model were more efficacious than any single agent. The combination of trametinib with anti–PD-1 increased tumor-infiltrating CD8+ T cells in CT26 tumors. Concurrent or phased sequential treatment, defined as trametinib lead-in followed by trametinib plus anti–PD-1 antibody, demonstrated superior efficacy compared with anti–PD-1 antibody followed by anti–PD-1 plus trametinib.

Conclusion: These findings support the potential for synergy between targeted therapies dabrafenib and trametinib and immunomodulatory antibodies. Clinical exploration of such combination regimens is under way. Clin Cancer Res; 21(7); 1639–51. ©2015 AACR.
CCR 20th Anniversary Commentary: A Chimeric Antibody, C225, Inhibits EGFR Activation and Tumor Growth
Authors: Mendelsohn John , Prewett Marie , Rockwell Patricia , Goldstein Neil I.
Published: January 2015

Murine mAb 225 was effective against the EGFR tyrosine kinase and inhibited tumor growth in preclinical studies. A phase I trial showed safety, tumor localization, and satisfactory pharmacokinetics. Human:murine chimeric C225 retained biologic activity, which was essential for the conduct of subsequent combination therapy trials and eventual regulatory approval. Clin Cancer Res; 21(2); 227–9. ©2015 AACR.

See related article by Goldstein et al., Clin Cancer Res 1995;1(11) November 1995;1311–8
Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer
Authors: Kummar Shivaani , Oza Amit M. , Fleming Gini F. , Sullivan Daniel M. , Gandara David R. , Naughton Michael J. , Villalona-Calero Miguel A. , Morgan Robert J. , Szabo Peter M. , Youn Ahrim , Chen Alice P. , Ji Jiuping , Allen Deborah E. , Lih Chih-Jian , Mehaffey Michele G. , Walsh William D. , McGregor Paul M. , Steinberg Seth M. , Williams P. Mickey , Kinders Robert J. , Conley Barbara A. , Simon Richard M. , Doroshow James H.
Published: January 2015

Purpose: Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC).

Experimental Design: Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression.

Results: Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit.

Conclusion: This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival. Clin Cancer Res; 21(7); 1574–82. ©2015 AACR.
Pilot Trial of Combined BRAF and EGFR Inhibition in BRAF-Mutant Metastatic Colorectal Cancer Patients
Authors: Yaeger Rona , Cercek Andrea , O'Reilly Eileen M. , Reidy Diane L. , Kemeny Nancy , Wolinsky Tamar , Capanu Marinela , Gollub Marc J. , Rosen Neal , Berger Michael F. , Lacouture Mario E. , Vakiani Efsevia , Saltz Leonard B.
Published: January 2015

Purpose: BRAF-mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of EGFR signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC.

Experimental Design: We undertook a pilot trial to assess the response rate and safety of the BRAF inhibitor vemurafenib combined with anti-EGFR antibody panitumumab in patients with BRAF-mutant mCRC. Patients received standard approved doses of panitumumab and vemurafenib.

Results: Fifteen patients were treated. Performance status was Eastern Cooperative Oncology Group (ECOG) 0 in 4 patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and 8 (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Treatment was well tolerated, with less cutaneous toxicity than would be expected with either agent, and no cases of keratoacanthomas/squamous cell carcinomas. Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients (100% and 64% regression lasting 40 and 24 weeks, respectively), and stable disease lasting over 6 months in 2 patients.

Conclusions: Combined RAF and EGFR inhibition is well tolerated, with less cutaneous toxicity than would be expected with either agent, and results in modest clinical activity in this highly aggressive and chemoresistant subset of CRC. Clin Cancer Res; 21(6); 1313–20. ©2015 AACR.
Synergistic Blockade of EGFR and HER2 by New-Generation EGFR Tyrosine Kinase Inhibitor Enhances Radiation Effect in Bladder Cancer Cells
Authors: Tsai Yu-Chieh , Ho Pei-Yin , Tzen Kai-Yuan , Tuan Tsung-Fan , Liu Wei-Lin , Cheng Ann-Lii , Pu Yeong-Shiau , Cheng Jason Chia-Hsien
Published: January 2015

Blockade of EGFR has been proved useful in enhancing the effect of radiotherapy, but the advantages of new-generation EGFR tyrosine kinase inhibitors (TKI) in radiosensitization are not well known. We used two human bladder cancer cells with wild-type EGFR to study the synergism between irradiation and afatinib (an EGFR/HER2 dual kinase inhibitor) or erlotinib (an EGFR kinase inhibitor). Here, we showed that afatinib has better radiosensitizing effect than erlotinib in increasing cancer cell killing, the percentage of apoptotic cells, and DNA damage. Afatinib is also superior to erlotinib in combining radiation to decrease tumor size, inhibit glucose metabolism, and enhance apoptotic proteins in vivo. Finally, erlotinib suppressed cell growth and induced more DNA damage in bladder cancer cells transfected with HER2 shRNA, but not in control vector-treated cells. In conclusion, concomitant blockade of radiation-activated EGFR and HER2 signaling by a new-generation EGFR TKI better inhibits the growth of bladder cancer cells both in vitro and in vivo. The absence of radiosensitization by EGFR inhibition alone and the greater radiosensitizing effect of EGFR inhibitor in HER2 knocked down cells suggest the synergism between HER2 and EGFR in determining radiosensitivity. The regained radiosensitizing activity of erlotinib implies that with proper HER2 inhibition, EGFR tyrosine kinase is still a potential target to enhance radiotherapy effect in these seemingly unresponsive bladder cancer cells. Mol Cancer Ther; 14(3); 810–20. ©2015 AACR.
The Preclinical Profile of the Duocarmycin-Based HER2-Targeting ADC SYD985 Predicts for Clinical Benefit in Low HER2-Expressing Breast Cancers
Authors: van der Lee Miranda M.C. , Groothuis Patrick G. , Ubink Ruud , van der Vleuten Monique A.J. , van Achterberg Tanja A. , Loosveld Eline M. , Damming Désirée , Jacobs Daniëlle C.H. , Rouwette Myrthe , Egging David F. , van den Dobbelsteen Diels , Beusker Patrick H. , Goedings Peter , Verheijden Gijs F.M. , Lemmens Jacques M. , Timmers Marco , Dokter Wim H.A.
Published: January 2015

SYD985 is a HER2-targeting antibody–drug conjugate (ADC) based on trastuzumab and vc-seco-DUBA, a cleavable linker-duocarmycin payload. To evaluate the therapeutic potential of this new ADC, mechanistic in vitro studies and in vivo patient-derived xenograft (PDX) studies were conducted to compare SYD985 head-to-head with T-DM1 (Kadcyla), another trastuzumab-based ADC. SYD985 and T-DM1 had similar binding affinities to HER2 and showed similar internalization. In vitro cytotoxicity assays showed similar potencies and efficacies in HER2 3+ cell lines, but in cell lines with low HER2 expression, SYD985 was 3- to 50-fold more potent than T-DM1. In contrast with T-DM1, SYD985 efficiently induced bystander killing in vitro in HER2-negative (HER2 0) cells mixed with HER2 3+, 2+, or 1+ cell lines. At pH conditions relevant for tumors, cathepsin-B cleavage studies showed efficient release of the active toxin by SYD985 but not by T-DM1. These in vitro data suggest that SYD985 might be a more potent ADC in HER2-expressing tumors in vivo, especially in low HER2-expressing and/or in heterogeneous tumors. In line with this, in vivo antitumor studies in breast cancer PDX models showed that SYD985 is very active in HER2 3+, 2+, and 1+ models, whereas T-DM1 only showed significant antitumor activity in HER2 3+ breast cancer PDX models. These properties of SYD985 may enable expansion of the target population to patients who have low HER2-expressing breast cancer, a patient population with still unmet high medical need. Mol Cancer Ther; 14(3); 692–703. ©2015 AACR.
Mechanism of Oncogenic Signal Activation by the Novel Fusion Kinase FGFR3–BAIAP2L1
Authors: Nakanishi Yoshito , Akiyama Nukinori , Tsukaguchi Toshiyuki , Fujii Toshihiko , Satoh Yasuko , Ishii Nobuya , Aoki Masahiro
Published: January 2015

Recent cancer genome profiling studies have identified many novel genetic alterations, including rearrangements of genes encoding FGFR family members. However, most fusion genes are not functionally characterized, and their potentials in targeted therapy are unclear. We investigated a recently discovered gene fusion between FGFR3 and BAI1-associated protein 2-like 1 (BAIAP2L1). We identified 4 patients with bladder cancer and 2 patients with lung cancer harboring the FGFR3–BAIAP2L1 fusion through PCR and FISH assay screens. To investigate the oncogenic potential of the fusion gene, we established an FGFR3–BAIAP2L1 transfectant with Rat-2 fibroblast cells (Rat-2_F3-B). The FGFR3–BAIAP2L1 fusion had transforming activity in Rat2 cells, and Rat-2_F3-B cells were highly tumorigenic in mice. Rat-2_F3-B cells showed in vitro and in vivo sensitivity in the selective FGFR inhibitor CH5183284/Debio 1347, indicating that FGFR3 kinase activity is critical for tumorigenesis. Gene signature analysis revealed that FGFR3–BAIAP2L1 activates growth signals, such as the MAPK pathway, and inhibits tumor-suppressive signals, such as the p53, RB1, and CDKN2A pathways. We also established Rat-2_F3-B-ΔBAR cells expressing an FGFR3–BAIAP2L1 variant lacking the Bin–Amphiphysin–Rvs (BAR) dimerization domain of BAIAP2L1, which exhibited decreased tumorigenic activity, FGFR3 phosphorylation, and F3-B-ΔBAR dimerization, compared with Rat-2_F3-B cells. Collectively, these data suggest that constitutive dimerization through the BAR domain promotes constitutive FGFR3 kinase activation and is essential for its potent oncogenic activity. Mol Cancer Ther; 14(3); 704–12. ©2015 AACR.
Amsacta moorei Entomopoxvirus Encodes a Functional Esterase (amv133) with Protease Activity
Authors: Özşahin Emine , Sezen Kazım , Demirbağ Zihni
Published: January 2015

Objectives: Lipolytic genes have been investigated in several viral genomes, and some of them show enzyme activity which can be used for various functions including the production of DNA replication metabolites, rescue from endosomes, and membrane fusion. Amsacta moorei entomopoxvirus (AMEV) replicates in nearly the entire insect body, especially in the adipose tissue. One of the open reading frames (ORFs) in the AMEV genome, amv133, encodes a putative lipase enzyme. In this study, we therefore investigate the enzyme activity of amv133. Methods:amv133 was aligned with known lipase genes and their homologs in entomopoxviruses. Expressed proteins were partially purified and assayed for lipase, esterase and protease. Results: We found that amv133 contains all the domains required for a functional lipase enzyme and that it shows a significant similarity with homologs in other entomopoxviruses. Since there is a similarity of the catalytic triad between lipases and serine proteases, we also investigated the protease activity of amv133. Lipase, esterase and protease assays showed that amv133 encodes a functional esterase enzyme with protease activity. Conclusion: The current data show that amv133 is a conserved gene in all entomopoxvirus genomes sequenced so far and might contribute greatly to degrading the lipids or proteins and hence improve the virus infection.
Characterization of Two Temperate Lactobacillus paracasei Bacteriophages: Morphology, Kinetics and Adsorption
Authors: Mercanti Diego J. , Ackermann Hans-Wolfgang , Quiberoni Andrea
Published: January 2015

Background/Aims: Adsorption and kinetic parameters, latent period, burst size and burst time, are characteristics of phage/host systems and can be affected by several environmental factors. As only few studies have focused on temperate dairy phages, we characterized these parameters on temperate Lactobacillus paracasei phages Φ iLp84 and Φ iLp1308, infective for probiotic strains. Methods: Phages were characterized by transmission electron microscopy and genomic DNA restriction. Adsorption under different environmental conditions, phage kinetics and efficiency of plating (EOP) were determined using the double-layer titration method. Results: Phages Φ iLp84 and Φ iLp1308 belong to the Siphoviridae family and have genome sizes of 38 and 34 kbp, respectively. Adsorption was affected by calcium concentration, pH, temperature and host viability, and reached a limit at very high multiplicity of infection. Latency, burst time and burst size were of 85 min, 131 min and 46 for Φ iLp84, and 51 min, 92 min and 28 for Φ iLp1308, respectively, at 37°C. A clear influence of temperature on phage kinetics was observed. Regarding EOP, Φ iLp84 produced plaques on only 1 out of 8 strains tested. Conclusion: Noticeable differences in adsorption, kinetics and EOP were found for two morphologically identical temperate L. paracasei phages of similar origin.
Role of Interferon-λ in Allergic Asthma
Authors: Koch Sonja , Finotto Susetta
Published: January 2015

Type III interferons (IFNs), or IFN-λ, are known to have potent antiviral and antiproliferative activities. It inhibits viral replication and upregulates cytotoxic responses to virally infected cells. Besides these characteristics, IFN-λ also has additional activities in the immune system. In fact, it induces the proliferation of Foxp3-expressing regulatory T cells mediated in part by dendritic cells and inhibit the production of IL-5 and IL-13 in vitro. Regulatory T cells and the Th2 cytokines like IL-5 and IL-13 play important roles in the pathogenesis of allergic asthma. In humans, there seems to be an inverse link between IFN-λ and the severity of allergic asthma and allergic asthma exacerbations. Asthmatic patients, without a detectable viral infection show an inverse correlation between IL-28 and IL-29 mRNA levels and severity of allergic responses in the airways. These additional features of IFN-λ that affect the adaptive immune system make it a potential immunotherapeutic agent for the treatment of allergic asthma.
An Astrocyte Regenerative Response from Vimentin-Containing Cells in the Spinal Cord of Amyotrophic Lateral Sclerosis's Disease-Like Transgenic (G93A SOD1) Mice
Authors: Zhou Yiyi , Lu Yi , Fang Xin , Zhang Jie , Li Jiao , Li Shujuan , Deng Xia , Yu Yaqing , Xu Renshi
Published: January 2015

The reason for regeneration in the adult spinal cord during motor neuron degeneration in amyotrophic lateral sclerosis (ALS) remains largely unknown. To this end, we studied the alteration of vimentin (a neural precursor cells marker in CNS)-containing cells (VCCs) in spinal cord during different stages of ALS used C57BL/6J G93A SOD1 transgenic mice mimicking ALS. Results showed that VCCs were mostly distributed in the ependymal zone (EZ) surrounding the central canal of spinal cord in SOD1 wild type mice; a few of VCCs were sparsely distributed in other regions. However, the number of VCCs significantly increased in the spinal cord during the onset and progression stages of ALS. They were extensively distributed in the EZ, the anterior, the lateral and the posterior horn of grey matter, particularly in the posterior horn region at the progression stage. A majority of VCCs in the anterior, the lateral and the posterior horn of grey matter (outside of EZ) generated astrocytes, but no neurons, oligodendrocytes and microgliocytes. Our results suggested that there was a potential astrocyte regenerative response to motor neuron degeneration in motor neurons-degenerated regions in the adult spinal cord during the onset and progression stages of ALS-like disease. The regenerative responses in the adult spinal cord of ALS-like mice may be a potential pathway in attempting to repair the degenerated motor neurons and restore the dysfunctional neural circuitry.
Final Results of Cilostazol-Aspirin Therapy against Recurrent Stroke with Intracranial Artery Stenosis (CATHARSIS)
Authors: Uchiyama Shinichiro , Sakai Nobuyuki , Toi Sono , Ezura Masayuki , Okada Yasushi , Takagi Makoto , Nagai Yoji , Matsubara Yoshihiro , Minematsu Kazuo , Suzuki Norihiro , Tanahashi Norio , Taki Waro , Nagata Izumi , Matsumoto Masayasu ,   for the CATHARSIS Study Group
Published: January 2015

Purpose: To compare the effect of cilostazol plus aspirin versus aspirin alone on the progression of intracranial arterial stenosis (IAS), and to compare ischemic and hemorrhagic events in patients with symptomatic IAS, an investigator-driven, nationwide multicenter cooperative randomized controlled trial (CATHARSIS; ClinicalTrials.gov Identifier 00333164) was conducted. Methods: 165 noncardioembolic ischemic stroke patients with >50% stenosis in the responsible intracranial artery after 2 weeks to 6 months from the onset were randomly allocated to receive either cilostazol 200 mg/day plus aspirin 100 mg/day (n = 83, CA group) or aspirin 100 mg/day alone (n = 82, A group). The primary endpoint was the progression of IAS on magnetic resonance angiography at 2 years after randomization. Secondary endpoints were any vascular events, any cause of death, serious adverse events, new silent brain infarcts, and worsening of the modified Rankin Scale score. Results: Progression of IAS was observed in 9.6% of the CA group patients and in 5.6% of the A group patients, with no significant intergroup difference (p = 0.53). The incidence of the secondary endpoints tended to be lower in the CA group compared with the A group, although the differences were not significant. By using exploratory logistic regression analysis adjusted for patient background characteristics, it was shown that the risk for certain combinations of secondary endpoints was lower in the CA group than in the A group [all vascular events and silent brain infarcts: odds ratio (OR) = 0.37, p = 0.04; stroke and silent brain infarcts: OR = 0.34, p = 0.04; all vascular events, worsening of modified Rankin Scale scores and silent brain infracts: OR = 0.41, p = 0.03]. Major hemorrhage was observed in 4 patients of the CA group and in 3 of the A group. Conclusion: Progression of IAS during the 2-year observation period appears to be less frequent than previously reported in stroke patients on antiplatelet agents after the acute phase, which could be due to the adequate control of risk factors, and because patients with stroke within 2 weeks after the onset were excluded. The results of the CATHARSIS trial suggest a potential utility of pharmacotherapies with cilostazol plus aspirin as well as of strict control of risk factors for the management of symptomatic IAS. Larger studies with higher statistical power are required to obtain conclusive results.
Novel Repeated DNAs in the Antarctic Polyplacophoran Nuttallochiton mirandus (Thiele, 1906)
Authors: Biscotti Maria A. , Canapa Adriana , Capriglione Teresa , Forconi Mariko , Odierna Gaetano , Olmo Ettore , Petraccioli Agnese , Barucca Marco
Published: January 2015

Within the scope of a project on the characterization of satellite DNAs in polar mollusks, the Antarctic chiton Nuttallochitonmirandus (Thiele, 1906) was analyzed. Two novel families of tandemly repeated DNAs, namely NmH and NmP, are described in their structure and chromosomal localization, and, furthermore, their presence was analyzed in related species. Data reported here display a particular variability in the structural organization of DNA satellites within this species. Processes driving satellite evolution, which are likely responsible for the intriguing variability of the identified satellite DNAs, are discussed.