bluuebunny/crossref_metadata_2025 huggingface dataset:
The Study of Intelligent Vehicle Navigation Path Based on Behavior Coordination of Particle Swarm
Authors: Han Gaining , Fu Weiping , Wang Wen
Published: January 2016

In the behavior dynamics model, behavior competition leads to the shock problem of the intelligent vehicle navigation path, because of the simultaneous occurrence of the time-variant target behavior and obstacle avoidance behavior. Considering the safety and real-time of intelligent vehicle, the particle swarm optimization (PSO) algorithm is proposed to solve these problems for the optimization of weight coefficients of the heading angle and the path velocity. Firstly, according to the behavior dynamics model, the fitness function is defined concerning the intelligent vehicle driving characteristics, the distance between intelligent vehicle and obstacle, and distance of intelligent vehicle and target. Secondly, behavior coordination parameters that minimize the fitness function are obtained by particle swarm optimization algorithms. Finally, the simulation results show that the optimization method and its fitness function can improve the perturbations of the vehicle planning path and real-time and reliability.
Extracellular Matrix‐Dependent Generation of Integration‐ and Xeno‐Free iPS Cells Using a Modified mRNA Transfection Method
Authors: Lee Kang-In , Lee Seo-Young , Hwang Dong-Youn
Published: January 2016

Human induced pluripotent stem cells (iPS cells) hold great promise in the field of regenerative medicine, especially immune‐compatible cell therapy. The most important safety‐related issues that must be resolved before the clinical use of iPS cells include the generation of “footprint‐free” and “xeno‐free” iPS cells. In this study, we sought to examine whether an extracellular matrix‐ (ECM‐) based xeno‐free culture system that we recently established could be used together with a microRNA‐enhanced mRNA reprogramming method for the generation of clinically safe iPS cells. The notable features of this method are the use of a xeno‐free/feeder‐free culture system for the generation and expansion of iPS cells rather than the conventional labor‐intensive culture systems using human feeder cells or human feeder‐conditioned medium and the enhancement of mRNA‐mediated reprogramming via the delivery of microRNAs. Strikingly, we observed the early appearance of iPS cell colonies (~11 days), substantial reprogramming efficiency (~0.2–0.3%), and a high percentage of ESC‐like colonies among the total colonies (~87.5%), indicating enhanced kinetics and reprogramming efficiency. Therefore, the combined method established in this study provides a valuable platform for the generation and expansion of clinically safe (i.e., integration‐ and xeno‐free) iPS cells, facilitating immune‐matched cell therapy in the near future.
Effects of Implementing Adaptable Channelization in Wi-Fi Networks
Authors: Hussain Abid , Saqib Nazar Abbas
Published: January 2016

The unprecedented increase of wireless devices is now facing a serious threat of spectrum scarcity. The situation becomes even worse due to inefficient frequency distribution protocols, deployed in trivial Wi-Fi networks. The primary source of this inefficiency is static channelization used in wireless networks. In this work, we investigate the use of dynamic and flexible channelization, for optimal spectrum utilization in Wi-Fi networks. We propose optimal spectrum sharing algorithm (OSSA) and analyze its effect on exhaustive list of essential network performance measuring parameters. The elementary concept of the proposed algorithm lies in the fact that frequency spectrum should be assigned to any access point (AP) based on its current requirement. The OSSA algorithm assigns channels with high granularity, thus maximizing spectrum utilization by more than 20% as compared to static width channel allocation. This optimum spectrum utilization, in turn, increases throughput by almost 30% in many deployment scenarios. The achieved results depict considerable decrease in interference, while simultaneously increasing range. Similarly signal strength values at relatively longer distances improve significantly at narrower channel widths while simultaneously decreasing bit error rates. We found that almost 25% reduction in interference is possible in certain scenarios through proposed algorithm.
Pilot-Less Time Synchronization for OFDM Systems: Application to Power Line Receivers
Authors: Lalos Aris S. , Vgenis Athanasios , Gioulekas Fotios , Birbas Michael
Published: January 2016

Power line networks provide high-speed broadband communications without the need for new wirings. However, these networks present a hostile environment for high-speed data communications. The most common modulation method used in such systems is OFDM, since it copes effectively with noise, multipath, fading selectivity, and attenuation. A potential drawback of OFDM is its sensitivity to receiver synchronization imperfections, such as timing and sampling frequency offsets. Although several approaches have been proposed for estimating the time and frequency offset, they are based on the use of pilot sequences that are not available in power line communication standards. More importantly, they focus on isolated algorithms for compensating either time or frequency offsets without providing a complete, low complexity, OFDM receiver architecture that mitigates jointly time and frequency errors. This paper focuses on providing an OFDM receiver architecture that can be compatible with many power line standards. Extensive simulation studies show under realistic channel and noise conditions that the proposed receiver provides enhanced robustness to synchronization imperfections as compared to conventional approaches.
Scheimpflug Imaging Parameters Associated with Tear Mediators and Bronchial Asthma in Keratoconus
Authors: Pásztor Dorottya , Kolozsvári Bence Lajos , Csutak Adrienne , Berta András , Hassan Ziad , Kettesy Beáta Andrea , Gogolák Péter , Fodor Mariann
Published: January 2016

Purpose.To determine associations between mediators in tears in the whole spectrum of keratoconus (KC); to explore connections between mediators and Scheimpflug parameters; to examine correlations between Scheimpflug parameters and bronchial asthma.Methods.Tear samples were collected from 69 patients and 19 controls. Concentrations of mediators—IL-6, -10; CXCL8, CCL5; MMP-9, -13; TIMP-1; t-PA, PAI-1—were measured by Cytometric Bead Array. Measured Pentacam parameters include keratometry values (K1,K2,Kmax), corneal thickness (Pachy Pupil, Apex, Min), and elevations and indices (including Belin-Ambrósio deviation (BAD-D)).Results.A number of significant positive associations were observed between pairs of mediator concentrations. Significant positive correlations were found between BAD-D and CXCL8/MMP-9 andK2and MMP-9. Significant negative associations were explored between Pachy Min and CXCL8/t-PA. Significant associations were found between pairs of mediators (IL-6 and CXCL8; CCL5 and CXCL8/MMP-9; TIMP-1 and MMP-9/-13/t-PA; t-PA and CXCL8/CCL5/PAI-1) and the severity of KC. Significant positive correlation between asthma and the severity of KC was explored.Conclusion.Cooperation of different mediators in tears all taking part in the complex pathomechanism of keratoconus was revealed. Our research verifies that inflammation plays a crucial role in the pathogenesis of KC. Additionally this study confirms the effect of bronchial asthma on keratoconus.
Characterization of a c-Rel Inhibitor That Mediates Anticancer Properties in Hematologic Malignancies by Blocking NF-κB–Controlled Oxidative Stress Responses
Authors: Shono Yusuke , Tuckett Andrea Z. , Liou Hsiou-Chi , Doubrovina Ekaterina , Derenzini Enrico , Ouk Samedy , Tsai Jennifer J. , Smith Odette M. , Levy Emily R. , Kreines Fabiana M. , Ziegler Carly G.K. , Scallion Mary I. , Doubrovin Mikhail , Heller Glenn , Younes Anas , O'Reilly Richard J. , van den Brink Marcel R.M. , Zakrzewski Johannes L.
Published: January 2016

NF-κB plays a variety of roles in oncogenesis and immunity that may be beneficial for therapeutic targeting, but strategies to selectively inhibit NF-κB to exert antitumor activity have been elusive. Here, we describe IT-901, a bioactive naphthalenethiobarbiturate derivative that potently inhibits the NF-κB subunit c-Rel. IT-901 suppressed graft-versus-host disease while preserving graft-versus-lymphoma activity during allogeneic transplantation. Further preclinical assessment of IT-901 for the treatment of human B-cell lymphoma revealed antitumor properties in vitro and in vivo without restriction to NF-κB–dependent lymphoma. This nondiscriminatory, antilymphoma effect was attributed to modulation of the redox homeostasis in lymphoma cells resulting in oxidative stress. Moreover, NF-κB inhibition by IT-901 resulted in reduced stimulation of the oxidative stress response gene heme oxygenase-1, and we demonstrated that NF-κB inhibition exacerbated oxidative stress induction to inhibit growth of lymphoma cells. Notably, IT-901 did not elicit increased levels of reactive oxygen species in normal leukocytes, illustrating its cancer selective properties. Taken together, our results provide mechanistic insight and preclinical proof of concept for IT-901 as a novel therapeutic agent to treat human lymphoid tumors and ameliorate graft-versus-host disease. Cancer Res; 76(2); 377–89. ©2016 AACR.
Activation of Hematopoietic Stem/Progenitor Cells Promotes Immunosuppression Within the Pre–metastatic Niche
Authors: Giles Amber Jin , Reid Caitlin Marie , Evans Justin DeWayne , Murgai Meera , Vicioso Yorleny , Highfill Steven Lorenz , Kasai Miki , Vahdat Linda , Mackall Crystal Lee , Lyden David , Wexler Leonard , Kaplan Rosandra Natasha
Published: January 2016

Metastatic tumors have been shown to establish microenvironments in distant tissues that are permissive to disseminated tumor cells. Hematopoietic cells contribute to this microenvironment, yet the precise initiating events responsible for establishing the pre-metastatic niche remain unclear. Here, we tracked the developmental fate of hematopoietic stem and progenitor cells (HSPC) in tumor-bearing mice. We show that a distant primary tumor drives the expansion of HSPCs within the bone marrow and their mobilization to the bloodstream. Treatment of purified HSPCs cultured ex vivo with tumor-conditioned media induced their proliferation as well as their differentiation into immunosuppressive myeloid cells. We furthered tracked purified HSPCs in vivo and found they differentiated into myeloid-derived suppressor cells in early metastatic sites of tumor-bearing mice. The number of CD11b+Ly6g+ cells in metastatic sites was significantly increased by HSPC mobilization and decreased if tumor-mediated mobilization was inhibited. Moreover, pharmacologic mobilization of HSPCs increased metastasis, whereas depletion of Gr1+ cells abrogated the metastasis-promoting effects of HSPC mobilization. Finally, we detected elevated levels of HSPCs in the circulation of newly diagnosed cancer patients, which correlated with increased risk for metastatic progression. Taken together, our results highlight bone marrow activation as one of the earliest steps of the metastatic process and identify circulating HSPCs as potential clinical indicators of metastatic niche formation. Cancer Res; 76(6); 1335–47. ©2015 AACR.
A Novel IL6 Antibody Sensitizes Multiple Tumor Types to Chemotherapy Including Trastuzumab-Resistant Tumors
Authors: Zhong Haihong , Davis April , Ouzounova Maria , Carrasco Rosa A. , Chen Cui , Breen Shannon , Chang Yong S. , Huang Jiaqi , Liu Zheng , Yao Yihong , Hurt Elaine , Moisan Jacques , Fung Michael , Tice David A. , Clouthier Shawn G. , Xiao Zhan , Wicha Max S. , Korkaya Hasan , Hollingsworth Robert E.
Published: January 2016

Elevated levels of the proinflammatory cytokine IL6 are associated with poor survival outcomes in many cancers. Antibodies targeting IL6 and its receptor have been developed for chronic inflammatory disease, but they have not yet been shown to clearly benefit cancer patients, possibly due to antibody potency or the settings in which they have been tested. In this study, we describe the development of a novel high-affinity anti-IL6 antibody, MEDI5117, which features an extended half-life and potent inhibitory effects on IL6 biologic activity. MEDI5117 inhibited IL6-mediated activation of STAT3, suppressing the growth of several tumor types driven by IL6 autocrine signaling. In the same models, MEDI5117 displayed superior preclinical activity relative to a previously developed anti-IL6 antibody. Consistent with roles for IL6 in promoting tumor angiogenesis, we found that MEDI5117 inhibited the growth of endothelial cells, which can produce IL6 and support tumorigenesis. Notably, in tumor xenograft assays in mice, we documented the ability of MEDI5117 to enhance the antitumor activities of chemotherapy or gefitinib in combination treatment regimens. MEDI5117 also displayed robust activity on its own against trastuzumab-resistant HER2+ tumor cells by targeting the CD44+CD24− cancer stem cell population. Collectively, our findings extend the evidence of important pleiotropic roles of IL6 in tumorigenesis and drug resistance, and offer a preclinical proof of concept for the use of IL6 antibodies in combination regimens to heighten therapeutic responses and overcome drug resistance. Cancer Res; 76(2); 480–90. ©2016 AACR.
HSPB1 Inhibits the Endothelial-to-Mesenchymal Transition to Suppress Pulmonary Fibrosis and Lung Tumorigenesis
Authors: Choi Seo-Hyun , Nam Jae-Kyung , Kim Bu-Yeo , Jang Junho , Jin Young-Bae , Lee Hae-June , Park Seungwoo , Ji Young Hoon , Cho Jaeho , Lee Yoon-Jin
Published: January 2016

The endothelial-to-mesenchymal transition (EndMT) contributes to cancer, fibrosis, and other pathologic processes. However, the underlying mechanisms are poorly understood. Endothelial HSP1 (HSPB1) protects against cellular stress and has been implicated in cancer progression and pulmonary fibrosis. In this study, we investigated the role of HSPB1 in mediating the EndMT during the development of pulmonary fibrosis and lung cancer. HSPB1 silencing in human pulmonary endothelial cells accelerated emergence of the fibrotic phenotype after treatment with TGFβ or other cytokines linked to pulmonary fibrosis, suggesting that HSPB1 maintains endothelial cell identity. In mice, endothelial-specific overexpression of HSPB1 was sufficient to inhibit pulmonary fibrosis by blocking the EndMT. Conversely, HSPB1 depletion in a mouse model of lung tumorigenesis induced the EndMT. In clinical specimens of non–small cell lung cancer, HSPB1 expression was absent from tumor endothelial cells undergoing the EndMT. Our results showed that HSPB1 regulated the EndMT in lung fibrosis and cancer, suggesting that HSPB1-targeted therapeutic strategies may be applicable for treating an array of fibrotic diseases. Cancer Res; 76(5); 1019–30. ©2016 AACR.
Non–Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases
Authors: Isozaki Hideko , Ichihara Eiki , Takigawa Nagio , Ohashi Kadoaki , Ochi Nobuaki , Yasugi Masayuki , Ninomiya Takashi , Yamane Hiromichi , Hotta Katsuyuki , Sakai Katsuya , Matsumoto Kunio , Hosokawa Shinobu , Bessho Akihiro , Sendo Toshiaki , Tanimoto Mitsune , Kiura Katsuyuki
Published: January 2016

Crizotinib is the standard of care for advanced non–small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult. Cancer Res; 76(6); 1506–16. ©2015 AACR.
Dynamic Patterns of Clonal Evolution in Tumor Vasculature Underlie Alterations in Lymphocyte–Endothelial Recognition to Foster Tumor Immune Escape
Authors: Corey Daniel M. , Rinkevich Yuval , Weissman Irving L.
Published: January 2016

Although tumor blood vessels have been a major therapeutic target for cancer chemotherapy, little is known regarding the stepwise development of the tumor microenvironment. Here, we use a multicolor Cre-dependent marker system to trace clonality within the tumor microenvironment to show that tumor blood vessels follow a pattern of dynamic clonal evolution. In an advanced melanoma tumor microenvironment, the vast majority of tumor vasculature clones are derived from a common precursor. Quantitative lineage analysis reveals founder clones diminish in frequency and are replaced by subclones as tumors evolve. These tumor-specific blood vessels are characterized by a developmental switch to a more invasive and immunologically silent phenotype. Gene expression profiling and pathway analysis reveals selection for traits promoting upregulation of alternative angiogenic programs such as unregulated HGF-MET signaling and enhanced autocrine signaling through VEGF and PDGF. Furthermore, we show a developmental switch in the expression of functionally significant primary lymphocyte adhesion molecules on tumor endothelium, such as the loss in expression of the mucosal addressin MAdCAM-1, whose counter receptor a4β7 on lymphocytes controls lymphocyte homing. Changes in adhesive properties on tumor endothelial subclones are accompanied by decreases in expression of lymphocyte chemokines CXCL16, CXCL13, CXCL12, CXCL9, CXCL10, and CCL19. These evolutionary patterns in the expressed genetic program within tumor endothelium will have both a quantitative and functional impact on lymphocyte distribution that may well influence tumor immune function and underlie escape mechanisms from current antiangiogenic pharmacotherapies. Cancer Res; 76(6); 1348–53. ©2015 AACR.
Peritoneal Dissemination Requires an Sp1-Dependent CXCR4/CXCL12 Signaling Axis and Extracellular Matrix–Directed Spheroid Formation
Authors: Kasagi Yuta , Harada Yui , Morodomi Yosuke , Iwai Toshiki , Saito Satoru , Yoshida Kumi , Oki Eiji , Saeki Hiroshi , Ohgaki Kippei , Sugiyama Masahiko , Onimaru Mitsuho , Maehara Yoshihiko , Yonemitsu Yoshikazu
Published: January 2016

Peritonitis carcinomatosa is an advanced and intractable state of gastrointestinal and ovarian cancer, where mechanistic elucidation might enable the development of more effective therapies. Peritoneal dissemination of this type of malignancy has been generally thought to initiate from “milky spots” of primitive lymphoid tissues in the peritoneal cavity. In this study, we offer evidence challenging this idea, based on the finding that tumor implantation and directional dissemination was not required for the presence of milky spots, but rather SCF/CXCL12–expressing niche-like cells located at the border regions of perivascular adipose tissue. Interestingly, we found that peritoneal cavity lavage fluid, which specifically contains peritoneal collagen type IV and plasma fibronectin, dramatically facilitated spheroid formation of murine and human colon cancer cells. Spheroid formation strongly induced the expression of CXCR4 in an Sp1-dependent manner to promote niche-directed metastasis. Notably, disrupting sphere formation or inhibiting Sp1 activity was sufficient to suppress tumor dissemination and potentiated chemosensitivity to 5-fluorouracil. Our findings illuminate mechanisms of peritoneal cancer dissemination and highlight the Sp1/CXCR4/CXCL12 signaling axis as a rational target for the development of therapeutics to manage this intractable form of malignancy. Cancer Res; 76(2); 347–57. ©2016 AACR.
PBX3 and MEIS1 Cooperate in Hematopoietic Cells to Drive Acute Myeloid Leukemias Characterized by a Core Transcriptome of the MLL-Rearranged Disease
Authors: Li Zejuan , Chen Ping , Su Rui , Hu Chao , Li Yuanyuan , Elkahloun Abdel G. , Zuo Zhixiang , Gurbuxani Sandeep , Arnovitz Stephen , Weng Hengyou , Wang Yungui , Li Shenglai , Huang Hao , Neilly Mary Beth , Wang Gang Greg , Jiang Xi , Liu Paul P. , Jin Jie , Chen Jianjun
Published: January 2016

Overexpression of HOXA/MEIS1/PBX3 homeobox genes is the hallmark of mixed lineage leukemia (MLL)-rearranged acute myeloid leukemia (AML). HOXA9 and MEIS1 are considered to be the most critical targets of MLL fusions and their coexpression rapidly induces AML. MEIS1 and PBX3 are not individually able to transform cells and were therefore hypothesized to function as cofactors of HOXA9. However, in this study, we demonstrate that coexpression of PBX3 and MEIS1 (PBX3/MEIS1), without ectopic expression of a HOX gene, is sufficient for transformation of normal mouse hematopoietic stem/progenitor cells in vitro. Moreover, PBX3/MEIS1 overexpression also caused AML in vivo, with a leukemic latency similar to that caused by forced expression of MLL-AF9, the most common form of MLL fusions. Furthermore, gene expression profiling of hematopoietic cells demonstrated that PBX3/MEIS1 overexpression, but not HOXA9/MEIS1, HOXA9/PBX3, or HOXA9 overexpression, recapitulated the MLL-fusion–mediated core transcriptome, particularly upregulation of the endogenous Hoxa genes. Disruption of the binding between MEIS1 and PBX3 diminished PBX3/MEIS1–mediated cell transformation and HOX gene upregulation. Collectively, our studies strongly implicate the PBX3/MEIS1 interaction as a driver of cell transformation and leukemogenesis, and suggest that this axis may play a critical role in the regulation of the core transcriptional programs activated in MLL-rearranged and HOX-overexpressing AML. Therefore, targeting the MEIS1/PBX3 interaction may represent a promising therapeutic strategy to treat these AML subtypes. Cancer Res; 76(3); 619–29. ©2016 AACR.
Cancer Stem-like Cells Act via Distinct Signaling Pathways in Promoting Late Stages of Malignant Progression
Authors: da Silva-Diz Victoria , Simón-Extremera Pilar , Bernat-Peguera Adrià , de Sostoa Jana , Urpí Maria , Penín Rosa M. , Sidelnikova Diana Pérez , Bermejo Oriol , Viñals Joan Maria , Rodolosse Annie , González-Suárez Eva , Moruno Antonio Gómez , Pujana Miguel Ángel , Esteller Manel , Villanueva Alberto , Viñals Francesc , Muñoz Purificación
Published: January 2016

Cancer stem-like cells (CSC) play key roles in long-term tumor propagation and metastasis, but their dynamics during disease progression are not understood. Tumor relapse in patients with initially excised skin squamous cell carcinomas (SCC) is characterized by increased metastatic potential, and SCC progression is associated with an expansion of CSC. Here, we used genetically and chemically-induced mouse models of skin SCC to investigate the signaling pathways contributing to CSC function during disease progression. We found that CSC regulatory mechanisms change in advanced SCC, correlating with aggressive tumor growth and enhanced metastasis. β-Catenin and EGFR signaling, induced in early SCC CSC, were downregulated in advanced SCC. Instead, autocrine FGFR1 and PDGFRα signaling, which have not been previously associated with skin SCC CSC, were upregulated in late CSC and promoted tumor growth and metastasis, respectively. Finally, high-grade and recurrent human skin SCC recapitulated the signaling changes observed in advanced mouse SCC. Collectively, our findings suggest a stage-specific switch in CSC regulation during disease progression that could be therapeutically exploited by targeting the PDGFR and FGFR1 pathways to block relapse and metastasis of advanced human skin SCC.Cancer Res; 76(5); 1245–59. ©2015 AACR.
Detection of Pancreatic Cancer–Induced Cachexia Using a Fluorescent Myoblast Reporter System and Analysis of Metabolite Abundance
Authors: Winnard Paul T. , Bharti Santosh K. , Penet Marie-France , Marik Radharani , Mironchik Yelena , Wildes Flonne , Maitra Anirban , Bhujwalla Zaver M.
Published: January 2016

The dire effects of cancer-induced cachexia undermine treatment and contribute to decreased survival rates. Therapeutic options for this syndrome are limited, and therefore efforts to identify signs of precachexia in cancer patients are necessary for early intervention. The applications of molecular and functional imaging that would enable a whole-body “holistic” approach to this problem may lead to new insights and advances for diagnosis and treatment of this syndrome. Here we have developed a myoblast optical reporter system with the purpose of identifying early cachectic events. We generated a myoblast cell line expressing a dual tdTomato:GFP construct that was grafted onto the muscle of mice-bearing human pancreatic cancer xenografts to provide noninvasive live imaging of events associated with cancer-induced cachexia (i.e., weight loss). Real-time optical imaging detected a strong tdTomato fluorescent signal from skeletal muscle grafts in mice with weight losses of only 1.2% to 2.7% and tumor burdens of only approximately 79 to 170 mm3. Weight loss in cachectic animals was also associated with a depletion of lipid, cholesterol, valine, and alanine levels, which may provide informative biomarkers of cachexia. Taken together, our findings demonstrate the utility of a reporter system that is capable of tracking tumor-induced weight loss, an early marker of cachexia. Future studies incorporating resected tissue from human pancreatic ductal adenocarcinoma into a reporter-carrying mouse may be able to provide a risk assessment of cachexia, with possible implications for therapeutic development. Cancer Res; 76(6); 1441–50. ©2015 AACR.
Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy
Authors: Pilon-Thomas Shari , Kodumudi Krithika N. , El-Kenawi Asmaa E. , Russell Shonagh , Weber Amy M. , Luddy Kimberly , Damaghi Mehdi , Wojtkowiak Jonathan W. , Mulé James J. , Ibrahim-Hashim Arig , Gillies Robert J.
Published: January 2016

Cancer immunotherapies, such as immune checkpoint blockade or adoptive T-cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of antitumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy of immunotherapy. An acidic pH environment blocked T-cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was posttranslational. Acidification did not affect cytoplasmic pH, suggesting that signals transduced by external acidity were likely mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T-cell infiltration. Furthermore, combining bicarbonate therapy with anti-CTLA-4, anti-PD1, or adoptive T-cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation. Cancer Res; 76(6); 1381–90. ©2015 AACR.
PDLIM1 Stabilizes the E-Cadherin/β-Catenin Complex to Prevent Epithelial–Mesenchymal Transition and Metastatic Potential of Colorectal Cancer Cells
Authors: Chen Hai-Ning , Yuan Kefei , Xie Na , Wang Kui , Huang Zhao , Chen Yan , Dou Qianhui , Wu Min , Nice Edouard C. , Zhou Zong-Guang , Huang Canhua
Published: January 2016

Metastasis is a major cause of death in patients with colorectal cancer, and increasing evidence supports the contribution of the epithelial–mesenchymal transition (EMT) to cancer progression. The dissociation of the E-cadherin/β-catenin adhesion complex represents a key step in EMT and promotes cancer invasion and metastasis, but the upstream signaling pathways regulating this interaction are poorly understood. Here, we show that PDLIM1, a member of the PDZ and LIM protein family, was downregulated in highly metastatic colorectal cancer cells and liver metastases from colorectal cancer patients. We found that loss of PDLIM1 promoted the expression of EMT markers and increased the invasive and migratory properties of multiple colorectal cancer cell lines. Furthermore, PDLIM1 knockdown increased colon-derived liver metastasis in an orthotopic colorectal cancer model and promoted distant metastatic colonization in an experimental lung metastasis model. Mechanistic investigations revealed that PDLIM1 interacted with and stabilized the E-cadherin/β-catenin complex, thereby inhibiting the transcriptional activity of β-catenin and preventing EMT. Accordingly, PDLIM1 overexpression attenuated EMT of colorectal cancer cells. Moreover, the downregulation of PDLIM1 in colorectal cancer samples correlated with reduced E-cadherin and membrane β-catenin levels, and was associated with shorter overall survival. In conclusion, our study demonstrates that PDLIM1 suppresses EMT and metastatic potential of colorectal cancer cells by stabilizing β-catenin at cell–cell junctions, and its loss in metastatic tissues may represent a potential prognostic marker of aggressive disease. Cancer Res; 76(5); 1122–34. ©2015 AACR.
TheMCT4Gene: A Novel, Potential Target for Therapy of Advanced Prostate Cancer
Authors: Choi Stephen Yiu Chuen , Xue Hui , Wu Rebecca , Fazli Ladan , Lin Dong , Collins Colin C. , Gleave Martin E. , Gout Peter W. , Wang Yuzhuo
Published: January 2016

Purpose: The management of castration-resistant prostate cancer (CRPC) is a major challenge in the clinic. Androgen receptor signaling–directed strategies are not curative in CRPC therapy, and new strategies targeting alternative, key cancer properties are needed. Using reprogrammed glucose metabolism (aerobic glycolysis), cancer cells typically secrete excessive amounts of lactic acid into their microenvironment, promoting cancer development, survival, and progression. Cellular lactic acid secretion is thought to be predominantly mediated by MCT4, a plasma membrane transporter protein. As such, the MCT4 gene provides a unique, potential therapeutic target for cancer.

Experimental Design: A tissue microarray of various Gleason grade human prostate cancers was stained for MCT4 protein. Specific, MCT4-targeting antisense oligonucleotides (MCT4 ASO) were designed and candidate MCT4 ASOs checked for effects on (i) MCT4 expression, lactic acid secretion/content, glucose consumption, glycolytic gene expression, and proliferation of human CRPC cells and (ii) growth of PC-3 tumors in nude mice.

Results: Elevated MCT4 expression was associated with human CRPC and an earlier time to relapse. The treatment of PC-3, DU145, and C4-2 CRPC cultures with candidate MCT4 ASOs led to marked inhibition of MCT4 expression, lactic acid secretion, to increased intracellular lactic acid levels, and markedly reduced aerobic glycolysis and cell proliferation. Treatment of PC-3 tumor-bearing nude mice with the MCT4 ASOs markedly inhibited tumor growth without inducing major host toxicity.

Conclusions: MCT4-targeting ASOs that inhibit lactic acid secretion may be useful for therapy of CRPC and other cancers, as they can interfere with reprogrammed energy metabolism of cancers, an emerging hallmark of cancer. Clin Cancer Res; 22(11); 2721–33. ©2016 AACR.
Survivin Autoantibodies Are Not Elevated in Lung Cancer When Assayed Controlling for Specificity and Smoking Status
Authors: Broodman Ingrid , VanDuijn Martijn M. , Stingl Christoph , Dekker Lennard J.M. , Germenis Anastasios E. , de Koning Harry J. , van Klaveren Rob J. , Aerts Joachim G. , Lindemans Jan , Luider Theo M.
Published: January 2016

The high mortality rate in lung cancer is largely attributable to late diagnosis. Case–control studies suggest that autoantibodies to the survivin protein are potential biomarkers for early diagnosis. We tested the hypothesis that sandwich ELISA can detect autoantibodies to survivin before radiologic diagnosis in patients with early-stage non–small cell lung cancer (NSCLC). Because previous studies assayed survivin autoantibodies with the direct antigen-coating ELISA (DAC-ELISA), we first compared that assay with the sandwich ELISA. Based on the more robust results from the sandwich ELISA, we used it to measure survivin autoantibodies in the serum of 100 individuals from a well-controlled population study [the Dutch–Belgian Lung Cancer Screening Trial (NELSON) trial] composed of current and former smokers (50 patients with NSCLC, both before and after diagnosis, and 50 matched, smoking-habit control subjects), and another 50 healthy nonsmoking control subjects. We found no difference in specific autoantibodies to survivin in NSCLC patients, although nonspecific median optical densities were 24% higher (P < 0.001) in both NSCLC patients and smokers, than in healthy nonsmokers. Finally, we confirmed the ELISA results with Western blot analysis of recombinant and endogenous survivin (HEK-293), which showed no anti-survivin reactivity in patient sera. We conclude that specific anti-survivin autoantibody reactivity is most likely not present in sera before or after diagnosis. Autoantibody studies benefit from a comparison to a well-controlled population, stratified for smoking habit. Cancer Immunol Res; 4(2); 165–72. ©2015 AACR.
Risk Related to Pre–Diabetes Mellitus and Diabetes Mellitus in Heart Failure With Reduced Ejection Fraction
Authors: Kristensen Søren L. , Preiss David , Jhund Pardeep S. , Squire Iain , Cardoso José Silva , Merkely Bela , Martinez Felipe , Starling Randall C. , Desai Akshay S. , Lefkowitz Martin P. , Rizkala Adel R. , Rouleau Jean L. , Shi Victor C. , Solomon Scott D. , Swedberg Karl , Zile Michael R. , McMurray John J.V. , Packer Milton
Published: January 2016

Background—

The prevalence of pre–diabetes mellitus and its consequences in patients with heart failure and reduced ejection fraction are not known. We investigated these in the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial.

Methods and Results—

We examined clinical outcomes in 8399 patients with heart failure and reduced ejection fraction according to history of diabetes mellitus and glycemic status (baseline hemoglobin A1c [HbA1c]: <6.0% [<42 mmol/mol], 6.0%–6.4% [42–47 mmol/mol; pre–diabetes mellitus], and ≥6.5% [≥48 mmol/mol; diabetes mellitus]), in Cox regression models adjusted for known predictors of poor outcome. Patients with a history of diabetes mellitus (n=2907 [35%]) had a higher risk of the primary composite outcome of heart failure hospitalization or cardiovascular mortality compared with those without a history of diabetes mellitus: adjusted hazard ratio, 1.38; 95% confidence interval, 1.25 to 1.52;
P
<0.001. HbA1c measurement showed that an additional 1106 (13% of total) patients had undiagnosed diabetes mellitus and 2103 (25%) had pre–diabetes mellitus. The hazard ratio for patients with undiagnosed diabetes mellitus (HbA1c, >6.5%) and known diabetes mellitus compared with those with HbA1c<6.0% was 1.39 (1.17–1.64);
P
<0.001 and 1.64 (1.43–1.87);
P
<0.001, respectively. Patients with pre–diabetes mellitus were also at higher risk (hazard ratio, 1.27 [1.10–1.47];
P
<0.001) compared with those with HbA1c<6.0%. The benefit of LCZ696 (sacubitril/valsartan) compared with enalapril was consistent across the range of HbA1c in the trial.

Conclusions—

In patients with heart failure and reduced ejection fraction, dysglycemia is common and pre–diabetes mellitus is associated with a higher risk of adverse cardiovascular outcomes (compared with patients with no diabetes mellitus and HbA1c <6.0%). LCZ696 was beneficial compared with enalapril, irrespective of glycemic status.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01035255.
Sugar-Sweetened Beverage Consumption Is Associated With Change of Visceral Adipose Tissue Over 6 Years of Follow-Up
Authors: Ma Jiantao , McKeown Nicola M. , Hwang Shih-Jen , Hoffmann Udo , Jacques Paul F. , Fox Caroline S.
Published: January 2016

Background—

Sugar-sweetened beverage (SSB) intake has been linked to abnormal abdominal adipose tissue. We examined the prospective association of habitual SSB intake and change in visceral adipose tissue (VAT) and subcutaneous adipose tissue.

Methods and Results—

The quantity (volume, cm
3
) and quality (attenuation, Hounsfield Unit) of abdominal adipose tissue were measured using computed tomography in 1003 participants (mean age 45.3 years, 45.0% women) at examination 1 and 2 in the Framingham’s Third Generation cohort. The 2 exams were ≈6 years apart. At baseline, SSB and diet soda intake were assessed using a valid food frequency questionnaire. Participants were categorized into 4 groups: none to <1 serving/mo (nonconsumers), 1 serving/mo to <1 serving/week, 1 serving/week to 1 serving/d, and ≥1 serving/d (daily consumers) of either SSB or diet soda. After adjustment for multiple confounders including change in body weight, higher SSB intake was associated with greater change in VAT volume (
P
trend<0.001). VAT volume increased by 658 cm
3
(95% confidence interval [CI], 602 to 713), 649 cm
3
(95% CI, 582 to 716), 707 cm
3
(95% CI, 657 to 757), and 852 cm
3
(95% CI, 760 to 943) from nonconsumers to daily consumers. Higher SSB intake was also associated with greater decline of VAT attenuation (
P
trend=0.007); however, the association became nonsignificant after additional adjustment for VAT volume change. In contrast, diet soda consumption was not associated with change in abdominal adipose tissue.

Conclusions—

Regular SSB intake was associated with adverse change in both VAT quality and quantity, whereas we observed no such association for diet soda.
The International Criminal Court’s Authority Crisis and Kant’s Political Ethics
Authors: Franceschet Antonio
Published: January 2016

The International Criminal Court (icc) faces a profound authority crisis. This article explores the underlying conditions and ethical implications of this crisis in light of Immanuel Kant’s (1724–1804) political theory. The icc’s authority crisis is twofold: First, having been constructed as a purely legal actor, the Court’s inevitable role in politics has undermined perceptions of its legitimacy. Second, having been constructed as a supranational substitute for domestic legal authority, the icc has been subverted by other, political branches of the state, such as the executive. These problems have been particularly salient in Africa where states have vociferously challenged the Court’s investigations and prosecutions. Kantian political ethics show that the icc’s authority crisis is an intractable moral problem that must be addressed collectively and coercively by sovereign states acting upon a larger, cosmopolitan duty to enforce universal rights.
Ukraine’s 2014 Elections
Authors: Carpenter Jacqueline
Published: January 2016

In 2014 Ukraine conducted two national elections against a backdrop of political upheaval and a separatist conflict in which national minority concerns were voiced by some parties. In the context of the election process, reports by international observers did not reflect discrimination against national minorities as voters or candidates. However, a dearth of candidates campaigning as national minorities or including national minority issues in their platforms was observed, and can be traced to peculiarities of the legal framework that disadvantage smaller and compact political forces. It was observed that candidates of various national minority backgrounds may campaign and win elections, but few declare themselves to be representing the interest of a national minority. This was true for both the proportional and simple majority races during the parliamentary elections, in which only five candidates campaigning as national minority representatives were elected to parliament. Ultimately the main issue for national minorities in Ukraine’s political process is not one of discrimination, but the realistic opportunity for robust representation and advocacy of their communities’ concerns at the national level.
Boundaries and rights after 2014
Authors: Grant Thomas D.
Published: January 2016

The Final Act of the Conference on Security and Co-operation in Europe reflected in its Decalogue the centrality of the territorial settlement to public order in Europe. It also reflected the hope that human rights would become more deeply entrenched across all States Parties to the Act. The intertwining of territorial provisions and human rights was not mere coincidence; it was at the heart of the compromise which enabled the parties to agree to the text as eventually adopted. The events of 2014—in particular the forcible seizure of Ukrainian territory—raise questions as to the continuing vitality of the compromise that had been reached in 1975 and long maintained. The new foreign policy of the Russian Federation, embracing a potentially far-ranging irredentism, places the territorial idea of the Final Act under stress. Simultaneously, a new domestic policy rejects not only the enforceability of human rights at the international level but also the applicability of human rights obligations in the national legal order. The new foreign and domestic policies in Russia have emerged in tandem. Their relation to one another needs to be considered if their effect on public order is to be understood.
Lessons from the mh17 disaster
Authors: ter Haar Barend
Published: January 2016

The mh17 disaster makes clear that international peace and security cannot be taken for granted. The widespread support in Ukraine for democratization and rule of law presents Western democracies with a strategic opportunity. They should look beyond their short term interests and develop a long term view on their relations with Ukraine and Russia. They should invest more in international organizations and conflict prevention. Finally: the proliferation of long-range anti-aircraft missiles has to be prevented.
The 21st osce Ministerial Council Meeting in Basel
Authors: Liechtenstein Stephanie
Published: January 2016

This article analyses the outcome of the 21stosce Ministerial Council (mc) meeting, held in Basel, Switzerland, on 4 and 5 December 2014. The larger political context is taken into account, especially the crisis in and around Ukraine and the renewed confrontation between the West and Russia. The article provides an extensive analysis of all adopted decisions in the three security dimensions as well as of a number of draft documents that failed to reach consensus. The main documents that are analyzed include declarations on the Helsinki+40 process and on protracted conflicts, and decisions on countering kidnapping for ransom and terrorist foreign fighters, preventing corruption, improving disaster risk reduction, and on combating violence against women. The article concludes that the Swiss osce Chairmanship helped to reaffirm the osce’s role as the main forum for political dialogue between East and West.
Amanita rufobrunnescens, a new species of Amanita section Amidella from South China
Authors: Deng Wangqiu , Li Taihui , HOSEN MD. IQBAL
Published: January 2016

Amanita rufobrunnescens is described as a new species in the subgenus Lepidella section Amidella from Guangdong Province, China. It is characterized by whitish basidiomes that bruise reddish brown, brownish sub-membranous to fibrillose volval remnants on the pileus, a striate pileus margin, white lamellae with truncate lamellulae, grayish orange to light brown volva, amyloid basidiospores that are ellipsoid to elongate (9.5–)10–12(–13) × (5–)5.5–6.5(–7) µm, and 5–10 μm wide pileipellis hyphae with yellowish vacuolar pigments. There are no clamp connections. Molecular phylogenetic analyses based on the nuclear ribosomal large subunit of nuclear ribosomal DNA (LSU) and internal transcribed spacer (ITS) sequences reveal that A. rufobrunnescens is a distinct species.
Four they are! Broadening the description of Mimosa flabellifolia (Leguminosae Mimosoideae), a rare species from the Brazilian Cerrado

Authors: Borges Leonardo Maurici , Antar Guilherme Medeiros
Published: January 2016

During a recent floristic survey in the Jalapão region, located in the state of Tocatins, Brazil, the second collection of Mimosa flabellifolia, a species known only from the type material, was made. Since the type collection presents only fruits, we herein broaden the description of the species to include floral features. Knowledge about flower morphology, in particular the number of organs, confirms the placement of M. flabellifolia in the tetramerous M. ser. Paucifoliatae. Illustrations, notes and a discussion on issues related to Mimosa taxonomy and conservation in the Jalapão region are presented.
A new species of Senecio (Compositae, Senecioneae) from Ecuador
Authors: Calvo Joel , Freire Efraín , Sklenář Petr
Published: January 2016

Senecio alatopetiolatus is described as a new species from the Ecuadorian Andes on the basis of morphological characters. It is a subshrub characterized by having a scandent habit, discoid nodding capitula, middle cauline leaves with winged petioles, and an indumentum composed of glandular-hirsute and sericeous trichomes.
Derivation of the Green Vegetation Fraction of the Whole China from 2000 to 2010 from MODIS Data
Authors: Li Xiaosong , Zhang Jin
Published: January 2016

The green vegetation fraction Fg, which represents the horizontal density of live vegetation, is an important parameter for the study of global energy, carbon, hydrological, and biogeochemical cycling. A common method of calculating Fg is to create a simple linear mixing model between two NDVI endmembers: bare soil NDVI, , and full vegetation NDVI, . However, many uncertainties exist for the determination of these parameters at large scales. The present study investigates how and determination can impact Fg calculations for all of China, based on different land-cover datasets, hyperspectral data, and soil type classification maps. The results show the following: 1) The regional ChinaCover dataset, with higher accuracy and more detailed classification, is preferable for calculating Fg in China, compared with the most commonly used MOD12Q1 dataset, although it would not lead to too much difference in values. 2) The soil NDVI from Hyperion datasets shows that soils have highly variable NDVI values (0.006–0.2), and 79.36% of the area studied has a much larger NDVI value than the commonly used value of 0.05. Therefore, the dynamic values with different soil types are much better for Fg calculation than the invariant value (0.05), which would yield a significant overestimation of Fg, especially for areas with low vegetation coverage. 3) A high-quality Fg dataset for China from 2000 to 2010 was established with and parameters based on MOD13Q1 250-m NDVI data.