bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise and Caloric Restriction Alter the Immune System of Mice Submitted to a High-Fat Diet
Authors: Wasinski Frederick , Bacurau Reury F. P. , Moraes Milton R. , Haro Anderson S. , Moraes-Vieira Pedro M. M. , Estrela Gabriel R. , Paredes-Gamero Edgar J. , Barros Carlos C. , Almeida Sandro S. , Câmara Niels O. S. , Araujo Ronaldo C.
Published: March 2013

As the size of adipocytes increases during obesity, the establishment of resident immune cells in adipose tissue becomes an important source of proinflammatory mediators. Exercise and caloric restriction are two important, nonpharmacological tools against body mass increase. To date, their effects on the immune cells of adipose tissue in obese organisms, specifically when a high-fat diet is consumed, have been poorly investigated. Thus, after consuming a high-fat diet, mice were submitted to chronic swimming training or a 30% caloric restriction in order to investigate the effects of both interventions on resident immune cells in adipose tissue. These strategies were able to reduce body mass and resulted in changes in the number of resident immune cells in the adipose tissue and levels of cytokines/chemokines in serum. While exercise increased the number of NK cells in adipose tissue and serum levels of IL-6 and RANTES, caloric restriction increased the CD4+/CD8+ cell ratio and MCP-1 levels. Together, these data demonstrated that exercise and caloric restriction modulate resident immune cells in adipose tissues differently in spite of an equivalent body weight reduction. Additionally, the results also reinforce the idea that a combination of both strategies is better than either individually for combating obesity.
Uncertainty Analysis of Light Water Reactor Fuel Lattices
Authors: Arenas C. , Bratton R. , Reventos F. , Ivanov K.
Published: March 2013

The study explored the calculation of uncertainty based on available cross-section covariance data and computational tool on fuel lattice levels, which included pin cell and the fuel assembly models. Uncertainty variations due to temperatures changes and different fuel compositions are the main focus of this analysis. Selected assemblies and unit pin cells were analyzed according to the OECD LWR UAM benchmark specifications. Criticality and uncertainty analysis were performed using TSUNAMI-2D sequence in SCALE 6.1. It was found that uncertainties increase with increasing temperature, whilekinfdecreases. This increase in the uncertainty is due to the increase in sensitivity of the largest contributing reaction of uncertainty, namely, the neutron capture reaction238U(n,γ) due to the Doppler broadening. In addition, three types (UOX, MOX, and UOX-Gd2O3) of fuel material compositions were analyzed. A remarkable increase in uncertainty inkinfwas observed for the case of MOX fuel. The increase in uncertainty ofkinfin MOX fuel was nearly twice the corresponding value in UOX fuel. The neutron-nuclide reaction of238U, mainly inelastic scattering (n,n′), contributed the most to the uncertainties in the MOX fuel, shifting the neutron spectrum to higher energy compared to the UOX fuel.
Morphological, Structural, and Electrical Characterization of Sol‐Gel‐Synthesized ZnO Nanorods
Authors: Kashif M. , Hashim U. , Ali M. E. , Foo K. L. , Usman Ali Syed M.
Published: March 2013

ZnO nanorods were grown on thermally oxidized p‐type silicon substrate using sol‐gel method. The SEM image revealed high‐density, well‐aligned, and perpendicular ZnO nanorods on the oxidized silicon substrate. The XRD profile confirmed the c‐axis orientation of the nanorods. PL measurements showed the synthesized ZnO nanorods have strong ultraviolet (UV) emission. The electrical characterization was performed using interdigitated silver electrodes to investigate the stability in the current flow of the fabricated device under different ultraviolet (UV) exposure times. It was notified that a stable current flow was observed after 60 min of UV exposure. The determination of stable current flow after UV exposure is necessary for UV‐based gas sensing and optoelectronic devices.
Splenium of Corpus Callosum: Patterns of Interhemispheric Interaction in Children and Adults
Authors: Knyazeva Maria G.
Published: March 2013

The splenium of the corpus callosum connects the posterior cortices with fibers varying in size from thin late-myelinating axons in the anterior part, predominantly connecting parietal and temporal areas, to thick early-myelinating fibers in the posterior part, linking primary and secondary visual areas. In the adult human brain, the function of the splenium in a given area is defined by the specialization of the area and implemented via excitation and/or suppression of the contralateral homotopic and heterotopic areas at the same or different level of visual hierarchy. These mechanisms are facilitated by interhemispheric synchronization of oscillatory activity, also supported by the splenium. In postnatal ontogenesis, structural MRI reveals a protracted formation of the splenium during the first two decades of human life. In doing so, the slow myelination of the splenium correlates with the formation of interhemispheric excitatory influences in the extrastriate areas and the EEG synchronization, while the gradual increase of inhibitory effects in the striate cortex is linked to the local inhibitory circuitry. Reshaping interactions between interhemispherically distributed networks under various perceptual contexts allows sparsification of responses to superfluous information from the visual environment, leading to a reduction of metabolic and structural redundancy in a child's brain.
Effects of Titanium Oxide Nanotube Arrays with Different Lengths on the Characteristics of Dye-Sensitized Solar Cells
Authors: Kuo Chin-Guo , Yang Cheng-Fu , Hwang Lih-Ren , Huang Jia-Sheng
Published: March 2013

The self-aligned highly ordered TiO2nanotube (TNT) arrays were fabricated by potentiostatic anodization of Ti foil, and we found that the TNT-array length and diameter were dependent on the electrolyte (NH4F) concentration in ethylene glycol and anodization time. The characteristics of the fabricated TNT arrays were characterized by XRD pattern, FESEM, and absorption spectrum. As the electrolyte NH4F concentration in the presence of H2O (2 vol%) with anodization was changed from 0.25 to 0.75 wt% and the anodization period was increased from 1 to 5 h, the TNT-array length was changed from 9.55 to 30.2 μm and the TNT-array diameter also increased. As NH4F concentration was 0.5 wt%, the prepared TNT arrays were also used to fabricate the dye-sensitized solar cells (DSSCs). We would show that the measured photovoltaic performance of the DSSCs was dependent on the TNT-array length.
A Multilevel Inverter Bridge Control Structure with Energy Storage Using Model Predictive Control for Flat Systems
Authors: Mercorelli Paolo
Published: March 2013

The paper presents a novel technique to control the current of an electromagnetic linear actuator fed by a multilevel IGBT voltage inverter with dynamic energy storage. The technique uses a “cascade model predictive control (MPC),” which consists of two MPCs. A predictive control of the trajectory position predicts the optimal current, which is considered to be the desired current for the second MPC controller in which a hysteresis control technique is also integrated. Energy is stored in a capacitor using energy recovery. The current MPC can handle a capacitor voltage higher than the source voltage to guarantee high dynamic current and disturbance compensation. The main contribution of this paper is the design of an optimal control structure that guarantees a capacitor recharge. In this context, the approach is quite new and can represent a general emerging approach allowing to reduce the complexity of the new generation of inverters and, in the meantime, to guarantee precision and acceptable switching frequency. The proposed technique shows very promising results through simulations with real actuator data in an innovative transportation technology.
Effect of Kramecyne on the Inflammatory Response in Lipopolysaccharide-Stimulated Peritoneal Macrophages
Authors: Sánchez-Miranda E. , Lemus-Bautista J. , Pérez S. , Pérez-Ramos J.
Published: March 2013

Kramecyne is a new peroxide, it was isolated fromKrameria cytisoides, methanol extract, and this plant was mostly found in North and South America. This compound showed potent anti-inflammatory activity; however, the mechanisms by which this compound exerts its anti-inflammatory effect are not well understood. In this study, we examined the effects of kramecyne on inflammatory responses in mouse lipopolysaccharide- (LPS-) induced peritoneal macrophages. Our findings indicate that kramecyne inhibits LPS-induced production of tumor necrosis factor (TNF-α) and interleukin- (IL-) 6. During the inflammatory process, levels of cyclooxygenase- (COX-) 2, nitric oxide synthase (iNOS), and nitric oxide (NO) increased in mouse peritoneal macrophages; however, kramecyne suppressed them significantly. These results provide novel insights into the anti-inflammatory actions and support its potential use in the treatment of inflammatory diseases.
Operating Protocol and Networking Issues of a Telemedicine Platform Integrating from Wireless Home Sensors to the Hospital Information System
Authors: Donati Massimiliano , Bacchillone Tony , Fanucci Luca , Saponara Sergio , Costalli Filippo
Published: March 2013

Chronic heart failure (CHF) is among the major causes of hospitalization for elderly citizens. Its considerable impact on patient quality of life, the resources congestion, and the related costs can be efficiently mitigated using remote wireless biosensors networks placed at patient home, able to communicate in secure way over the public Internet with the cardiology departmental Hospital Information System (HIS). In this way, physicians can monitor the situation of several patients at distance and quickly realize and act alterations in vital parameters. In this scenario, the Health@Home (H@H) platform is conceived. The pool of Bluetooth sensors enables patients to daily collect vital signs at home in noninvasive fashion. A home gateway receives and processes all signals before sending them to a server node in charge of interfacing with the usual HIS. The novel concept of operating protocol (OP) represents a list of actions, remotely configurable, that the domestic network has to follow (required measurements, transmissions, comparisons with personalized thresholds, etc.). The first medical tests on 30 patients (1 month) allowed to verify the model, both from the patient and the medical perspective. The main evaluation metrics were usability, flexibility, and reliability of the communication from sensors to HIS.
A Stackelberg-Game-Based Power Control Algorithm for Wireless Mesh Networks
Authors: Liu Yanbing , Wu Tao , Huang Jun , Jia Shousheng
Published: March 2013

Wireless mesh networks (WMNs) are a promising networking paradigm for next generation wireless networking system. Power control plays a vital role in WMNs and is realized to be a crucial step toward large-scale WMNs deployment. In this paper, we address the problem of how to allocate the power for both optimizing quality of service (QoS) and saving the power consumption in WMNs based on the game theory. We first formulate the problem as a noncooperative game, in which the QoS attributes and the power of each node are defined as a utility function, and all the nodes attempt to maximize their own utility. In such game, we correlate all the interfering nodes to be an interfering object and the receiving node to be the interfering object's virtual destination node. We then present an equilibrium solution for the noncooperative game using Stackelberg model, and we propose an iterative, distributed power control algorithm for WMNs. Also, we conduct numeric experiments to evaluate the system performance, our results show that the proposed algorithm can balance nodes to share the limited network resources and maximize total utility, and thus it is efficient and effective for solving the power control problem in WMNs.
An Improved Secure Image Encryption Algorithm Based on Rubik's Cube Principle and Digital Chaotic Cipher
Authors: Diaconu Adrian-Viorel , Loukhaoukha Khaled
Published: March 2013

A recently proposed secure image encryption scheme has drawn attention to the limited security offered by chaos-based image encryption schemes (mainly due to their relatively small key space) proposing a highly robust approach, based on Rubik's cube principle. This paper aims to study a newly designed image cryptosystem that uses the Rubik's cube principle in conjunction with a digital chaotic cipher. Thus, the original image is shuffled on Rubik's cube principle (due to its proven confusion properties), and then XOR operator is applied to rows and columns of the scrambled image using a chaos-based cipher (due to its proven diffusion properties). Finally, the experimental results and security analysis show that the newly proposed image encryption scheme not only can achieve good encryption and perfect hiding ability but also can resist any cryptanalytic attacks (e.g., exhaustive attack, differential attack, statistical attack, etc.).
Some Sufficient Conditions for Starlikeness and Convexity of Order
Authors: Cang Yi-Ling , Liu Jin-Lin
Published: March 2013

We derive certain sufficient conditions for starlikeness and convexity of order of analytic functions in the unit disk. Applications are indicated for the subordination results to electromagnetic cloaking.
Material Demands for Storage Technologies in a Hydrogen Economy
Authors: Kunowsky M. , Marco-Lózar J. P. , Linares-Solano A.
Published: March 2013

A hydrogen economy is needed, in order to resolve current environmental and energy-related problems. For the introduction of hydrogen as an important energy vector, sophisticated materials are required. This paper provides a brief overview of the subject, with a focus on hydrogen storage technologies for mobile applications. The unique properties of hydrogen are addressed, from which its advantages and challenges can be derived. Different hydrogen storage technologies are described and evaluated, including compression, liquefaction, and metal hydrides, as well as porous materials. This latter class of materials is outlined in more detail, explaining the physisorption interaction which leads to the adsorption of hydrogen molecules and discussing the material characteristics which are required for hydrogen storage application. Finally, a short survey of different porous materials is given which are currently investigated for hydrogen storage, including zeolites, metal organic frameworks (MOFs), covalent organic frameworks (COFs), porous polymers, aerogels, boron nitride materials, and activated carbon materials.
Differential Cytotoxicity Responses by Dog and Rat Hepatocytes to Phospholipogenic Treatments
Authors: Morelli James K. , Ciaccio Paul J.
Published: March 2013

Dog and rat hepatocytes were treated with phospholipogenics to identify the more sensitive species and to determine whether lysosomal or mitochondrial changes were the primary cause of cytotoxicity. Endpoints included cell death, lysosome membrane integrity, mitochondrial membrane polarization, and fluorescent phospholipid (NBD-PE). Dog cells exhibited lower survival IC50values than did rat cells with all phospholipogenic treatments and exhibited a lower capacity to accumulate NBD-PE in 4 of 5 phospholipogenic test conditions. The lysosomal modulator Bafilomycin A1 (Baf) rescued dog cells from cytotoxicity caused by 3 phospholipogenic 5HT1bantagonists and hydroxychloroquine, but not fluoxetine, and rescued rat cells from hydroxychloroquine and NMTMB, a 5HT1bantagonist. Following NMTMB treatment, rat mitochondrial membrane hyperpolarization was observed at modestly cytotoxic concentrations and depolarization at the highest concentration. At the highest test concentration, lysosomal loss of acridine orange occurred by 30 min, mitochondrial polarity changes by 1 hr, and NBD-PE accumulation by 2 hr, respectively. Baf shifted mitochondrial polarity from a depolarized state to a hyperpolarized state. These data demonstrate that (a) dog hepatocytes were generally less capable of mounting an adaptive, protective phospholipidotic response than rat hepatocytes, (b) effects on mitochondria and survival were preventable by lysosomal protection, and (c) destabilizing changes in both organelles are involved causally in cytotoxicity.
Abstract A1: MicroRNAs expression profile associated with radioresistance in lung cancer
Authors: Arechaga-Ocampo Elena , Noriega-Reyes Yamilet , Lopez-Camarillo Cesar , Lopez-Moreno Perla , Perez-Plasencia Carlos , Angeles-Zaragoza Oscar , Herrera Luis A.
Published: March 2013

Lung cancer is the neoplasia with highest incidence and mortality worldwide. One of the strategies of treatment for this tumor type is based on ionizing radiation. Radiation induces cytotoxicity through some mechanisms, including gene expression changes. Recently, microRNAs (miRNAs) have been described as one of the molecules that regulate expression genes and may contributes to radioresistance in several tumor types. Global miRNAs expression profiles of radiosensitive and radioresistant lung tumor cells may elucidate the molecular mechanism related to tumoral radioresistance. In order to identify miRNAs associated with innate and acquired radioresistance, we will evaluate the miRNAs expression profiles in two lung carcinoma cell lines and in the same cell lines with acquire radioresistance by fractionated doses radiation treatment. For establish the median lethal dose radiation, H1944 and Calu-1 lung carcinoma cell lines were treated with increasing doses of X-rays (from 2 to 12 Gy). Cell survival, proliferative ability and clonogenic potential postradiation were evaluated. Moreover, we will generate a model of acquired radioresistance by treating lung tumor cells with fractionated doses of 2 Gy X-rays up to total dose of 60 Gy for to evaluate the expression of miRNAs in cells with acquired radioresistance. Results showed differential sensitivity to radiotherapy from lung tumors cells, whit 8 Gy as median lethal dose radiation. For to evaluate the expression of miRNAs during innate response to radiotherapy, total RNA was obtained from tumor cells treated with 8 Gy of X-rays. Additionally, it has been obtained lung tumor cells clones with treatment total doses of 28 Gy in a fractionated radiation scheme. These results will allow compare miRNAs expression during immediate cell response to radiation and those whose expression will modified during fractionated radiation treatment and may be associated with radioresistance acquired, which contribute to understanding the molecular mechanism to radioresistance in lung cancer.
Abstract A10: Prognostic significance of CXCL10/CXCR3 overexpression in mucinous bronchioloalveolar carcinoma
Authors: Duruisseaux Michael , Antoine Martine , Rabbe Nathalie , Poulot Virginie , Leprieur Etienne Giroux , Lavolé Armelle , Cadranel Jacques , Wislez Marie
Published: March 2013

Introduction: The 2004 WHO Pathological classification distinguishes two cytological subtypes of bronchioloalveolar carcinoma (BAC): mucinous (M) and non-mucinous (NM). This distinction appears to be relevant in terms of clinical characteristics, prognostic and treatment effectiveness. We attempted to better characterize the molecular profile of M relative to NM.

Experimental procedures: Bronchoalveolar lavage fluid (BALF) supernatants from M-BACs (n = 23) and NM-BACs (n = 11) were analyzed for 30 cytokines (IL-1β, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, FGF, PDGF, HGF, VEGF, Eotaxin, G-CSF, GM-CSF, IFNγ, CXCL-1, CXCL-8, CXCL-10, MCP-1, MIP-1α, MIP-1β, TNF-α, RANTES, VCAM-1) by Bio-Plex multiplex bead-based assay (BIORAD, Marne la Coquette, France). Cytokines of interest expression was studied on paraffin embedded specimens from surgical specimens (n = 45) using immunochemistry. EGFR and K-ras mutation analysis using direct PCR and Alk overexpression detection using immunochemistry were also performed. Univariate and multivariate analysis by Cox model was undertaken to identify the variables associated with a risk for shortened survival.

Summary of results: Among the 30 chemokines analyzed, CXCL10 was the only one for which concentration was significantly higher in BALF supernatants from M-BAC (n = 23) compared to NM-BAC (n = 11) and control (n = 4) (p = 0.041). The cellular source of CXCL10 was not yet identified while CXCR3, its receptor, was expressed by tumor cells. CXCR3 was more frequently and more intensively expressed in M-BAC (n = 21) than in NM-BAC (n = 24) (52% vs 17%, p=0.023 and 52±16 vs 12±6, p = 0.047, respectively). EGFR mutation was never found in M-BAC (0%, 0/21) while present in 21% (5/24) of NM-BAC (p = 0.026). K-ras mutation and Alk overexpression did not differ between the two subtypes (2/21 vs 1/24, p > 0,05 and 3/21 vs 2/24, p > 0,05, respectively). The expression of CXCR3 was not associated with EGFR or K-ras mutation or Alk overexpression. In univariate analysis, factors associated with shorter survival were CXCL10 BALF concentration (HR=2.615, 95% CI: 1.102–6.206), PS > 0 (HR=1.308, 95% CI: 1.131–1.726) and bilateral extension (HR=2.914, 95% CI: 1.208–7.031). Multivariate analysis did not show any independent prognostic factor.

Conclusions: Our results show a CXCL10/CXCR3 overexpression in M-BAC compared to NM-BAC and suggest an association between CXCL10 overexpression and shorter survival.
Abstract A14: Small Tumor Diameter at Cure Threshold (< 20mm) Among Aggressive Lung Cancers Predicts both Chest X-ray and CT Screening Outcomes in a Novel Simulation Framework
Authors: Goldwasser Deborah Lynn , Kimmel Marek
Published: March 2013

Background: The population distribution of lung cancer growth and tumor diameter at cure threshold is an important component of a model of the natural course of lung cancer.

Methods: We simulate outcomes in the Mayo CT lung screening study using an existing simulation model of lung cancer progression calibrated to the Mayo Lung Project (males only) and evaluate the goodness of fit. We perform a likelihood-based analysis to determine whether the conditional probability of five-year lung cancer survival given tumor diameter at detection depends significantly on detection modality. A novel probabilistic model characterizes growth and tumor progression after transformation of a single malignant cell, governed by two parameters f and μ, the branching fraction and cellular mutation rate, respectively. We identify distinct sets of parameter pairs (f,μ), each of which satisfies a method of moments condition given a survival function governing detection in the absence of screening. We examine their goodness of fit with respect to simulated tumor size and five-year lung cancer survival among detected incident lung cancers in the MLP and Mayo CT studies.

Results: An existing model of lung cancer progression under-predicts the number of advanced-stage incident lung cancers among males in the Mayo CT study (p-value = 0.004). The probability of five-year lung cancer survival given size at detection depends significantly on detection modality (p-value = 0.0312). Selected models having a median tumor diameter at cure threshold ranging from 16.7–27.0 mm predict both MLP and Mayo CT outcomes.

Conclusions: The median lung tumor diameter at cure threshold among aggressive lung cancers may be small (< 20 mm).
Abstract A16: Aberrant signaling pathways in squamous cell lung carcinoma
Authors: Sadraei Nooshin Hashemi , Shi Ivy , Duan Zhong-Hui , Shi Ting
Published: March 2013

Lung cancer is the second most commonly occurring non-cutaneous cancer in the United States with the highest mortality rate among both men and women. In this study, we utilized three lung cancer microarray datasets generated by previous researchers to identify differentially expressed genes, altered signaling pathways, and assess the involvement of Hedgehog (Hh) pathway. The three datasets contain the expression levels of tens of thousands genes in normal lung tissues and squamous cell lung carcinoma. The datasets were combined and analyzed. The dysregulated genes and altered signaling pathways were identified using statistical methods. We then performed Fisher's exact test on the significance of the association of Hh pathway downstream genes and squamous cell lung carcinoma. 395 genes were found commonly differentially expressed in squamous cell lung carcinoma. The genes encoding fibrous structural protein keratins and cell cycle dependent genes encoding cyclin-dependent kinases were significantly up-regulated while the ones encoding LIM domains were down. Over 100 signaling pathways were implicated in squamous cell lung carcinoma, including cell cycle regulation pathway, p53 tumor-suppressor pathway, IL-8 signaling, Wnt-β-catenin pathway, mTOR signaling and EGF signaling. In addition, 37 out of 223 downstream molecules of Hh pathway were altered. The pvalue from the Fisher's exact test indicates that Hh signaling is implicated in squamous cell lung carcinoma. Numerous genes were altered and multiple pathways were dysfunctional in squamous cell lung carcinoma. Many of the altered genes have been implicated in different types of carcinoma while some are organ-specific. Hh signaling is implicated in squamous cell lung cancer, opening the door for exploring new cancer therapeutic treatment using GLI antagonist GANT 61.
Abstract A2: Cells of origin of the different subtypes of lung cancer
Authors: Filby Caitlin , Viitaniemi Kati , McQualter Jonathan , Antippa Philip , Irving Lou , Bertoncello Ivan , Asselin-Labat Marie-Liesse
Published: March 2013

Lung cancer is the leading cause of cancer death worldwide. Five-year lung cancer survival is only 15% and lung cancer is responsible for more deaths than prostate, colon, pancreas, and breast cancers combined.

Understanding the cellular and molecular mechanism at the origin of lung cancer will generate great insights for better management of the disease. However, the lack of cell surface markers to identify and isolate early progenitor or stem cells in the normal lung represents a gap of knowledge that needs to be filled to identify cells of origin of lung cancers. By macroscopic isolation of different morphological region of the human lung and staining with cell surface markers, we have isolated distinct cell subpopulations by flow cytometry. Interestingly, these markers are expressed in some types of lung cancers but not others. We are characterizing the different subpopulations by immunostaining of cytospun cells and evaluating their in vitro colony formation capacity. In order to address potential cells of origin for the different lung tumor subtypes, gene signatures of the different normal epithelial subpopulations will be compared to the gene expression profiles of lung carcinomas available from public database.

These cell surface markers may be critical tools to identify stem/progenitor cells in the normal lung that could be the cell of origin of one type of lung cancer and not others.
Abstract A46: Identification of ALDH1A3 as an important biomarker and therapeutic target for non-small cell lung cancer (NSCLC) cancer stem cells (CSCs)
Authors: Shao Chunli , Sullivan James P. , Girard Luc , Sullivan Laura A. , Augustyn Alexander , Xie Yang , Behrens Carmen , Wistuba Ignacio , Minna John D.
Published: March 2013

A considerable amount of evidence reveals the important roles of cancer stem cells (CSCs, also called “cancer initiating cells”) in tumor growth, metastasis, relapse and drug resistance. Our group has identified lung CSCs in both lung cancer cell lines and patient tumor samples by their elevated Aldehyde Dehydrogenase (ALDH) activity and demonstrated that NSCLC patients whose tumors are enriched in ALDH+ cells have inferior survival, and that the ALDH+ subpopulations (ranging from 0.5 to 30% of tumor cells) are self renewing, and significnatly more clonogenic and tumorigencic (in xenograft models) than the ALDH− population. To further define the molecular profile of lung CSCs and to identify key pathways involved in lung CSC function we performed genome wide microarray expression profiling of isolated ALDH+ and ALDH− cell populations from 8 non-small cell lung cancer (NSCLC) lines representing a variety of oncogenotypes to determine genes that are differentially expressed in these two populations. Strikingly we found that different lung cancers exhibited different ALDH+ cell population expression profiles but that the ALDH1A3 isozyme was one of the few commonly genes whose expression was elevated. (Previously our group and other investigators in lung and other cancers had found the ALDH1A1 and not ALDH1A3 isozyme to be a marker of the ALDH+ population). ALDH1A3 differential expression was confirmed by q RT PCR and elevated ALDH1A3 protein levels which in turn was correlated with the % of ALDH+ tumor cells in each tumor. ALDH1A3 mRNA levels in (N = 182) resected lung adenocarcinoma samples showe that the highest levels of ALDH1A3 were associated with inferior survival. Of great importance, shRNA mediated knockdown of ALDH1A3 dramatically reduced both NSCLC cell colony formation in vitro and tumor growth in vivo demonstrating the functional importance of ALDH1A3 expression in NSCLCs. However, ectopic expression of ALDH1A3 in NSCLC cells did not enhance lung cancer cell growth and tumor formation, suggesting that ALDH1A3 alone is not sufficient to promote lung cancer progression. We conclude that ALDH1A3 is the predominant ALDH isozyme responsible for ALDH activity in NSCLCs of many oncogenotypes, is of potential prognostic importance, and a new therapeutic target for eliminating NSCLC stem cells.
Abstract A8: Mutation mapping in non-small cell lung cancer: A meta-analysis by geography and histology (MutMap)
Authors: Dearden Simon P. , Stevens James , Wu Yi-Long , Blowers David
Published: March 2013

This study comprises a meta-analysis of publicly available and newly generated mutation data in non-small cell lung cancer patients to identify differences between histological subtypes and geographical populations. In addition to mutations in individual genes, comparisons are also made between mutation co-occurrences in these subgroups. These patterns of mutation co-occurrence have been termed The MutMap.

Publications reporting mutation data on two or more genes, in histologically and geographically defined populations were identified. Assessments of single gene mutation frequencies and 2-gene mutation co-occurrences were performed in Western and Eastern populations. These were further separated into adenocarcinoma and squamous cell carcinoma histologies.

In total, 21 studies were identified which matched the criteria above. In addition, data were generated at AstraZeneca and the Guangdong Lung Cancer Institute for inclusion in the meta-analysis. Mutation data were collated for 8 genes (EGFR, KRAS, TP53, LKB1, BRAF, PIK3CA, PTEN and ERBB2) in the 4 subgroups. Overall, mutations were more commonly reported in adenocarcinoma cases than squamous cell carcinoma cases. The most commonly mutated gene in NSCLC was TP53, however, mutation frequencies varied between Eastern and Western populations and between adenocarcinoma and squamous cell carcinoma cases. Mutations in EGFR were common (46.3%) in Eastern adenocarcinoma patients but rarer in Western cases (14.8%). Conversely KRAS mutations were more common in Western adenocarcinoma patients (25.7%) than Eastern cases (11.2%). Mutations in LKB1 were also more common in Western patients. Mutations in BRAF, PIK3CA and ERBB2 were rare in all NSCLC subgroups. Mutations in PTEN were common in Eastern squamous samples (9.8%) but rarer in the other 3 subtypes.

Co-occurrences between mutations in 2 genes were also examined. As reported in other studies, mutations in EGFR and KRAS were exclusive to each other. In addition, in Western adenocarcinoma patients, mutations in both EGFR and LKB1 occurred significantly less often than would be expected by chance. There were several 2-gene mutation co-occurrences which were detected at levels >=5% of the NSCLC population, including TP53 with either KRAS or EGFR in adenocarcinoma and TP53 with LKB1 mutation in squamous cell carcinoma.

Overall, this study confirms and expands the observation that mutation prevalence in NSCLC is complex, with variation not only between histological subtypes, but also between geographical populations. The co-occurrence of mutations may also be important in future treatment paradigms as clinically relevant segments of NSCLC possess both activating oncogenic driver mutations and mutations in tumour suppressor genes.
Abstract B42: The lineage-specific transcription factor ASCL1 defines a subtype of neuroendocrine non-small cell lung cancers with poor prognosis and points to potential therapeutic targets
Authors: Augustyn Alexander , Minna John , Tan Christopher , Sullivan James , Borromeo Mark , Girard Luc , Johnson Jane , Behrens Carmen , Wistuba Ignacio , Xie Yang
Published: March 2013

The future of cancer therapy relies on identifying certain patient populations that will respond to one treatment but not another based on the properties of the tumor and additionally creating specific drugs that target genetic pathways required for a particular tumor's formation, growth, and maintenance. We have developed a pre-clinical model for a genetically identifiable clade of non-small cell lung cancer that exhibits neuroendocrine features. We utilized whole-genome mRNA expression array data from 119 NSCLC cell lines to identify a class of NSCLC lines that fit the neuroendocrine phenotype (NE-NSCLC). We identified 11 NSCLC cell lines (9.2%) that display a distinct neuroendocrine gene signature. A gene expressed in all putative NE-NSCLC cell lines is the potent neural-specific transcription factor ASCL1. We hypothesize that ASCL1 acts as a “lineage dependent oncogene” for NE-NSCLC and that associated with ASCL1's function in the molecular pathogenesis of these lung cancers will be a gene expression profile that contributes to the malignant phenotype, which will provide insight towards therapeutic targeting of this subset of NSCLC. In this regard, ASCL1 ChIP-Seq data combined with genome wide mRNA expression data identified a subset of genes whose expression appears to be regulated by ASCL1. In NSCLC patient populations, tumors expressing ASCL1 and the neuroendocrine gene signature demonstrated impaired prognosis compared to the other NSCLCs. Knockdown of ASCL1 in representative NSCLC cell lines reduced target gene expression, caused significant cell cycle defects, and induced marked apoptosis. NSCLC cell lines expressing ASCL1 demonstrate a cancer stem cell marker phenotype similar to that of small cell lung cancer, providing clues to the pathogenesis of the NE-NSCLC disease subset. Our results suggest that neuroendocrine gene expression in NSCLC is of clinical relevance, that ASCL1 is required for survival of the NE-NSCLC disease subset, while the integrated ASCL1 ChIP-Seq and mRNA expression data provide a roadmap for systematically searching for therapeutic targets for this phenotype and their mechanistic role in a cancer stem cell (initiating cell) subpopulation within these tumors.
Abstract IA1: microRNAs and lung cancer
Authors: Slack Frank J.
Published: March 2013

microRNAs are small noncoding RNAs that regulate gene expression to control important aspects of development and metabolism such as cell differentiation, apoptosis and lifespan. let-7 encodes a microRNA implicated in human cancer. Specifically, human let-7 is poorly expressed or deleted in lung cancer, and over-expression of let-7 in lung cancer cells inhibits their growth, demonstrating a role for let-7 as a tumor suppressor in lung tissue. let-7 is expressed in the developing mammalian lung and regulates the expression of important oncogenes implicated in lung cancer, suggesting a mechanism for let-7's involvement in cancer. We are focused on the role of let-7 and other oncomiRs in regulating proto-oncogene expression during development and cancer, and on using miRNAs to suppress tumorigenesis.
Abstract IA14: Cetuximab in NSCLC and predictive markers
Authors: Hirsch Fred R.
Published: March 2013

The role of the EGFR humanized monoclonal antibody cetuximab (Erbitux®, Bristol-Myers Squibb) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) has until recently been controversial. While it is clear that the EGFR pathway plays an important role in NSCLC development and progression, the clinical data with cetuximab in NSCLC has not been consistent from the different studies including the two large phase III studies (BMS -099 and FLEX), despite the overall survival in the FLEX study was statistically significant in favor the combination of chemotherapy plus cetuximab (HR 0.87 [0.76–1.0]) (1, 2). The FLEX study comparing gemcitabine/cisplatin with and without cetuximab required EGFR positive tumor (IHC > 1% positive cells) as inclusion criteria, while the non-significant results from BMS -099 was based on “all comers”. However, most recently a more detailed analysis of the EGFR protein expression in the FLEX study, by using the H-score (intensity:0–3 x percentage of cells within each intensity category:0–100% for a final H-score of 0–300) was presented (3). Patients having tumors with EGFR H-score≥ 200 (about 30% of the patients) had a significant better survival from chemotherapy plus cetuximab compared to cetuximab alone (HR=0.73 [0.58–0.93]), and even better for the largest subgroup of patients; the Caucasians with H-score ≥ 200 (HR=0.64 [0.49–0.83]) with a 3.5 months difference in median survival (11.4 months vs. 7.9 months HR= 0.49 [0.29–0.81]). Patients with high EGFR expression and adenocarcinoma had a median survival of 20.2 months on the combined therapy versus 8.0 months for chemotherapy alone (3). A reproducibility study of the H-score classification showed a high concordance (91%) among 10 pathologists after specific assessment training (4). A previous reported randomized phase II study comparing chemotherapy with concomitant cetuximab versus sequential cetuximab from SWOG (0342) demonstrated a doubling of PFS and OS in the EGFR FISH positive patients compared to the FISH negative patients (5), while he EGFR FISH assay did not show a significant impact on outcomes in the large randomized BMS -099 study or the FLEX study.

Thus, very encouraging biomarker results are achieved retrospectively for selection of patients to chemotherapy plus cetuximab therapy, and these biomarkers are currently being prospectively validated in the large prospective randomized phase III study SWOG 0819, which compare chemotherapy (+/− bevacizumab) with and without cetuximab.
Abstract IA20: Targeted lung cancer chemoprevention through reverse migration
Authors: Ki Hong Waun
Published: March 2013

The hypothesis that lung cancer can be prevented with agents selected on the basis of epidemiologic data has, unfortunately, been disproven in many large randomized trials conducted in the last 25 years.

The results of these trials have overwhelmingly demonstrated not only the lack of benefit of most chemopreventive agents selected in this manner but also, importantly, the harmful effects of some of these agents in subsets of patients including current smokers.

Despite limited progress in the multimodality treatment of lung cancer, the cure rate for this disease is very disappointing; however, more recent discoveries of molecular “driver mutation” targets in lung cancer and treatment approaches with “matched” targeted agents in selected patient cohorts has been highly promising. This latter approach demonstrates that progression of even heterogeneous cancers can be intercepted by “molecularly relevant” targeted agents for the treatment of advanced disease.

A proposed new strategy for lung cancer prevention, therefore, is to apply a “reverse migration” of agents from the advanced disease to the chemopreventive setting; that is, to first identify the molecular drivers in the premalignant target tissue, and then to match these “hallmark” changes with molecularly targeted agents seen to be effective in advanced disease. This approach can be applied in the adjuvant as well as prevention settings, as has been demonstrated by the use of tamoxifen in breast cancer.

Thus, the major points I am going to present include the current landscape of chemoprevention in lung cancer and a new strategy of “reverse migration” for future chemoprevention trials in the 21st century.
Abstract A23: HER2 levels affect sensitivity and resistance to EGFR inhibition in EGFR mutant lung cancer
Authors: Takezawa Ken , Melnick Mary Ann , Riely Greg , Kris Mark , Miller Vincent , Ladanyi Marc , Politi Katerina , Pao William , Pirazzoli Valentina , Song Xiaoling , Arcila Maria , De Stanchina Elisa , Ohashi Kadoaki , Janjigian Yelena , Spitzler Paula , Nebhan Caroline
Published: March 2013

EGFR mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib. The combination of an irreversible EGFR TKI, afatinib, and the anti-EGFR monoclonal antibody, cetuximab, depletes both phosphorylated and total EGFR and can overcome resistance in mouse lung tumor models and human patients with acquired resistance. Since afatinib is also a potent HER2 inhibitor, here we investigated the role of HER2 in EGFR mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab or the related antibody, panitumumab, significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. Fluorescent in situ hybridization analysis revealed that HER2 was amplified in 3 of 26 (12%) tumors with acquired resistance versus only 1 of 99 (1%) untreated lung adenocarcinomas (p=0.03 Fisher's exact test). Notably, HER2 amplification and EGFR T790M were mutually exclusive (0 of 17 T790M-positive versus 3 of 9 T790M-negative cases (p=0.02 Fisher's exact test)). Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR mutant tumors with acquired resistance to EGFR TKIs.
Abstract A36: Doxorubicin loaded lactoferrin nanoparticles: Treatment of hepatocellular carcinoma in rats induced by diethylnitrosamine
Authors: Golla Kishore , Cherukuvada Bhaskar , Farhan Ahmed , Kondapi Anand Kumar
Published: March 2013

Hepatocellular carcinoma (HCC) is a highly incident malignancy. Doxorubicin is one of the effective chemotherapeutic agents for treating HCC. This problem is addressed in the present study based on an effort to enhance the efficacy of the drug through improvement of bioavailability and reduction of the cardiotoxicity of doxorubicin when intravenously (IV) administered. Doxorubicin-loaded lactoferrin nanoparticles (Nano-Doxo) were prepared by sol-oil chemistry. HCC was induced in rats by feeding drinking water containing 100 mg/l diethylnitrosamine for 8 weeks. Doxorubicin (Doxo) and Nano-Doxo (2 mg of drug/kg body weight) were administered IV. The results showed that Nano-Doxo is preferentially localized in liver and plasma as compared to that in heart, kidney, and spleen suggesting advantage of using Nano-Doxo in treatment of the liver cancer due to its higher bioavailability. The efficacy and safety of the Nano-Doxo and Doxo was further evaluated in terms of nodules formed on the liver. The results showed that the incidence of tumor is significantly decreased in Nano-Doxo treated rats compared to Doxo-treated rats. The higher efficacy of Nano-Doxo compared to Doxo is further confirmed by the levels of tumor-specific gene markers p53, p21, and VEGFR1. The drug-induced toxicity is evaluated in terms of cardiotoxicity by catalase and troponin, liver toxicity by SGPT and SGOT, and kidney toxicity by creatinine and blood urea. In conclusion, Nano-Doxo, with its increased bioavailability and reduced toxicity effects, is a safe and efficacious IV formulation for treatment of liver cancer.
Abstract A37: Anti-telomerase therapy provokes ALT and mitochondrial adaptive mechanism in cancer
Authors: Hu Jian , Hwang Sarah , Boutin Adam , Wang Alan , Chin Lynda , Liesa Marc , Shiriha Orian , DePinho Ronald
Published: March 2013

Because telomerase is activated in 85–90% of all human cancers, inhibition of telomerase activity has been proposed as an anti-cancer strategy. However, telomere erosion resulting from telomerase inhibition can generate rampant genomic instability which may fuel adaptive mechanisms. Here, we determined the impact of telomerase activation and its subsequent extinction in T-cell lymphomas arising in Atm−/− mice engineered with an inducible telomerase reverse transcriptase-estrogen receptor (TERT-ER) knock-in allele. Endogenous telomerase reactivation in late generation TERTER/ER Atm−/− mice with telomere dysfunction enabled full malignant progression with accompanying alleviation of telomere checkpoint signaling and acquisition of copy number alterations targeting genes known to be important in human T-cell lymphomas/leukemia. Upon telomerase extinction, tumors eventually showed impaired growth due to reinstatement of telomere dysfunction-induced checkpoint signaling, yet subsequently resumed growth with accompanying alternative lengthening of telomeres (ALT) features. Transcriptomic analysis of ALT+ tumors showed altered transcriptional networks centering on mitochondrial biology and oxidative defense, and genomic analysis showed amplification of PGC-1β, a master regulator of mitochondrial biogenesis and oxidative defense. Relative to telomerase+ tumors, ALT+ tumors showed marked sensitivity to PGC-1β or SOD2 knockdown which compromised mitochondrial function and/or caused increased reactive oxygen species (ROS). Together, these studies provide in vivo genetic evidence that naturally arising tumors adapt to telomerase extinction by acquisition of both ALT and mitochondrial maintenance mechanisms, and show that targeting mitochondrial function and oxidative defense may enhance the effectiveness of anti-telomerase therapy in cancer.
Abstract A4: A novel class of selective ERα degraders acts as full antagonists/ inverse agonists and displays efficacy in pre-clinical models of endocrine-resistant breast cancer and endometrial cancer
Authors: Darimont Beatrice , Lu Ninh , Sensintaffar John , Lee Kyoung-Jin , Aparicio Anna , Kaufman Joshua , Bischoff Eric , Rix Peter , Heyman Rich , Smith Nicholas , Hager Jeffrey , Joseph James , Grillot Katherine , Qian Jing , Gang Shao , Govek Steven , Nagasawa Johnny , Lai Andiliy , Kahraman Mehmet
Published: March 2013

While endocrine therapies are initially effective to treat estrogen receptor (ERα) positive breast cancer tumors, acquired resistance invariably emerges. Although resistant tumors typically display changes in PI3K or other kinase pathways, the majority of these tumors continue to express and depend on ERα for growth and survival. Exploring the hypothesis that endocrine resistance might involve hormone-independent activities of ERα, we have developed two distinct classes of potent, non-steroidal ERα modulators that antagonize hormone-mediated transcriptional activities of ER and lower ERα steady state levels. These compounds showed robust efficacy in pre-clinical models of endocrine-resistant breast cancer, including some with up-regulated PI3K pathways. In contrast to their activity as full antagonists/ inverse agonists in the breast, the two classes of ERα modulators displayed distinct abilities to oppose the activity of estradiol in the uterine endometrium, another well-characterized ERα target tissue. Similar to endocrine-resistant breast cancer, a large percentage of endometrial cancers have altered PI3K pathways and typically respond poorly to endocrine therapy. In mouse xenograft models one of our compounds inhibited the growth of ECC-1 endometrial cancer tumors with substantially higher efficacy than the selective ER modulator arzoxifene, which in a phase II clinical trial exhibited a 30% response rate in patients with recurring ERα-positive endometrial cancers. Hence, beyond their promise as a next generation therapy for the treatment of endocrine resistant ER+ breast cancer, these novel classes of selective estrogen receptor degraders might also open new opportunities for endocrine therapies targeting endometrial cancer.