bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma-assisted oxide removal from p-type GaSb for low resistivity ohmic contacts
Authors: Tran Thanh-Nam , Patra Saroj Kumar , Breivik Magnus , Fimland Bjørn-Ove
Published: November 2015

The effect of several plasma-assisted oxide removal techniques prior to metallization of p-type GaSb was investigated. Compared to conventional chemical methods, the plasma-assisted oxide removal resulted in significant improvement of the specific contact resistivities, obtained from transfer length method measurements. Very low specific contact resistivities of less than 5 × 10−8 Ω cm2 were observed after surface pretreatment by H2/Ar sputter etching and low-ion-energy argon irradiation. By eliminating sample exposure to air, in situ Ar irradiation becomes a promising technique for high performance GaSb-based semiconductor diode lasers.
Effects of symmetrical foundation on sound radiation from a submarine hull structure
Authors: Li Chenyang , Su Jinpeng , Wang Jian , Hua Hongxing
Published: November 2015

The effects of a passive noise control method for suppressing sound radiation from a submarine hull structure are investigated. The control method is realized by symmetrizing the foundation about the horizontal plane. The coupled finite element method and boundary element method are adopted to compute the acoustic characteristics of the submerged hull. From the numerical results, the symmetrical foundation has advantages in sound radiation reduction when the hull is subjected to the axial load, but has little influences in the vertical and transverse load cases. Using the modal decomposition technique, the contributions of each individual mode to the sound radiation are analyzed to reveal the mechanism of the control method.
The Effect of Blocked, Random and Mixed Practice Schedules on Speech Motor Learning of Tongue Twisters in Unimpaired Speakers
Authors: Jones Kelly , Croot Karen
Published: November 2015

There are few investigations comparing practice schedules in speech motor learning, despite certain schedules being recommended for the clinical treatment of speech motor disorders. This study compared effects of random, blocked and mixed practice on tongue twister accuracy in unimpaired speakers. We hypothesized that blocked practice would benefit acquisition of learning, but that random practice and mixed blocked-then-random practice would yield superior retention of learning. We found that the random and blocked-random practice schedules yielded superior accuracy at the end of the acquisition phase of learning and at a 1-week retention test. Exploratory post hoc analyses raised the possibility that the retention effects were most evident when tongue twisters were elicited in a random schedule. Theoretical accounts of these results are discussed.
Effects of Unilateral Muscle Fatigue on Performance and Force Coordination in Bimanual Manipulation Tasks
Authors: Feeney Daniel , Jelaska Igor , Uygur Mehmet , Jaric Slobodan
Published: November 2015

We examined the effects of unilateral muscle fatigue on the performance and coordination of grip (GF; normal component acting between the hand and object) and load force (LF; tangential component) in bimanual manipulation tasks, as well as the associated lateral differences. Eleven participants performed various symmetric bimanual tasks either without fatigue, or after fatiguing the GF producing muscles of either the nondominant or dominant hand. The GF/LF ratio of the fatigued and nonfatigued hand decreased and increased, respectively, while the neither the effects of fatigue on the task performance and GF-LF coordination, nor the lateral differences were revealed. The lack of the fatigue associated effects on most of the tested variables typically observed from unimanual tasks could be explained by bimanual assimilation. The findings also suggest that in daily life switching to bimanual tasks when one hand becomes fatigued could be beneficial regarding preserving the high level of both the manipulation performance and force coordination.
Two staged modified substitution urethroplasty using appendix-free flap
Authors: Hiradfar Mehran , Shojaeian Reza , Saeedi Sharifabad Parisa
Published: November 2015

Reconstruction of long posterior urethra defect is technically challenging. Substitution urethroplasty is used in long, complex, recurrent posterior urethral strictures. This article presents a modified technique and the clinical outcome of two-stage substitution urethroplasty with appendix free flap and microvascular anastomosis. A three-year-old boy with a 5 cm iatrogenic posterior urethral defect was managed by urethral substitution using the appendix. An appendix-free flap was used according to anatomic limitations, employing the transposed inferior epigastric artery and saphenous vein to maintain conduit blood supply. The conduit was buried in the scrotum for 3 weeks and its viability monitored until the final reconstructive stage. Two-year follow-up with ultrasound and cystoscopy revealed satisfactory results. A well-vascularised bed and flap are the mainstays of substitution urethroplasty, so we suggest inferior epigastric artery perineal transposition and staged reconstruction as alternatives that may improve the blood supply of the neourethra.
Primary glottic malignant melanoma of the larynx (PGMML): a very rare entity
Authors: Aggarwal Sumeet , Kaushal Vivek , Singla Sujata , Sen Rajeev
Published: November 2015

Primary glottic malignant melanoma of the larynx (PGMML) is a very rare clinical entity with less than 20 cases reported in the literature so far. The most frequently reported subsite in primary malignant melanomas of the larynx is the supraglottic larynx. The vocal cord as a subsite for primary malignant melanoma is very rare. The present case is a primary glottic malignant melanoma involving both vocal cords. PGMML may present early due to associated hoarseness of voice, unlike other non-cutaneous melanomas in the head and neck. Non-cutaneous malignant melanomas in the head and neck are historically very aggressive in nature and known for poor outcomes and survival. Most non-cutaneous melanomas described in the literature have been superficial spreading or ulcerative in nature, unlike the present case, in which proliferative, polypoidal growth was seen. No associated risk factor was present in this case. Every reported case of this rare entity further adds to the better understanding of tumour biology and expression.
Novel oral anticoagulants and HIV: dabigatran use with antiretrovirals
Authors: Perram Jacinta , Joseph Joanne , Holloway Cameron
Published: November 2015

Compatibility of novel oral anticoagulants in patients with HIV taking combined antiretroviral therapy has not been established, with no published reports of successful concurrent use. We present a case where chronic anticoagulation was indicated in a patient with treated HIV and non-valvular atrial fibrillation who refused warfarin therapy. The patient tolerated the combination, with dabigatran blood levels within the expected range at a standard dosing regimen, without evidence of bleeding or other adverse outcomes. While further research is needed to establish the role of novel oral anticoagulants in patients taking antiretrovirals, this case suggests that dabigatran may be a viable option for selected patients.
A life in veterinary public health
Authors: Radakovic Milorad
Published: November 2015

Milorad Radakovic studied veterinary medicine in Zagreb. Circumstances brought him to the UK in the early 1990s, and he worked in meat inspection while studying for the examinations that would give him full membership of the RCVS
A genomic investigation of the putative contact zone between divergent Brown Creeper (Certhia americana) lineages: chromosomal patterns of genetic differentiation
Authors: Manthey Joseph D. , Robbins Mark B. , Moyle Robert G.
Published: November 2015

Sky islands, or montane forest separated by different lowland habitats, are highly fragmented regions that potentially limit gene flow between isolated populations. In the sky islands of the Madrean Archipelago (Arizona, USA), various taxa display different phylogeographic patterns, from unrestricted gene flow among sky islands to complex patterns with multiple distinct lineages. Using genomic-level approaches allows the investigation of differential patterns of gene flow, selection, and genetic differentiation among chromosomes and specific genomic regions between sky island populations. Here, we used thousands of SNPs to investigate the putative contact zone of divergent Brown Creeper (Certhia americana) lineages in the Madrean Archipelago sky islands. We found the two lineages to be completely allopatric (during the breeding season) with a lack of hybridization and gene flow between lineages and no genetic structure among sky islands within lineages. Additionally, the two lineages inhabit different climatic and ecosystem conditions and have many local primary song dialects in the southern Arizona mountain ranges. We identified a positive relationship between genetic differentiation and chromosome size, but the sex chromosome (Z) was not found to be an outlier. Differential patterns of genetic differentiation per chromosome may be explained by genetic drift—possibly in conjunction with non-random mating and non-random gene flow—due to variance in recombination rates among chromosomes.
Exploring branched Hamiltonians for a class of nonlinear systems
Authors: Bagchi Bijan , Modak Subhrajit , Panigrahi Prasanta K. , Ruzicka František , Znojil Miloslav
Published: November 2015

One of the less well-understood ambiguities of quantization is emphasized to result from the presence of higher-order time derivatives in the Lagrangians resulting in multiple-valued Hamiltonians. We explore certain classes of branched Hamiltonians in the context of nonlinear autonomous differential equation of Liénard type. Two eligible elementary nonlinear models that emerge are shown to admit a feasible quantization along these lines.
Identification of highly deformed even–even nuclei in the neutron- and proton-rich regions of the nuclear chart from the B(E2)↑ and E2 predictions in the generalized differential equation model
Authors: Nayak R. C. , Pattnaik S.
Published: November 2015

We identify here the possible occurrence of large deformations in the neutron- and proton-rich ([Formula: see text]-rich and [Formula: see text]-rich) regions of the nuclear chart from extensive predictions of the values of the reduced quadrupole transition probability [Formula: see text] for the transition from the ground state to the first [Formula: see text] state and the corresponding excitation energy [Formula: see text] of even–even nuclei in the recently developed generalized differential equation (GDE) model exclusively meant for these physical quantities. This is made possible from our analysis of the predicted values of these two physical quantities and the corresponding deformation parameters derived from them such as the quadrupole deformation [Formula: see text], the ratio of [Formula: see text] to the Weisskopf single-particle [Formula: see text] and the intrinsic electric quadrupole moment [Formula: see text], calculated for a large number of both known as well as hitherto unknown even–even isotopes of oxygen to fermium (0 to FM; [Formula: see text]–100). Our critical analysis of the resulting data convincingly support possible existence of large collectivity for the nuclides [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text], whose values of [Formula: see text] are found to exceed 0.3 and even 0.4 in some cases. Our findings of large deformations in the exotic [Formula: see text]-rich regions support the existence of another “island of inversion” in the heavy-mass region possibly caused by breaking of the [Formula: see text] subshell closure.
Hyperspherical three-body model calculation for the bound 3,1S-states of Coulombic systems
Authors: Khan Md. Abdul
Published: November 2015

In this paper, hyperspherical three-body model formalism has been applied for the calculation of energies of the low-lying bound [Formula: see text]-states of neutral helium and helium like Coulombic three-body systems having nuclear charge (z) in the range [Formula: see text]. Energies of [Formula: see text]-states are also calculated for those having nuclear charge in the range [Formula: see text]. The calculation of the coupling potential matrix elements of the two-body potentials has been simplified by the use of Raynal–Revai Coefficients (RRC). The three-body wave function in the Schrödinger equation when expanded in terms of hyperspherical harmonics (HH), leads to an infinite set of coupled differential equation (CDE) which for practical purposes is truncated to a finite set and the truncated set of CDE’s are solved by renormalized Numerov method (RNM) to get the energy (E). The calculated energy is compared with the ones of the literature.
Repatriate Knowledge Sharing Environment: Scale Development and Validation
Authors: Peterson Stacey , Steelman Lisa
Published: November 2015

The transfer of repatriate international knowledge to their colleagues is essential for organisations to capitalise on the benefits international assignments can offer and to gain a competitive edge. Literature on knowledge sharing and repatriate effectiveness was reviewed for the development of the repatriate knowledge sharing environment (RKSE) measure. The first phase of the study created and pilot tested a proposed seven-dimension measure of the RKSE. Phase two confirmed the dimensions of the measure and examined the validity of the measure. The first phase alluded to an eight-dimension RKSE factor structure: source credibility, knowledge quality, source awareness, employee interaction, source recognition, workplace professionalism, supervisor support and promotion of knowledge exchange. Phase two exploratory and confirmatory factor analysis confirmed the eight-dimension RKSE scale. Furthermore, construct validity was found for the eight dimensions of RKSE scale and criterion-related validity was established. Through the use of this new instrument, organisations can improve their understanding of the organisations support towards repatriate knowledge management.
Study on Flow Fields of Boundary-Layer Separation and Hydraulic Jump during Rundown Motion of Shoaling Solitary Wave
Authors: Lin Chang , Kao Ming-Jer , Tzeng Guang-Wei , Wong Wei-Ying , Yang James , Raikar Rajkumar V. , Wu Tso-Ren , Liu Philip Li-Fang
Published: November 2015

The characteristics of flow fields for a complete evolution of the non-breaking solitary wave, having a wave-height to water-depth ratio of 0.363 and propagating over a 1:5 sloping bottom, are investigated experimentally. This study mainly focuses on the occurrences of both flow separation on the boundary layer under an adverse pressure gradient and subsequent hydraulic jump with the abrupt rising of free surface during rundown motion of the shoaling wave, together with emphasis on the evolution of vortex structures underlying the separated shear layer and hydraulic jump. A flow visualization technique with particle trajectory method and a high-speed particle image velocimetry (HSPIV) system with a high-speed digital camera were used. Based on the instantaneous flow images visualized and/or the ensemble-averaged velocity fields measured, the following interesting features, which are unknown up-to-date, are presented and discussed in this study: (1) Flow bifurcation occurring on both offshore and onshore sides of the explicit demarcation curve and the stagnation point during runup motion; (2) The dependence of the diffuser-like flow field, being changed from the supercritical flow in the shallower region to the subcritical flow in the deeper counterpart, on the Froude number during the early and middle stages of rundown motion; (3) The positions and times for the occurrences of the incipient flow separation and the sudden rising of free surface of the hydraulic jump; (4) The associated movement and evolution of vortex structures under the separated shear layer, the hydraulic jump and/or the high-speed external main stream of the retreated flow; and (5) The entrainment of air bubbles from the free surface into the external main stream of the retreated flow.
Iterative Design and Field Trial of an Aphasia-Friendly Email Tool
Authors: Mahmud Abdullah Al , Martens Jean-Bernard
Published: November 2015

In this article, we describe the iterative design and field trial of Amail, an email client specifically designed for people with aphasia who have problems expressing themselves verbally. We conducted a 3-month study with eight persons with aphasia to better understand how people with aphasia could integrate Amail in their daily life. Subjective data (questionnaires, interviews, and diaries) and objective data (usage logs) were collected to gain understanding of the usage patterns. All persons with aphasia in our study were able to use Amail independently, and four participants continued using Amail after the study period. The usage patterns, especially the frequency and length of the composed email messages, indicated that, over time, persons with aphasia were able to improve their email communication. Email partners also had the impression that their email partners with aphasia were improving gradually. Last but not least, the use of Amail positively influenced the number and quality of social contacts for the persons with aphasia. We also report some of the challenges encountered while conducting the field trial.
Analyzing the Network for AWS Distributed Cloud Computing
Authors: Gandhi Anshul , Chan Justin
Published: November 2015

Cloud computing is a global service. Cloud Service Providers, such as AWS, allow users to launch VM instances on multiple data centers (regions) around the world. However, the network connectivity and bandwidth between these different geographically distributed regions varies significantly depending on the user's location. In this paper, we analyze the network performance between pairs of AWS instances hosted on all available regions. We leverage our analysis to derive the optimal hosting region for web service providers depending on the customer locations.
Towards Designing a Truthful Online Auction Framework for Deadline-aware Cloud Resource Allocation
Authors: Zhang Tianrong , Xin Yufeng
Published: November 2015

Auction-based resource allocation mechanisms have been believed as promising approaches to effectively managing cloud resource supply and demand, and thus recently attracted substantial research interests. In this paper, we present a novel online auction framework for deadline-aware cloud resource allocation. Our framework consists of two major parts. We first design an offline auction mechanism taking into account deadline requirements from different resource requests, and further present an online framework built on top of the offline auction mechanism. Our theoretical analysis shows that both the offline and online auction mechanisms are truthful.
Impact of age on the vasodilatory function of human skeletal muscle feed arteries
Authors: Park Song-Young , Ives Stephen J. , Gifford Jayson R. , Andtbacka Robert H. I. , Hyngstrom John R. , Reese Van , Layec Gwenael , Bharath Leena P. , Symons John D. , Richardson Russell S.
Published: November 2015

Although advancing age is often associated with attenuated skeletal muscle blood flow and skeletal muscle feed arteries (SMFAs) have been recognized to play a regulatory role in the vasculature, little is known about the impact of age on the vasodilatory capacity of human SMFAs. Therefore, endothelium-dependent and -independent vasodilation were assessed in SMFAs (diameter: 544 ± 63 μm) obtained from 24 (equally represented) young (33 ± 2 yr) and old (71 ± 2 yr) subjects in response to three stimuli: 1) flow-induced shear stress, 2) ACh, and 3) sodium nitropusside (SNP). Both assessments of endothelium-dependent vasodilation, flow (young subjects: 68 ± 1% and old subjects: 32 ± 7%) and ACh (young subjects: 92 ± 3% and old subjects: 73 ± 4%), were significantly blunted ( P < 0.05) in SMFAs of old compared with young subjects, with no such age-related differences in endothelium-independent vasodilation (SNP). In response to an increase in flow-induced shear stress, vasodilation kinetics (time constant to reach 63% of the amplitude of the response: 55 ± 1 s in young subjects and 92 ± 7 s in old subjects) and endothelial nitric oxide synthase (eNOS) activation (phospho-eNOSs1177/total eNOS: 1.0 ± 0.1 in young subjects and 0.2 ± 0.1 in old subjects) were also significantly attenuated in old compared with young subjects ( P < 0.05). Furthermore, the vessel superoxide concentration was greater in old subjects (old subjects: 3.9 ± 1.0 area under curve/mg and young subjects: 1.7 ± 0.1 area under the curve/mg, P < 0.05). These findings reveal that the endothelium-dependent vasodilatory capacity, including vasodilation kinetics but not smooth muscle function, of human SMFAs is blunted with age and may be due to free radicals. Given the potential regulatory role of SMFAs in skeletal muscle blood flow, these findings may explain, at least in part, the often observed attenuated perfusion of skeletal muscle with advancing age that may contribute to exercise intolerance in the elderly.
Abstract A1-14: Discovery of a functional SNP in an estrogen receptor binding site in the IGF1R gene
Authors: Bahreini Amir , Bahreini Amir , Santanas Lucas , Wang Peilu , Benos Panayiotis V. , Lee Adrian V. , Lee Adrian V. , Oesterreich Steffi , Oesterreich Steff
Published: November 2015

Estrogen receptor (ER) positive luminal breast cancer represents approx 70% of all newly diagnosed breast cancers. ER is known to drive breast cancer development and progression, and targeting ER has been one of the most successful targeted therapies in oncology. Given the paucity of functional DNA sequence variants (DSVs) within the ER in primary breast tumors, we asked whether DSVs in ER binding sites could contribute to altered hormone response through changes in ER recruitment to DNA.

We developed a pipeline to extract DSVs in ER binding sites, and to assess their impact on ER binding in a genome-wide manner, using ChIP-seq data from hormone responsive breast cancer cells. We utilized MACS for peak calling and GATK for calling DSVs including SNVs and short indels. Using 22,143 ER binding sites which overlapped in at least six data sets, we detected 1,409,406 DSVs from 441,855,039 reads. Position weight matrix (PWM) was used to scan the genome for potential ERE motifs, and identified 126 potential DSVs which were predicted to change ER binding. Of those, 29 DSV-containing EREs were in proximity or within estrogen regulated genes. Intriguingly, the top hit was a previously reported SNP within intron 2 of the IGF1R gene (rs62022087), which our data predicted to increase the affinity for ER binding. The ERE lies in a regulatory region characterized by active histone marks such as H3K29ac and H3k4Me1, and recruitment of a number of transcription factors including c-myc, FoxA1, GATA-1, and finally DNase I hypersensitive sites. Further analysis of published ChIP-seq studies on 6 ER+ cell lines and 15 primary tumors revealed that the presence of rs62022087 was associated with the enrichment of reads over the ER binding site, suggesting that the DSV indeed increases binding affinity of ER. Our further in-vitro functional studies confirmed that ER is more preferentially binding to mutant allele vs wild-type allele.

In summary, we have shown that our pipeline is capable of predicting potential regulatory DSVs in ER binding sites. Studies are ongoing to understand functional and clinical relevance of rs62022087, especially with respect to crosstalk between estrogen and IGF1 signaling.

Citation Format: Amir Bahreini, Amir Bahreini, Lucas Santanas, Peilu Wang, Panayiotis V. Benos, Adrian V. Lee, Adrian V. Lee, Steffi Oesterreich, Steff Oesterreich. Discovery of a functional SNP in an estrogen receptor binding site in the IGF1R gene. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-14.
Abstract A1-28: Chromosome fusions triggered by noncoding RNA
Authors: Bracht John , Wang Xing , Shetty Keerthi , Chen Xiao , Nowacki Mariusz , McCloud Sierra , Clay Derek , Landweber Laura
Published: November 2015

Chromosomal fusion is a frequent occurrence in cancer cells and can promote transformation through the generation of oncogenic gene products. There are two non-exclusive models for how these chromosome fusions may occur: (1) the instability of the cancer genome produces chromosomal fusions randomly and those promoting transformation enjoy a selective advantage, or (2) some non-random mechanism drives chromosome fusion. Evidence for (2) comes from recurrent fusion events and correlative human data linking noncoding RNA expression with chromosome fusion. To help address this important fundamental question, we functionally tested the role of noncoding RNA, specifically piRNAs, in promoting chromosomal fusion in the ciliate, Oxytricha trifallax, a microbial eukaryote. We microinjected custom piRNAs into cells and observed chromosome fusion in four cases (of four tested), including a double fusion event and a chromosome circularization event (self-fusion). Furthermore, these RNA-mediated inter-and-intra-chromosomal fusions are heritable over multiple sexual generations, illustrating the ability of noncoding RNAs to program genome architecture, including chromosome fusion and circularization.

Citation Format: John Bracht, Xing Wang, Keerthi Shetty, Xiao Chen, Mariusz Nowacki, Sierra McCloud, Derek Clay, Laura Landweber. Chromosome fusions triggered by noncoding RNA. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-28.
Abstract A1-48: Whole genome expression based drug repurposing
Authors: Geeleher Paul , Bhutra Steven , Wang Jacqueline , Huang R. Stephanie
Published: November 2015

Currently, personalizing cancer chemotherapy relies on pathology and more recently molecular biomarker-based approaches. However, as the driving biology is normally not fully understood, the majority of existing biomarkers do not capture a substantial proportion of variability in drug response. This partly explains the commonly observed lack of reproducibility of findings (e.g. from many conventional gene expression signatures) when these markers are applied to new datasets. We developed an approach to predict in vivo drug sensitivity that leverages whole-genome gene expression microarray data and allows the expression of every gene to influence the prediction by a small amount. Our approach builds statistical models from gene expression and drug sensitivity data in a very large panel of cell lines, then applies these models to gene expression data from primary tumor biopsies. In this study, we applied this approach to tumor samples collected in The Cancer Genome Atlas (TCGA). We derived predicted sensitivity for over one hundred drugs in each of the tumor samples. As a proof-of-concept, we demonstrated that a targeting agent (lapatinib) designed against a specific tumor marker (HER2 positive) is indeed predicted to be more sensitive in HER2 positive breast cancers when compared to the other type of cancers. Meanwhile, we identified other agents that exhibit similar or superior sensitivity when compared to commonly prescribed agents in different disease settings. These findings warrant further evaluation of these agents to be repurposed for possible new indications. Interestingly, some of our derived drug sensitivity predictive estimates are correlated with observed survival outcomes in certain cancer patients. When screening all tumor types based on their molecular profiles, we defined several classes of drugs that maybe differentially effective based on tumor molecular profiles. In conclusion, a genome-wide expression drug sensitivity model built in cell lines can be a powerful approach in repurposing drug in cancer treatment.

Citation Format: Paul Geeleher, Steven Bhutra, Jacqueline Wang, R. Stephanie Huang. Whole genome expression based drug repurposing. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-48.
Abstract A1-54: Pan-cancer analysis of the etiology and consequences of intratumor heterogeneity
Authors: Andor Noemi , Graham Trevor A. , Petritsch Claudia , Ji* Hanlee P. , Maley* Carlo C.
Published: November 2015

This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR03) of the Conference Proceedings.

Citation Format: Noemi Andor, Trevor A. Graham, Claudia Petritsch, Hanlee P. Ji*, Carlo C. Maley*. Pan-cancer analysis of the etiology and consequences of intratumor heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-54.
Abstract A1-56: Applying TCGA data for breast cancer diagnostics and pathway analysis
Authors: Andersen Jannik , Shah Parantu , Ibbs Matthew , Filas Violetta , Korski Konstanty , Marszalek Andrzej , Wu Yuanqing , Chang Edward , Toniatti Carlo , Draetta Giulio , Wiznerowicz Maciej
Published: November 2015

The main objective of our project is to obtain a comprehensive insight into oncogenic signaling in order to develop novel diagnostic tools for molecular subtypes of breast cancer (BRCA). We have provided about 100 BRCA samples along with full pathology and clinical annotations to the TCGA program. These cancer samples have been extensively characterized using all available genomics platforms and the obtained molecular data contributed to the molecular characterization of BRCA. This integrated effort identified four major molecular subtypes of breast cancer that can be identified across five profiling platform including genomics, transcriptomics and proteomics (Nature, 490 (7418):61-70). Building upon these datasets we aim to translate these genomics profiles into diagnostic tools that can be used in every day medical practice. In the first step, we have generated tissue microarrays (TMAs) from FFPE BRCA samples obtained from the patients enrolled into the TCGA project. Next, the TMA slides were used for immunohistochemistry (IHC) using about 100 antibodies specific for major cancer markers, including oncogenic kinases frequently activated or overexpressed in BRCA. The obtained IHC results have been scored and verified independently for each marker by two board-certified pathologists. To identify markers that correlate with or are specific to the molecular subtypes of BRCA, the TMA/IHC read- outs from each tumor sample were correlated with all TCGA genomic data. In addition, we integrate the pathology and genomics results with clinical data obtained from the TCGA-enrolled patients, including up to 4 years follow-up. Finally, we apply system biology tools to integrate the genomic data from TCGA with the proteomic analysis to understand causalities between changes in DNA, transcriptome and signal transduction pathways. Our long-term goal is to identify novel diagnostic biomarkers that will precisely identify each molecular subtype of BRCA and which may be predictive of patient response to therapy thus paving the way for novel personalized therapies for cancer.

Note: This abstract was not presented at the conference.

Citation Format: Jannik Andersen, Parantu Shah, Matthew Ibbs, Violetta Filas, Konstanty Korski, Andrzej Marszalek, Yuanqing Wu, Edward Chang, Carlo Toniatti, Giulio Draetta, Maciej Wiznerowicz. Applying TCGA data for breast cancer diagnostics and pathway analysis. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-56.
Abstract A1-69: Predicting drug response by profiling the epigenome: Super-enhancers as biomarkers
Authors: Orlando David A. , McKeown Michael R. , Chen Mei Wei , Collins Cindy , Guenther Matthew G. , Fritz Christian C.
Published: November 2015

Identifying biomarkers that predict clinical responses to anticancer therapies is an important challenge in oncology. A desirable biomarker is a cell-identifying feature that can distinguish between drug responsive and unresponsive cell types. Most of the best studied biomarkers are gene mutations or copy-number changes, where the genomic alteration is the key defining feature. However, not all differences in clinical responses can be attributed to genetic differences. Therefore, it is critical that we identify other cellular features that can predict response. A recently described epigenomic feature, termed super-enhancer (SE), defines key cell identity and disease genes and SEs are effectors of initiating and maintaining cell type-specific gene expression programs. In this work we generate super-enhancer maps across multiple cancer cell lines and connect those maps to response to different drug treatments. We show that super-enhancers can be used as biomarkers to predict response to drugs across multiple cell-line models of cancer. This work suggests that interrogating epigenomic features, and in particular super-enhancers, can be a powerful biomarker discovery platform and can enable rational patient selection and therapeutic strategies.

Citation Format: David A. Orlando, Michael R. McKeown, Mei Wei Chen, Cindy Collins, Matthew G. Guenther, Christian C. Fritz. Predicting drug response by profiling the epigenome: Super-enhancers as biomarkers. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A1-69.
Abstract A2-66: Integrative analysis of gene expression and metabolism in isocitrate dehydrogenase 1 mutant acute myeloid leukemia and myeloid knock in mouse model
Authors: Tseng Alan , Li Wanda , Lee Kim-Chung , Yung Karrie , Lam Ching-Wan , Mak Tak
Published: November 2015

Isocitrate dehydrogenase 1 (IDH1) mutations are common drivers of acute myeloid leukemia (AML). While mutant IDH1 is known to disrupt DNA methylation, gene expression, and metabolism in cell lines, it is not known how mutant IDH1 alters global metabolism in vivo. The purpose of this study is to find differential enzymes and metabolites in IDH1 wild type versus mutant AML and knock in mice by integrating differential genes and metabolites in a metabolic network.

Differential genes were found by comparing gene expression and DNA methylation in IDH1 mutant (n = 12) and wild type (n = 89) cytogenetically normal AML patients from The Cancer Genome Atlas. Differential metabolites were found by untargeted liquid chromatography-mass spectrometry of urine, plasma, and bone marrow hematopoietic stem and progenitor cells from unpaired 1-2 year old mixed-sex IDH1 myeloid knock in (n = 13) and control mice (n = 14). Integrative analysis was performed using the MetScape 2 Cytoscape plugin.

71 differential genes and 52 differential metabolites were mapped to the global metabolic network. The set of differential genes and metabolites formed 10 connected subnetworks containing reactions in sphingolipid, phospholipid, and bile acid metabolism. Two enzymes in the subnetworks were differentially expressed in an independent IDH1 mutant versus wild type AML dataset: acyl-CoA thioesterase 4 (ACOT4) and galactosylceramidase (GALC) (P < 0.05, false discovery rate ≤ 0.3). ACOT4 and GALC were significantly upregulated (P < 0.02) in acute promyelocytic leukemia cells treated with all-trans retinoic acid.

In conclusion, we have found novel differential genes and metabolites in IDH1 mutant systems which may be relevant to leukemia differentiation treatment. Integrative analysis of gene expression and metabolite levels could be useful for finding dysregulated metabolic subnetworks in cancer.

Citation Format: Alan Tseng, Wanda Li, Kim-Chung Lee, Karrie Yung, Ching-Wan Lam, Tak Mak. Integrative analysis of gene expression and metabolism in isocitrate dehydrogenase 1 mutant acute myeloid leukemia and myeloid knock in mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-66.
Abstract IA02: Cancer genomics: Translational challenges
Authors: Griffith Malachi , Griffith Obi , Spies Nicholas , Ainscough Benjamin , Skidmore Zachary , Trani Lee , Ramu Avinash , Krysiak Killanin , Mardis Elaine R.
Published: November 2015

The use of next-generation sequencing and analysis has become the standard approach to studying cancer genomics in the research setting. The knowledge gained has been considerable across multiple tumor types, in many ways changing our perceptions about the genomic basis for cancer. Coincident with this new information is the continuing development and introduction of targeted therapies for cancer treatment. Bringing these two developments together is exciting and challenging for numerous reasons. My talk will focus on some of the challenges that are commonly faced, on the decision-support tools and databases we are creating to help with these challenges, and the ways in which the clinical cancer expert can contribute to these tools.

Citation Format: Malachi Griffith, Obi Griffith, Nicholas Spies, Benjamin Ainscough, Zachary Skidmore, Lee Trani, Avinash Ramu, Killanin Krysiak, Elaine R. Mardis. Cancer genomics: Translational challenges. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA02.
Abstract IA14: Single-cell sequencing in cancer genomics
Authors: Love J. Christopher
Published: November 2015

Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming multiple hurdles. This talk will present a collaborative research program that has generated an integrated process to isolate, qualify, and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs.

We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis, and nine cores of the primary tumor. 51 of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes.

The talk will also present some technical considerations for enabling single-cell sequencing of tumor cells, including a description of statistical methods to quantitatively assess the amplification bias resulting from whole-genome amplification of single-cell genomic DNA.

This study establishes a foundation for CTC genomics in the clinic, and initial applications to patient monitoring will be described.

Citation Format: J. Christopher Love. Single-cell sequencing in cancer genomics. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA14.
Abstract IA18: The application of integrative sequencing for precision oncology
Authors: Chinnaiyan Arul
Published: November 2015

Studies of the genomic landscape of human cancers have demonstrated that most solid cancers have a multitude of mutations, a subset of which may be actionable with current drugs. Thus, the personalization of therapy for cancer will require molecular characterization of unique and shared genetic aberrations. Patients who have advanced/refractory cancer and are candidates for clinical trials could potentially benefit by identifying eligibility for targeted drugs based on the actionable genes in their specific tumor. Growing technological advances in genomic sequencing has now made it possible to consider the use of sequence data in a clinical setting. MI-ONCOSEQ initiative brings together expertise at the University of Michigan including clinical oncology, cancer genetics, bioinformatics, clinical pathology, social and behavioral sciences, and bioethics in order to implement clinical cancer sequencing. Our study identifies patients with advanced or refractory cancers that are eligible for clinical trials, consent them to the study, obtain biospecimens (tumor tissue, germline tissue) and store clinical data. The clinical sequencing team processes biospecimens, performs comprehensive sequencing and analysis of tumors to identify point mutations, copy number changes, rearrangements/gene fusions, and aberrant gene expression. Finally, a multi-disciplinary Sequencing Tumor Board deliberates on return of actionable or incidental genomic results.

Citation Format: Arul Chinnaiyan. The application of integrative sequencing for precision oncology. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA18.
Abstract IA19: Towards the next clinical option: Experience from a precision cancer medicine trial
Authors: Rubin Mark A.
Published: November 2015

Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low frequency mutations. We describe an evidence-based precision medicine program designed to bring whole exome sequencing (WES) into clinical practice and illustrate how this can be utilized to identify novel predictive biomarkers associated with exceptional systemic response.

Metastatic and treatment-resistant cancer patients are prospectively enrolled for paired metastatic tumor and normal WES. Using a comprehensive computational pipeline, point mutations, indels and copy number alterations are detected. Mutations are categorized as Category I-III based on actionability and a report is generated and discussed in tumor board. Patients are followed prospectively for correlation of molecular information with clinical response and patient outcomes. A rapid response functional team follows on key findings to expand actionability based on the WES results.

In the first year, 154 tumor-normal pairs from 97 patients were sequenced, with an average coverage of 95X of over 21,000 genes and 16 somatic alterations detected on average per patient. In total, 16 mutations were Category I, 98 were Category II, and 1474 were Category III. Tumor purity ranged from 14 to near 100%. Among unexpected findings, a prostate cancer exceptional responder was identified that harbored a somatic hemizygous deletion of the DNA repair gene FANCA and likely loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response.

The establishment of a clinical program for whole exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response.

Citation Format: Mark A. Rubin. Towards the next clinical option: Experience from a precision cancer medicine trial. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA19.
Abstract PR09: The prognostic landscape of genes and infiltrating immune cells across human cancers
Authors: Gentles Andrew J. , Newman Aaron M. , Liu Chih Long , Bratman Scott V. , Feng Weiguo , Kim Dongkyoon , Nair Viswam S. , Yue Xu , Khuong Amanda , Hoang Chuong D. , Diehn Maximilian , West Robert B. , Plevritis Sylvia K. , Alizadeh Ash A.
Published: November 2015

Molecular profiles of tumors and tumor-associated cells hold great promise as biomarkers of clinical outcomes. However, existing datasets are fragmented and difficult to analyze systematically. We present a pan-cancer resource and comprehensive meta-analysis of expression signatures from ~18,000 human tumors with overall survival outcomes across 39 malignancies. While a third of prognostic genes were cancer-specific, a FOXM1 regulatory network is a major predictor of adverse outcomes, while favorably prognostic genes largely reflect tumor-associated leukocytes. Using a novel computational approach, we enumerated leukocyte subsets in bulk tumor transcriptomes, revealing complex novel malignancy-specific associations between 22 distinct leukocytes and cancer survival. Tumor-associated neutrophil-like polymorphonuclear cell and plasmacytic cells emerged as significant but opposite predictors of survival for diverse solid tumors, including breast and lung adenocarcinomas. Our results introduce new analytical tools for delineating prognostic genes and leukocytes within and across cancers, and shed light on the impact of tumour heterogeneity on cancer outcomes, with applications for discovering novel biomarkers and therapeutic targets

Citation Format: Andrew J. Gentles, Aaron M. Newman, Chih Long Liu, Scott V. Bratman, Weiguo Feng, Dongkyoon Kim, Viswam S. Nair, Xu Yue, Amanda Khuong, Chuong D. Hoang, Maximilian Diehn, Robert B. West, Sylvia K. Plevritis, Ash A. Alizadeh. The prognostic landscape of genes and infiltrating immune cells across human cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr PR09.
Melanocortin-4 Receptor Gene Variation Is Associated with Eating Behavior in Chilean Adults
Authors: Vega Javier A. , Salazar Gloria , Hodgson María Isabel , Cataldo Luis Rodrigo , Valladares Macarena , Obregón Ana María , Santos José Luis
Published: November 2015

Background/Aims: To evaluate the association between allelic variants of melanocortin receptors -3 and -4 (MC3R and MC4R, respectively) and leptin receptor (LEPR) genes with body mass index (BMI) and eating behavior. Methods: We selected 344 Chilean adults (57.8% women; age 39.1 ± 6.6 years) with a wide variation in BMI (30.3 ± 6.3 kg/m2). The Three-Factor Eating Questionnaire-R18 that measures uncontrolled eating (UE), emotional eating (EE) and cognitive restraint scores was adapted, validated and assessed for association with BMI. Genotypes were determined by polymerase chain reaction followed by restriction fragment length polymorphism techniques and Taqman assays. Results: Higher EE scores were found in obese vs. non-obese in both men (p = 0.01) and women (p < 0.001). UE scores were significantly associated with BMI only in women (p = 0.002). No significant differences in eating behavior scores or BMI were found by LEPR (rs1137101, rs8179183 and rs1137100 polymorphisms) or MC3R (rs3746619 and rs3827103). Carriers of the C allele for MC4R rs17782313 showed significantly higher scores of UE compared to non-carriers (2.3 ± 0.8 vs. 2.0 ± 0.7; p = 0.02). Additionally, we also report a monogenic case of obesity carrying the pathogenic mutation 449C>T (Thr150Ile) in MC4R gene with no apparent alterations in eating behavior scores. Conclusions: UE scores were higher in C-allele carriers of MC4R-rs17782313 compared to non-carriers.