bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-Term Wind Speed Forecasting Using Support Vector Regression Optimized by Cuckoo Optimization Algorithm
Authors: Wang Jianzhou , Zhou Qingping , Jiang Haiyan , Hou Ru
Published: July 2015

This paper develops an effectively intelligent model to forecast short-term wind speed series. A hybrid forecasting technique is proposed based on recurrence plot (RP) and optimized support vector regression (SVR). Wind caused by the interaction of meteorological systems makes itself extremely unsteady and difficult to forecast. To understand the wind system, the wind speed series is analyzed using RP. Then, the SVR model is employed to forecast wind speed, in which the input variables are selected by RP, and two crucial parameters, including the penalties factor and gamma of the kernel function RBF, are optimized by various optimization algorithms. Those optimized algorithms are genetic algorithm (GA), particle swarm optimization algorithm (PSO), and cuckoo optimization algorithm (COA). Finally, the optimized SVR models, including COA-SVR, PSO-SVR, and GA-SVR, are evaluated based on some criteria and a hypothesis test. The experimental results show that (1) analysis of RP reveals that wind speed has short-term predictability on a short-term time scale, (2) the performance of the COA-SVR model is superior to that of the PSO-SVR and GA-SVR methods, especially for the jumping samplings, and (3) the COA-SVR method is statistically robust in multi-step-ahead prediction and can be applied to practical wind farm applications.
Finite Element Simulation of Medium-Range Blast Loading Using LS-DYNA
Authors: Han Yuzhen , Liu Huabei
Published: July 2015

This study investigated the Finite Element simulation of blast loading using LS-DYNA. The objective is to identify approaches to reduce the requirement of computation effort while maintaining reasonable accuracy, focusing on blast loading scheme, element size, and its relationship with scale of explosion. The study made use of the recently developed blast loading scheme in LS-DYNA, which removes the necessity to model the explosive in the numerical models but still maintains the advantages of nonlinear fluid-structure interaction. It was found that the blast loading technique could significantly reduce the computation effort. It was also found that the initial density of air in the numerical model could be purposely increased to partially compensate the error induced by the use of relatively large air elements. Using the numerical approach, free air blast above a scaled distance of 0.4 m/kg1/3was properly simulated, and the fluid-structure interaction at the same location could be properly duplicated using proper Arbitrary Lagrangian Eulerian (ALE) coupling scheme. The study also showed that centrifuge technique, which has been successfully employed in model tests to investigate the blast effects, may be used when simulating the effect of medium- to large-scale explosion at small scaled distance.
Genetic Geostatistical Framework for Spatial Analysis of Fine-Scale Genetic Heterogeneity in Modern Populations: Results from the KORA Study
Authors: Diaz-Lacava A. N. , Walier M. , Holler D. , Steffens M. , Gieger C. , Furlanello C. , Lamina C. , Wichmann H. E. , Becker T.
Published: July 2015

Aiming to investigate fine-scale patterns of genetic heterogeneity in modern humans from a geographic perspective, a genetic geostatistical approach framed within a geographic information system is presented. A sample collected for prospective studies in a small area of southern Germany was analyzed. None indication of genetic heterogeneity was detected in previous analysis. Socio-demographic and genotypic data of German citizens were analyzed (212 SNPs;n=728). Genetic heterogeneity was evaluated with observed heterozygosity (HO). Best-fitting spatial autoregressive models were identified, using socio-demographic variables as covariates. Spatial analysis included surface interpolation and geostatistics of observed and predicted patterns. Prediction accuracy was quantified. Spatial autocorrelation was detected for both socio-demographic and genetic variables. Augsburg City and eastern suburban areas showed higherHOvalues. The selected model gave best predictions in suburban areas. Fine-scale patterns of genetic heterogeneity were observed. In accordance to literature, more urbanized areas showed higher levels of admixture. This approach showed efficacy for detecting and analyzing subtle patterns of genetic heterogeneity within small areas. It is scalable in number of loci, even up to whole-genome analysis. It may be suggested that this approach may be applicable to investigate the underlying genetic history that is, at least partially, embedded in geographic data.
Preparation and Properties of OMMT/PU Composites
Authors: Yufei Chen , Yang Han , Qiwang Dai , Xiwang Zhang , Zhang Qingyu
Published: July 2015

Prepolymer of polyurethane (PU) was prepared by toluene diisocyanate (TDI) and polyether diol through polymerization, organically modified montmorillonite (OMMT) gained by montmorillonite (MMT) that was modified by octadecyl trimethyl ammonium chloride (OTAC), and the OMMT was used as intercalator; alcohol-based OMMT/PU adhesive was synthesized. The micromorphology of OMMT/PU adhesives was observed by XRD, SEM, and AFM, and the shear strength, elongation at break, peel strength, and water resistance were tested and the relationship between structure and properties of the adhesives was observed and analyzed. XRD suggested that OMMT has been completely peeled in the polyurethane matrix and the spacing of layers has increased. SEM and AFM indicated that the OMMT dispersed evenly in the PU matrix and had a good transition with PU matrix, and the interface effects between two phases were strong. The results of the mechanical properties showed that OMMT could significantly help to improve properties of OMMT/PU adhesive, and the shearing strength, fracture tensile strength, and peel strength of 4 wt% OMMT/PU adhesive were 7.24 MPa, 2.14 MPa, and 451.2 N/m, respectively; the water absorption quantity was 2.82%. Compared with the unmodified PU, the shearing strength, tensile strength, and elongation at break of 4 wt% OMMT/PU adhesive were increased by 36.75%, 134.90%, and 76.80%, respectively. The peel strength decreased by 30.76%, and the water absorption decreased by 17.54%, in the meanwhile.
Semantic Processing Impairment in Patients with Temporal Lobe Epilepsy
Authors: Jaimes-Bautista Amanda G. , Rodríguez-Camacho Mario , Martínez-Juárez Iris E. , Rodríguez-Agudelo Yaneth
Published: July 2015

The impairment in episodic memory system is the best-known cognitive deficit in patients with temporal lobe epilepsy (TLE). Recent studies have shown evidence of semantic disorders, but they have been less studied than episodic memory. The semantic dysfunction in TLE has various cognitive manifestations, such as the presence of language disorders characterized by defects in naming, verbal fluency, or remote semantic information retrieval, which affects the ability of patients to interact with their surroundings. This paper is a review of recent research about the consequences of TLE on semantic processing, considering neuropsychological, electrophysiological, and neuroimaging findings, as well as the functional role of the hippocampus in semantic processing.
The evidence from these studies shows disturbance of semantic memory in patients with TLE and supports the theory of declarative memory of the hippocampus. Functional neuroimaging studies show an inefficient compensatory functional reorganization of semantic networks and electrophysiological studies show a lack of N400 effect that could indicate that the deficit in semantic processing in patients with TLE could be due to a failure in the mechanisms of automatic access to lexicon.
Life Threatening Idiopathic Recurrent Angioedema Responding to Cannabis
Authors: Frenkel Amit , Roy-Shapira Aviel , Evgeni Brotfain , Leonid Koyfman , Borer Abraham , Klein Moti
Published: July 2015

We present a case of a 27-year-old man with recurrent episodes of angioedema since he was 19, who responded well to treatment with medical grade cannabis. Initially, he responded to steroids and antihistamines, but several attempts to withdraw treatment resulted in recurrence. In the last few months before prescribing cannabis, the frequency and severity of the attacks worsened and included several presyncope events, associated with scrotal and neck swelling. No predisposing factors were identified, and extensive workup was negative. The patient reported that he was periodically using cannabis socially and that during these periods he was free of attacks. Recent data suggest that cannabis derivatives are involved in the control of mast cell activation. Consequently, we decided to try a course of inhaled cannabis as modulators of immune cell functions. The use of inhaled cannabis resulted in a complete response, and he has been free of symptoms for 2 years. An attempt to withhold the inhaled cannabis led to a recurrent attack within a week, and resuming cannabis maintained the remission, suggesting a cause and effect relationship.
Probabilistic Short-Term Wind Power Forecasting Using Sparse Bayesian Learning and NWP
Authors: Pan Kaikai , Qian Zheng , Chen Niya
Published: July 2015

Probabilistic short-term wind power forecasting is greatly significant for the operation of wind power scheduling and the reliability of power system. In this paper, an approach based on Sparse Bayesian Learning (SBL) and Numerical Weather Prediction (NWP) for probabilistic wind power forecasting in the horizon of 1–24 hours was investigated. In the modeling process, first, the wind speed data from NWP results was corrected, and then the SBL was used to build a relationship between the combined data and the power generation to produce probabilistic power forecasts. Furthermore, in each model, the application of SBL was improved by using modified-Gaussian kernel function and parameters optimization through Particle Swarm Optimization (PSO). To validate the proposed approach, two real-world datasets were used for construction and testing. For deterministic evaluation, the simulation results showed that the proposed model achieves a greater improvement in forecasting accuracy compared with other wind power forecast models. For probabilistic evaluation, the results of indicators also demonstrate that the proposed model has an outstanding performance.
Towards the Elimination of Syphilis in a Small Developing Country
Authors: Mungrue Kameel , Edwards Jeffrey , Fyzul Azizah , Boodhai Billy , Narinesingh Adita , Nanlal Shasta
Published: July 2015

Objective. To describe the current epidemiological features of syphilis and congenital
syphilis in Trinidad, 2009–2012. Methods. All laboratory confirmed syphilis cases diagnosed through a vertical
program in the Ministry of Health, between 1/1/2009 and 31/12/2012, were identified. All relevant data were collected including address which was geocoded and mapped using ArcGIS 10.0 (Esri). Both spatial techniques and standardized incidence ratios were
used to determine hot spots. Results. The annual cumulative incidence rate for syphilis remains high varying from
39 per 100 000 population in 2009 to 29 per 100 000 in 2012. We identified 3 “hot spots,” in urban areas of Trinidad. Young men and particularly young women in childbearing age 15–35 living in urban high density populations were commonly infected groups. Conclusion. The incidence of syphilis continues to be very high in Trinidad. New initiatives will have to be formulated in order to attain the global initiative to eradicate syphilis by 2015.
Decoding the Formation of New Semantics: MVPA Investigation of Rapid Neocortical Plasticity during Associative Encoding through Fast Mapping
Authors: Atir-Sharon Tali , Gilboa Asaf , Hazan Hananel , Koilis Ester , Manevitz Larry M.
Published: July 2015

Neocortical structures typically only support slow acquisition of declarative memory; however, learning through fast mapping may facilitate rapid learning-induced cortical plasticity and hippocampal-independent integration of novel associations into existing semantic networks. During fast mapping the meaning of new words and concepts is inferred, and durable novel associations are incidentally formed, a process thought to support early childhood’s exuberant learning. The anterior temporal lobe, a cortical semantic memory hub, may critically support such learning. We investigated encoding of semantic associations through fast mapping using fMRI and multivoxel pattern analysis. Subsequent memory performance following fast mapping was more efficiently predicted using anterior temporal lobe than hippocampal voxels, while standard explicit encoding was best predicted by hippocampal activity. Searchlight algorithms revealed additional activity patterns that predicted successful fast mapping semantic learning located in lateral occipitotemporal and parietotemporal neocortex and ventrolateral prefrontal cortex. By contrast, successful explicit encoding could be classified by activity in medial and dorsolateral prefrontal and parahippocampal cortices. We propose that fast mapping promotes incidental rapid integration of new associations into existing neocortical semantic networks by activating related, nonoverlapping conceptual knowledge. In healthy adults, this is better captured by unique anterior and lateral temporal lobe activity patterns, while hippocampal involvement is less predictive of this kind of learning.
Factors That Influence Technical Efficiency of Sorghum Production: A Case of Small Holder Sorghum Producers in Lower Eastern Kenya
Authors: Chepng’etich Evaline , Nyamwaro Sospeter Onchoke , Bett Eric Kiprotich , Kizito Kwena
Published: July 2015

Majority of the rural households in Kenya depend on agriculture as a source of food and livelihood. Agricultural productivity has been declining due to many factors resulting in increased food insecurity in the country. Consequently, there is a renewed interest in promoting drought-tolerant crops such as sorghum which thrives in the arid and semiarid lands of the developing world. However, performance of sorghum production among the smallholder farmers has still remained low. This study was thus carried out to identify factors that influence technical efficiency of sorghum production among smallholder farmers in Machakos and Makindu districts of the lower eastern Kenya. Collected data on farm and farmer characteristics were analysed by use of descriptive statistics and Tobit model. Result highlights show that technical efficiency was influenced positively by formal education level of the household, experience in sorghum farming, membership in farmers associations, use of hired labour, production advice, and use of manure. Surprisingly household size, meant to enhance labour, had a negative influence. To increase technical efficiency, efforts should focus on improving information flows on agronomic practices. Farmers should also be encouraged to form and actively participate in various farmers associations, which enhance learning and pooling of labour resources, hence improving technical efficiency.
Data Normalization to Accelerate Training for Linear Neural Net to Predict Tropical Cyclone Tracks
Authors: Jin Jian , Li Ming , Jin Long
Published: July 2015

When pure linear neural network (PLNN) is used to predict tropical cyclone tracks (TCTs) in South China Sea, whether the data is normalized or not greatly affects the training process. In this paper, min.-max. method and normal distribution method, instead of standard normal distribution, are applied to TCT data before modeling. We propose the experimental schemes in which, with min.-max. method, the min.-max. value pair of each variable is mapped to (−1, 1) and (0, 1); with normal distribution method, each variable’s mean and standard deviation pair is set to (0, 1) and (100, 1). We present the following results: (1) data scaled to the similar intervals have similar effects, no matter the use of min.-max. or normal distribution method; (2) mapping data to around 0 gains much faster training speed than mapping them to the intervals far away from 0 or using unnormalized raw data, although all of them can approach the same lower level after certain steps from their training error curves. This could be useful to decide data normalization method when PLNN is used individually.
Abstract A23: Epigenetic Cis-regulatory interactions in HIF1a-activated melanocytes
Authors: Loftus Stacie , Cronin Julie , Fufa Temesgen , McCallion Andrew , Crawford Gregory , Pavan William
Published: July 2015

Melanoma tumors are heterogeneous lesions that progress through distinct cellular phenotypes exhibiting either highly proliferative or invasive cell state gene expression signatures (SOX10+ vs. TGFB+ pathways, respectively) as disease progression occurs. It is appreciated that even within a single tumor, individual cells respond to hypoxic conditions through Hypoxia Inducible Factor 1a (HIF1a) activation, leading to gene expression that promotes invasive cell properties. Regulation of gene expression integrates the binding of intrinsic cell lineage factors and general transcription machinery to key cis-regulatory DNA sequences that are epigenetically defined. In order to identify the cis-regulatory sequences that are utilized in a cell's response to HIF1a activation, we have established an integrated regulatory dataset from melan-Ink4a-ARF-/- immortalized mouse melanocytes. This dataset includes Dnase1 HS regions, enhancer regions marked by H3K4me1 and EP300 co-binding, ChIP-Seq for the transcription factors HIF1a and SOX10, and RNA-SEQ datasets under proliferative and HIF1a-activated growth conditions. We are evaluating HIF1a binding regions in order to identify the cis-regulatory sequences utilized to regulate gene expression, identify the key factors engaged at these sites, and assess the role that DNA variation has in modulating factor binding and gene transcription in the switch from proliferative to hypoxic cell signaling conditions. By identifying the epigenetic cis-regulatory interactions that occur as a result of HIF1a activation, we hypothesize that we will highlight pathways important for melanoma progression that may be relevant to future therapeutics.

Citation Format: Stacie Loftus, Julie Cronin, Temesgen Fufa, Andrew McCallion, Gregory Crawford, William Pavan. Epigenetic Cis-regulatory interactions in HIF1a-activated melanocytes. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A23.
Abstract A34: MC1R signaling reduces UV mutagenesis by ATR-mediated recruitment of XPA to photolesions
Authors: Jarrett Stuart Gordon , Horrell Erin M. Wolf , Christian Perry A. , Vanover Jillian C. , Boulanger Mary C. , Zou Yue , D'Orazio John August
Published: July 2015

The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic Gs-coupled transmembrane receptor activated by binding to its high-affinity ligand, α-melanocyte stimulating hormone (MSH). Besides influencing pigment phenotype and mediating adaptive tanning, MC1R signaling is intricately linked with genome maintenance and DNA repair. Individuals harboring loss-of-function MC1R polymorphisms are UV sensitive and melanoma-prone. We have determined that MC1R-mediated cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435 which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing UV mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA and elevates UV-induced mutagenesis. PKA-mediated ATR phosphorylation on Ser435 appears to induce a DNA repair-specific function of ATR independent of Chk1 phosphorylation and cell cycle arrest. Importantly, MC1R signaling defects and sub-optimal DNA repair are overcome by forskolin-mediated cAMP induction in melanocytes and in whole skin. Our findings mechanistically link cAMP-PKA signaling to NER and illustrate the potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.

Citation Format: Stuart Gordon Jarrett, Erin M. Wolf Horrell, Perry A. Christian, Jillian C. Vanover, Mary C. Boulanger, Yue Zou, John August D'Orazio. MC1R signaling reduces UV mutagenesis by ATR-mediated recruitment of XPA to photolesions. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr A34.
Abstract B05: Targeting BRAF and CDK4 in BRAF mutant melanoma induces sustained tumor regression
Authors: Sheppard Karen E. , Carleen Cullinane , Kirby Laura , Waldeck Kelly , Young Richard , Martin Claire , VanArsdale Todd , Randolph Sophia , McArthur Grant A.
Published: July 2015

Background: The p16-cyclinD-CDK4-RB1 pathway (CDK4 pathway) is deregulated in 90% of melanomas. The main outcome of CDK4 activation is the phosphorylation and thus, inhibition of RB1 leading to G1–S cell-cycle transition. In addition, CDK4 directly phosphorylates other proteins that promote cell-cycle progression and inhibit both cell senescence and apoptosis. The MAPK/ERK pathway is deregulated in 90% of melanoma and enhances CDK4 pathway signaling through increasing cyclin D1 expression. We have previously demonstrated in a panel of melanoma cell lines that the majority of cell lines were sensitive to a CDK4/6 inhibitor (Palbociclib) and consistent with the concept of CDK4 pathway-dependent oncogene addiction, cell lines with loss of functional p16INK4A were significantly more sensitive to Palbociclib than cells with wild-type p16INK4A. We hypothesized that dual targeting the MAPK/ERK and CDK4 pathways would lead to robust inhibition of the CDK4/Cyclin D complex and consequently induce greater tumor regression than single agent treatment.

Results: In vitro, PLX4720, Palbociclib or their combination inhibited BRAF mutant melanoma cell line proliferation and clonogenic survival, however, only with the combination treatment group was a rapid sustained inhibition achieved. Enlarged flattened cells and a significant increase in SA-β-galactosidase staining indicated that the dual treatment resulted in robust cellular senescence. In a BRAFV600E mutant A375 xenograft model, Palbociclib and PLX4720 initially induced tumor regression and tumor stasis respectively, but resistance eventually developed. In contrast, in the combination treatment, tumors regressed and sustained inhibition of tumor growth was maintained. Preliminary biomarker studies indicate resistance to PLX4720 was due to reactivation MAPK/ERK pathway and resistance to Palbociclib to partial restoration of phosphorylated RB1.

Conclusions: Combination therapy of MAPK/ERK pathway inhibitors with CDK4 inhibitors is likely to be an effective treatment for BRAF mutant melanoma and in addition delay resistance to single agent targeted therapy.

Citation Format: Karen E. Sheppard, Cullinane Carleen, Laura Kirby, Kelly Waldeck, Richard Young, Claire Martin, Todd VanArsdale, Sophia Randolph, Grant A. McArthur. Targeting BRAF and CDK4 in BRAF mutant melanoma induces sustained tumor regression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B05.
Abstract B11: Manipulating senescence to combat melanoma initiation and progression
Authors: Pawlikowski Jeff S. , Holmes Malorie , Richmond Ann
Published: July 2015

Senescence has been identified as a tumor suppression mechanism in many premalignant tissues. The most widely studied example is the melanocytic nevus that guards against the onset of melanoma. Senescence therefore acts as a barrier to malignancies and reinforcing this growth-arrested state can be a valuable way to combat tumorigenesis. Accordingly, therapy induced senescence (TIS) has been shown to be a promising approach for treatment of cancer. Here we further study how specific factors govern TIS.

Numerous clinical trials are currently ongoing that inhibit MDM2 or CDK4/6, which regulate the tumor suppressors p53 and RB/p16, respectively. As these tumor suppressors are the master regulators of senescence and senescence is an important mechanism in melanoma initiation, we analyzed the effect of their inhibition in primary melanocytes and transformed melanoma cell lines. As anticipated, we show that upon administration of the MDM2 and CDK4/6 inhibitors (-)-Nutlin-3a (1uM) and PD2991 (8uM, respectively), primary human melanocytes and human melanoma cell lines stop proliferating. While MDM2 and CDK4/6 inhibitors have been shown to induce senescence, we were surprised to find that induction of senescence was not conserved among all cell types studied. Analysis of the cell cycle arrest showed that human melanocytes do not display senescence associated beta-galactosidase activity while melanoma cell lines do stain positive for this marker of senescence. Furthermore, members of the senescence associated secretory phenotype (SASP) are not increased upon MDM2 and CDK4/6 inhibition in primary melanocytes, whereas the same treatment in melanoma cells causes SASP up-regulation in a similar fashion to that triggered by oncogene induced senescence (OIS). The induction of the SASP members was particularly evident upon combined treatment with MDM2 and CDK4/6 inhibitors. These results suggest that TIS may be influenced by the expression of the SASP.

We have previously showed that many members of the SASP whose expression increases with senescence also expressed in metastatic disease. By further evaluating SASP following OIS vs TIS, we may better understand the mechanisms behind existing senescence inducing therapies and define additional routes for pro-senescence cancer therapy. Senescence is a highly complex process that is able to control multiple cell fates, often due in part to the SASP. Consequently, by manipulating the SASP we may be able to regulate melanoma initiation and progression.

Citation Format: Jeff S. Pawlikowski, Malorie Holmes, Ann Richmond. Manipulating senescence to combat melanoma initiation and progression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B11.
Abstract B19: Discovery of novel tubulin inhibitor ABI-274 whose synergistic combination with vemurafenib overcome acquired vemurafenib resistance in BRAF mutated melanoma
Authors: Wang Jin , Chen Jianjun , Miller Duane D. , Li Wei
Published: July 2015

Acquired clinical resistance to BRAF inhibitors such as vemurafenib or dabrafefnib arises frequently after short term of these targeted therapy. We hypothesized that a combined therapy using vemurafenib with a G2/M phase blocking agent will arrest resistant cells and overcome vemurafenib resistance. To test this hypothesis, we performed combination studies using our recently discovered tubulin inhibitor ABI-274 and vemurafenib on both vemurafenib-sensitive cells and a resistant A375RF21 sub line. The combination showed strong synergy in vitro, synergistically arrested cells in G1/G2/M phase, and significantly enhanced cancer cell apoptosis. In vivo co-administration of vemurafenib with ABI-274 showed strong synergistic efficacy in the vemurafenib-resistant xenograft model in nude mice. Overall, these results offer a rational combination strategy to significantly enhance the therapeutic benefit in melanoma patients who inevitably become resistant to current vemurafenib therapy. This work was supported by NIH grants R01CA148706, 1S10OD010678-01 and 1S10RR026377-01.

Citation Format: Jin Wang, Jianjun Chen, Duane D. Miller, Wei Li. Discovery of novel tubulin inhibitor ABI-274 whose synergistic combination with vemurafenib overcome acquired vemurafenib resistance in BRAF mutated melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B19.
Abstract B28: In vivo ERK1/2 pathway reporting during acquired resistance to combined RAF/MEK inhibition
Authors: Sanchez Ileine , Aplin Andrew
Published: July 2015

The MEK-ERK1/2 signaling pathway is constitutively activated in BRAF V600E/K melanomas. Concurrent BRAF and MEK inhibitor treatment was recently FDA-approved for BRAF V600E melanoma; however, acquired resistance to the drug combination limits durable responses. Our lab has developed a luciferase reporter system that temporally and non-invasively quantitates ERK1/2 activity in mutant BRAF melanoma xenografts. We used this reporter system to examine the temporal kinetics of ERK1/2 activity in vivo upon treatment with combined BRAF/MEK inhibition. Using a 1205Lu reporter system, all established tumors regressed to levels that were not detectable visually. After prolonged treatment with BRAF and MEK inhibitors, only 2 out of 8 mice regrew resistant tumors. In similar experiments with A375 xenografts, only 1 out 12 tumors developed resistance. In 1205Lu tumors, re-activation of the ERK1/2 pathway was evident prior to re-growth. Additionally, cell lines generated from these resistant tumors exhibited elevated levels of ERK1/2 suggesting that resistance to BRAF + MEK inhibitors involves re-activation of ERK1/2 signaling. In comparison to parental cells, resistant cells in vitro displayed reduced levels of apoptosis, increased proliferation, and increased viability in the presence of BRAF plus MEK inhibitor. Furthermore, when removed from drugs, combination-resistant cells showed increased apoptosis and reduced proliferation and viability, suggesting that the resistant lines may be addicted to the dual therapy. RPPA analysis and whole exome sequencing to elucidate mechanisms of resistance are ongoing.

Citation Format: Ileine Sanchez, Andrew Aplin. In vivo ERK1/2 pathway reporting during acquired resistance to combined RAF/MEK inhibition. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B28.
Abstract B35: Vinyl sulfone analogues of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma
Authors: Murph Mandi , Jiang Guowei , Altman Molly , Wei Jia , Tran Sterling , Nguyen Duy , Alshamrani Ali , Hardman William , Zhang Jianxing , Prestwich Glenn
Published: July 2015

Autotaxin is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. Autotaxin is a unique ectonucleotide pyrophosphatase and phosphodiesterase that facilitates the removal of a choline headgroup from lysophosphatidylcholine to yield lysophosphatidic acid, which is a potent lipid stimulator of tumorigenesis. Thus, autotaxin has received renewed attention because it has a prominent role in malignant progression and represents a promising area of research with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Our goal was to discover agents with therapeutic efficacy in melanoma. For this purpose, we synthesized a set of lysophosphatidylcholine analogs that function as irreversible inhibitors of autotaxin and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 – 0.39 μM, consistent with a Ki of 3.50 μM for inhibition of autotaxin by the analog CVS-16 (10b). A control compound, GWJ-A-10, which is missing the critical moiety, had little effect on cell viability and did not inhibit autotaxin. In addition, CVS-16 (10b) significantly inhibited melanoma cell wound closure and pore migration (data not presented herein). Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent autotaxin inhibitor with significant biological activity, both in vitro and in vivo.

Citation Format: Mandi Murph, Guowei Jiang, Molly Altman, Jia Wei, Sterling Tran, Duy Nguyen, Ali Alshamrani, William Hardman, Jianxing Zhang, Glenn Prestwich. Vinyl sulfone analogues of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B35.
Abstract B36: The effects of dasatinib in KIT L579P and NRAS Q61K mutant canine melanoma cells
Authors: Lu Lu-Ping , Lin Chen-Si , Liao Albert Taiching
Published: July 2015

Purpose: Malignant melanoma is a common malignant tumor in dog. It is a fatal disease with local invasiveness and frequently metastatic propensity and the poor response has been observed. The aim of this study was to establish the drug-screening platform and used that platform to evaluate small molecular inhibitor, Dasatinib, for therapy of canine melanoma.

Experimental Design: Various phenotypes of eight canine melanoma cell lines, CM01, M1, M3, M4, M5, Pu, C1 and KMeC, were examined in this study. Mutation analysis of kit, Nras and Braf was done by PCR/DNA sequencing. Expression of S100, KIT and KIT downstream signaling cascades NRAS, phospho-ERK and phospho-AKT were evaluated by immunocytochemistry. KMeC, M5 and CM01 cell lines were selected for further evaluation of Dasatinib. Proliferation assay and wound healing assay were performed to assess cell viability and motility in the presence of dasatinib. Cell cycle analysis and Annexin V apoptosis assay were also applied to realize the mechanism of cell death caused by Dasatinib.

Results: Expressions of S100 and KIT were observed in all of the cell lines. NRAS and activated ERK were identified in several cell lines with different expression levels. However, no activated AKT was identified in any cell lines. kit T1736C mutation causing KIT L579P change was detected in M3, KMeC and C1 cells, while Nras C181A mutation causing NRAS Q61K change was found in M5 cell. ERK activity in KMeC (KIT L579P), M5 (NRAS Q61K) and CM01 (KIT & NRAS wild type) cells was down-regulated when Dasatinib was administered. Dasatinib reduced cell viability with the IC50 values of 0.64 μM in KMeC, 0.24 μM in M5 and 0.37 μM in CM01 cells. In wound healing assay, Dasatinib inhibited cell motility in all of the three cell lines. Cell cycle analysis and Annexin V apoptosis assay revealed that the treatment of Dasatinib causes a G1 cell cycle arrest and induction of apoptosis. The analysis of Dasatinib caused signaling change in canine melanoma cell is ongoing.

Conclusions: Various phenotypes of eight canine melanoma cell lines were identified in DNA and protein levels. The NRAS Q61K mutation was first found in canine melanoma. The results showed that KIT L579P mutant type, NRAS Q61K mutant type and wild type canine melanoma cells are sensitive to the treatment of Dasatinib. It caused the reduction of cell viability, and inhibition of motility, moreover, the promotion of G1 cell cycle arrest and cell apoptosis. Dasatinib may potentially be selected as a candidate for therapy of canine melanoma.

Citation Format: Lu-Ping Lu, Chen-Si Lin, Albert Taiching Liao. The effects of dasatinib in KIT L579P and NRAS Q61K mutant canine melanoma cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B36.
Abstract IA05: Small RNAs reveal nuclear hormone receptor targeting as a novel therapy for melanoma
Authors: Tavazoie Sohail
Published: July 2015

In recent years, numerous genes that drive melanoma metastasis or progression of established metastatic melanoma have been identified. The identification of such genes and their associated pathways have revealed insights into the cellular processes involved in these clinically important events. Our laboratory has found that deregulated expression of microRNAs is a major mechanism by which such gene-expression states that enable metastatic progression are achieved in various solid cancers. In melanoma, we have identified 3 microRNAs (miR-1908, miR-199a5p, and miR-199a3p) to be over-expressed in metastatic sub-populations of human melanoma cells. The expression levels of these microRNAs predict metastatic relapse in primary cutaneous melanomas. These microRNAs convergently target the gene ApoE, which through genetic, molecular, pharmacological, and clinical association analyses, we have identified as a robust suppressor of melanoma metastasis and metastatic progression. We have demonstrated pre-clinical proof-of-concept for the therapeutic activation of ApoE through transcriptional engagement of the Liver-X nuclear hormone receptor (LXR). Oral administration of multiple LXR agonists suppressed the growth of primary and metastatic melanoma in mice. Genetic studies revealed that the effects of LXR agonists are mediated through LXRβ, which elicits these effects through ApoE induction in the stromal and tumoral compartments. LXRβ; agonism suppressed progression in immunocompetent, xenograft, patient-derived xenograft, and genetically initiated melanomas. Moreover, LXRβ agonism exhibited combinatorial efficacy with B-Raf inhibitors and anti-CTLA4 immunotherapy. We provide pre-clinical proof-of-concept for therapeutic activation of nuclear hormone receptors in melanoma.

Citation Format: Sohail Tavazoie. Small RNAs reveal nuclear hormone receptor targeting as a novel therapy for melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA05.
Abstract IA27: Combination immunotherapy for melanoma
Authors: Wolchok Jedd D.
Published: July 2015

The past decade has been a period of significant progress in the area of cancer immunotherapy enabled by significant advances in basic science allowing for a better understanding of molecular mechanisms of immune regulation and immune cell dynamics, stressing the importance of close collaboration between basic and translational and clinical scientists. Blockade of CTLA-4 was suggested to be an impactful means to augment tumor immunity based on the pioneering studies of Jim Allison, who hypothesized that impairment of this critical molecular brake would overcome tumor-induced immune suppression and allow for more robust immune response to tumors. In 2011, the US FDA approved ipilimumab for the treatment of metastatic melanoma with two randomized phase 3 trials demonstrating prolongation of overall survival, the first intervention ever to demonstrate this important endpoint in this challenging clinical situation. Investigation of blockade of the PD-1 (programmed death-1) pathway followed very shortly after the efficacy of ipilimumab was observed. PD-1 is a marker on T cells which, while being up-regulated after activation, serves to mark T cells as being exhausted and, when engaging one of its ligands (PD-L1 or -L2), can lower the threshold for apoptosis in T cells. An ever-expanding list of antibodies that block either PD-1 or PD-L1 has entered clinical trials with some currently in phase 3 investigation. It was therefore not completely surprising that PD-1 blockade showed clinical efficacy in melanoma. Given the activity noted with both CTLA-4 and PD-1 blockade and the complementary mechanism of action as well as supportive pre-clinical data, clinical trials are now investigating combination checkpoint blockade. The most mature data has come from a combination of ipilimumab + nivolumab in patients with melanoma and showed an overall response rate of 40% across dose cohorts with over 50% of patients in some cohorts showing rapid and deep (>80% reduction) tumor regressions in the context of manageable toxicity. Responses are generally rapidly apparent and durable. Two-year overall survival rates have been estimated at 79% across all cohorts. Phase 2 and 3 trials of this combination are ongoing.

Citation Format: Jedd D. Wolchok. Combination immunotherapy for melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA27.
Abstract IA29: PI3′ -kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAFV600E/PTENNull melanoma
Authors: Deuker Marian M. , Marsh-Durban Victoria , Phillips Wayne A. , Silva Jillian M. , McMahon Martin
Published: July 2015

Phosphatidylinositide 3′ (PI3′)-lipid signaling promotes the growth of BRAF-mutated melanomas initiated by expression of oncogenic BRAFV600E. Elevation of PI3′-lipid signaling commonly occurs via silencing of the PTEN tumor suppressor, which encodes a PI3′-lipid phosphatase. However mutational activation of PIK3CA, encoding the p110α catalytic subunit of PI3′-kinase (PI3K), or alterations in the PI3′-lipid effectors AKT1-3 have also been observed, albeit infrequently. To characterize the PI3K catalytic isoform dependency of BRAF-mutated melanoma, we utilized a panel of pharmacological isoform-selective PI3K inhibitors in conjunction with melanoma-derived cell lines and genetically engineered mouse (GEM) models of BRAF-mutated melanoma. While BRAFV600E/PIK3CAH1047R mutated melanoma was sensitive to p110α selective blockade, inhibition of BRAFV600E/PTENNull melanoma cell proliferation required combined blockade of p110α, p110δ and p110γ isoforms, and was insensitive to p110β blockade. In GEM models of BRAF-mutated melanoma, PI3K pathway inhibition elicited largely cytostatic effects, and significantly potentiated melanoma regression in response to BRAFV600E pathway-targeted inhibition. Interestingly, an inhibitor of p110α, δ and γ forestalled the onset of MEK inhibitor resistance in a GEM model of BRAFV600E/PTENNull melanoma. Thus, although single agent PI3K inhibition failed to elicit dramatic regression of BRAFV600E expressing melanomas, PI3K inhibitors may be useful in extending the duration of response to BRAFV600E pathway-targeted therapy.

Citation Format: Marian M. Deuker, Victoria Marsh-Durban, Wayne A. Phillips, Jillian M. Silva, Martin McMahon. PI3′ -kinase inhibition forestalls the onset of MEK1/2 inhibitor resistance in BRAFV600E/PTENNull melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA29.
Recent Advances in Tumor Ablation for Hepatocellular Carcinoma
Authors: Kang Tae Wook , Rhim Hyunchul
Published: July 2015

Image-guided tumor ablation for early stage hepatocellular carcinoma (HCC) is an accepted non-surgical treatment that provides excellent local tumor control and favorable survival benefit. This review summarizes the recent advances in tumor ablation for HCC. Diagnostic imaging and molecular biology of HCC has recently undergone marked improvements. Second-generation ultrasonography (US) contrast agents, new computed tomography (CT) techniques, and liver-specific contrast agents for magnetic resonance imaging (MRI) have enabled the early detection of smaller and inconspicuous HCC lesions. Various imaging-guidance tools that incorporate imaging-fusion between real-time US and CT/MRI, that are now common for percutaneous tumor ablation, have increased operator confidence in the accurate targeting of technically difficult tumors. In addition to radiofrequency ablation (RFA), various therapeutic modalities including microwave ablation, irreversible electroporation, and high-intensity focused ultrasound ablation have attracted attention as alternative energy sources for effective locoregional treatment of HCC. In addition, combined treatment with RFA and chemoembolization or molecular agents may be able to overcome the limitation of advanced or large tumors. Finally, understanding of the biological mechanisms and advances in therapy associated with tumor ablation will be important for successful tumor control. All these advances in tumor ablation for HCC will result in significant improvement in the prognosis of HCC patients. In this review, we primarily focus on recent advances in molecular tumor biology, diagnosis, imaging-guidance tools, and therapeutic modalities, and refer to the current status and future perspectives for tumor ablation for HCC.
Inflammasome Inhibition Suppresses Alveolar Cell Permeability Through Retention of Neuregulin-1 (NRG-1)
Authors: Venugopal Rajanbabu , Galam Lakshmi , Cox Ruan , Fukumoto Jutaro , Cho Young , Parthasarathy Prasanna Tamarapu , Lockey Richard F. , Kolliputi Narasaiah
Published: July 2015

Background: Neuregulin (NRG)-1-human epidermal receptor (HER)-2 signaling pathway is a key regulator of IL-1β-mediated pulmonary inflammation and epithelial permeability. The inflammasome is a newly discovered molecular platform required for caspase-1 activation and maturation of IL-1β. However, the role of the inflammasome in NRG-1-HER2 signaling-mediated alveolar cell permeability is unknown. Methods: The inflammasome was activated or inhibited in THP-1 cells; supernatants from these cells were added to A549 cells and human small airway epithelial cells (HSAEC). The protein expression of NRG-1 and phospho-HER2 (pHER2) were measured by Western blot analysis and epithelial permeability was measured using Lucifer yellow dye. Results: Results reveal that alveolar permeability in A549 cells and HSAEC is increased when treated with supernatants of inflammasome-activated THP-1 cells. Alveolar permeability is significantly suppressed when treated with supernatant of inflammasome-inhibited THP-1 cells. Inflammasome-mediated permeability is decreased when A549 cells and HSAEC are pretreated with IL-1β receptor antagonist (IL-1βRA). In addition, HER2 kinase inhibitor AG825 or NRG-1 inhibitor TAPI inhibits inflammasome-mediated permeability in A549 cells and HSAEC demonstrating critical roles of IL-1β, NRG-1, and HER2 in inflammasome-mediated alveolar permeability. Conclusion: These findings suggest that inflammasome-induced alveolar cell permeability is mediated by NRG-1/HER2 signaling through IL-1β regulation.
TRAP1 Provides Protection Against Myocardial Ischemia-Reperfusion Injury by Ameliorating Mitochondrial Dysfunction
Authors: Zhang Peng , Lu Yong , Yu Dong , Zhang Dadong , Hu Wei
Published: July 2015

Background: Tumor necrosis factor receptor-associated protein 1 (TRAP1), an essential mitochondrial chaperone is induced in rat hearts following ischemia/reperfusion (I/R), but its role in myocardial I/R injury is unclear. The present study examined the function of TRAP1 in cardiomyocyte hypoxia/reoxygenation injury in vitro and myocardial I/R injury in vivo. Methods: HL-1 cardiomyocytes transfected with TRAP1 or vector were subjected to simulated I/R (SI/R) in vitro. Cell death and mitochondrial function were assessed. Wild type (WT) and TRAP1 knockout (TRAP1 KO) mice were subjected to cardiac I/R in vivo. The infarct size and myocardial apoptosis were determined. WT and TRAP1 KO cardiomyocytes were subjected to SI/R in vitro. Mitochondrial function was assessed. Results: TRAP1 overexpression protects HL-1 cardiomyocytes from SI/R-induced cell death in vitro. The reduced cell death was associated with decreased ROS generation, better-preserved mitochondrial ETC complex activity, membrane potential, and ATP production, as well as delayed mPTP opening. Loss of TRAP1 aggravates SI/R-induced mitochondrial damage in cardiomyocytes in vitro and myocardial I/R injury and apoptosis in vivo. Conclusion: The results of the present study show that TRAP1 provides cardioprotection against myocardial I/R by ameliorating mitochondrial dysfunction.