bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA14: Single-cell sequencing in cancer genomics
Authors: Love J. Christopher 
Published: November 2015

Abstract
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 &gt;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

Abstract
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

Abstract
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

Abstract
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.
Balancing in Neorealism
Authors: Parent Joseph M. , Rosato Sebastian 
Published: November 2015

Abstract
Does neorealism offer a convincing account of great power balancing behavior? Many scholars argue that it does not. This conclusion rests on a misunderstanding of neorealist theory and an erroneous reading of the evidence. Properly specified, neorealism holds that great powers place an overriding emphasis on the need for self-help. This means that they rely relentlessly both on arming and on imitating the successful military practices of their peers to ensure their security. At the same time, they rarely resort to alliances and treat them with skepticism. There is abundant historical evidence to support these claims. Since 1816, great powers have routinely achieved an effective balance in military capabilities with their relevant competitors and promptly copied the major military innovations of the period. Case studies show that these outcomes are the product of states' efforts to ensure security against increasingly capable rivals. Meanwhile, the diplomatic record yields almost no examples of firm peacetime balancing coalitions over the past 200 years. When alliances have formed, great powers have generally doubted the reliability of their allies and of their opponents' allies. Thus neorealism provides a solid foundation for explaining great power balancing behavior.
Spectral Characteristics of Instrumental and Climate Model Surface Temperatures
Authors: Fredriksen Hege-Beate , Rypdal Kristoffer 
Published: November 2015

Abstract
The spatiotemporal temperature variability for several gridded instrumental and general circulation climate model data is characterized, contrasting power spectra of local and global temperatures, land and sea temperatures, and temperatures of different regions. There is generally a high degree of agreement between the spectral characteristics of instrumental and climate model data. All but the equatorial spectra exhibit a power-law shape and are hence more consistent with the spectra expected from long-memory processes than from short-memory processes. The power-law exponent β of the spectra is a measure of memory, or persistence, of the temperatures and is observed to be about twice as large for global temperature than for local temperatures. However, there are large variations, in particular between land and sea surface temperatures. This is shown by estimates of the spectra for different regions and global maps of β. It is also demonstrated that global spectra are related to local spectra via teleconnections between local temperatures.
Climatology of Wind, Kinetic Energy, and Temperature Spectra Using a High-Resolution Climate Model for Mid-Europe
Authors: Zentek Rolf , Heinemann Günther , Sachs Ekkehard 
Published: November 2015

Abstract
Spectra of wind, kinetic energy, and temperature are investigated for a dataset of 10 years of regional climate simulations for mid-Europe. The nonhydrostatic Consortium for Small-Scale Modeling (COSMO) model in Climate Mode [COSMO-CLM (CCLM)] climate model is used in a hindcast mode for 1991–2000. The three-step nesting chain starts with a CCLM run with 18-km resolution covering all of Europe nested in ERA-40 reanalyses and then a run with a resolution of 4.4 km is performed for mid-Europe. Finally, the 1.3-km run focuses on the region of mid-Germany and Luxembourg. In the present study, only results for the 4.4- and 1.3-km runs are shown. Different methods based on the Fourier and cosine transformations for the computation of the spectra are evaluated.
The kinetic energy spectra show the expected slope in the mesoscale (up to the effective resolution), while the spectrum of the vertical wind shows a zero-slope behavior. The spectra of the horizontal wind components and temperature compare well to the observations. The effective model resolution was found to be about 7–10 (5–7) times the horizontal grid spacing for the one-dimensional (two-dimensional) spectral methods. A comparison between the different model resolutions shows a benefit of the 1.3-km simulations for the boundary layer for horizontal scales up to 25 km. The multiyear time-scale simulations allow for a climatological study of the seasonal cycle. The kinetic energy spectrum is found to have the largest values in summer.
Wind, Waves, and Fronts: Frictional Effects in a Generalized Ekman Model
Authors: Wenegrat Jacob O. , McPhaden Michael J. 
Published: November 2015

AbstractOcean currents in the surface boundary layer are sensitive to a variety of parameters not included in classic Ekman theory, including the vertical structure of eddy viscosity, finite boundary layer depth, baroclinic pressure gradients, and surface waves. These parameters can modify the horizontal and vertical flow in the near-surface ocean, making them of first-order significance to a wide range of phenomena of broad practical and scientific import. In this work, an approximate Green’s function solution is found for a model of the frictional ocean surface boundary layer, termed the generalized Ekman (or turbulent thermal wind) balance. The solution admits consideration of general, more physically realistic forms of parameters than previously possible, offering improved physical insight into the underlying dynamics. Closed form solutions are given for the wind-driven flow in the presence of Coriolis–Stokes shear, a result of the surface wave field, and thermal wind shear, arising from a baroclinic pressure gradient, revealing the common underlying physical mechanisms through which they modify currents in the ocean boundary layer. These dynamics are further illustrated by a case study of an idealized two-dimensional front. The solutions, and estimates of the global distribution of the relative influence of surface waves and baroclinic pressure gradients on near-surface ocean currents, emphasize the broad importance of considering ocean sources of shear and physically realistic parameters in the Ekman problem.
A comparison of human and mouse gene co-expression networks reveals conservation and divergence at the tissue, pathway and disease levels
Authors: Monaco Gianni , van Dam Sipko , Casal Novo Ribeiro João Luis , Larbi Anis , de Magalhães João Pedro 
Published: November 2015

Abstract
Background
A deeper understanding of differences and similarities in transcriptional regulation between species can uncover important information about gene functions and the role of genes in disease. Deciphering such patterns between mice and humans is especially important since mice play an essential role in biomedical research.

Results
Here, in order to characterize evolutionary changes between humans and mice, we compared gene co-expression maps to evaluate the conservation of co-expression. We show that the conservation of co-expression connectivity of homologous genes is negatively correlated with molecular evolution rates, as expected. Then we investigated evolutionary aspects of gene sets related to functions, tissues, pathways and diseases. Genes expressed in the testis, eye and skin, and those associated with regulation of transcription, olfaction, PI3K signalling, response to virus and bacteria were more divergent between mice and humans in terms of co-expression connectivity. Surprisingly, a deeper investigation of the PI3K signalling cascade revealed that its divergence is caused by the most crucial genes of this pathway, such as mTOR and AKT2. On the other hand, our analysis revealed that genes expressed in the brain and in the bone, and those associated with cell adhesion, cell cycle, DNA replication and DNA repair are most strongly conserved in terms of co-expression network connectivity as well as having a lower rate of duplication events. Genes involved in lipid metabolism and genes specific to blood showed a signature of increased co-expression connectivity in the mouse. In terms of diseases, co-expression connectivity of genes related to metabolic disorders is the most strongly conserved between mice and humans and tumor-related genes the most divergent.

Conclusions
This work contributes to discerning evolutionary patterns between mice and humans in terms of gene interactions. Conservation of co-expression is a powerful approach to identify gene targets and processes with potential similarity and divergence between mice and humans, which has implications for drug testing and other studies employing the mouse as a model organism.
Evolutionary comparison of prenylation pathway in kinetoplastid Leishmania and its sister Leptomonas
Authors: Chauhan Indira Singh , Kaur Jaspreet , Krishna Shagun , Ghosh Arpita , Singh Prashant , Siddiqi Mohammad Imran , Singh Neeloo 
Published: November 2015

Abstract
Background
Leptomonas is monogenetic kinetoplastid parasite of insects and is primitive in comparison to Leishmania. Comparative studies of these two kinetoplastid may share light on the evolutionary transition to dixenous parasitism in Leishmania. In order to adapt and survive within two hosts, Leishmania species must have acquired virulence factors in addition to mechanisms that mediate susceptibility/resistance to infection in the pathology associated with disease. Rab proteins are key mediators of vesicle transport and contribute greatly to the evolution of complexity of membrane transport system. In this study we used our whole genome sequence data of these two divergent kinetoplastids to analyze the orthologues/paralogues of Rab proteins.

Results
During change of lifestyle from monogenetic (Leptomonas) to digenetic (Leishmania), we found that the prenyl machinery remained unchanged. Geranylgeranyl transferase-I (GGTase-I) was absent in both Leishmania and its sister Leptomonas. Farnesyltransferase (FTase) and geranylgeranyl transferase-II (GGTase-II) were identified for protein prenylation. We predict that activity of the missing alpha-subunit (α-subunit) of GGTase-II in Leptomonas was probably contributed by the α-subunit of FTase, while beta-subunit (β-subunit) of GGTase-II was conserved and indicated functional conservation in the evolution of these two kinetoplastids. Therefore the β-subunit emerges as an excellent target for compounds inhibiting parasite activity in clinical cases of co-infections. We also confirmed that during the evolution to digenetic life style in Leishmania, the parasite acquired capabilities to evade drug action and maintain parasite virulence in the host with the incorporation of short-chain dehydrogenase/reductase (SDR/MDR) superfamily in Rab genes.

Conclusion
Our study based on whole genome sequences is the first to build comparative evolutionary analysis and identification of prenylation proteins in Leishmania and its sister Leptomonas. The information presented in our present work has importance for drug design targeted to kill L. donovani in humans but not affect the human form of the prenylation enzymes.
Identification of the Long-Sought Leptin in Chicken and Duck: Expression Pattern of the Highly GC-Rich Avian leptin Fits an Autocrine/Paracrine Rather Than Endocrine Function
Authors: Seroussi Eyal , Cinnamon Yuval , Yosefi Sara , Genin Olga , Smith Julia Gage , Rafati Nima , Bornelöv Susanne , Andersson Leif , Friedman-Einat Miriam 
Published: November 2015

AbstractMore than 20 years after characterization of the key regulator of mammalian energy balance, leptin, we identified the leptin (LEP) genes of chicken (Gallus gallus) and duck (Anas platyrhynchos). The extreme guanine-cytosine content (∼70%), the location in a genomic region with low-complexity repetitive and palindromic sequence elements, the relatively low sequence conservation, and low level of expression have hampered the identification of these genes until now. In vitro-expressed chicken and duck leptins specifically activated signaling through the chicken leptin receptor in cell culture. In situ hybridization demonstrated expression of LEP mRNA in granular and Purkinje cells of the cerebellum, anterior pituitary, and in embryonic limb buds, somites, and branchial arches, suggesting roles in adult brain control of energy balance and during embryonic development. The expression patterns of LEP and the leptin receptor (LEPR) were explored in chicken, duck, and quail (Coturnix japonica) using RNA-sequencing experiments available in the Short Read Archive and by quantitative RT-PCR. In adipose tissue, LEP and LEPR were scarcely transcribed, and the expression level was not correlated to adiposity. Our identification of the leptin genes in chicken and duck genomes resolves a long lasting controversy regarding the existence of leptin genes in these species. This identification was confirmed by sequence and structural similarity, conserved exon-intron boundaries, detection in numerous genomic, and transcriptomic datasets and characterization by PCR, quantitative RT-PCR, in situ hybridization, and bioassays. Our results point to an autocrine/paracrine mode of action for bird leptin instead of being a circulating hormone as in mammals.
Reducing Adiposity in a Critical Developmental Window Has Lasting Benefits in Mice
Authors: Lerea Jaclyn S. , Ring Laurence E. , Hassouna Rim , Chong Angie C. N. , Szigeti-Buck Klara , Horvath Tamas L. , Zeltser Lori M. 
Published: November 2015

AbstractAlthough most adults can lose weight by dieting, a well-characterized compensatory decrease in energy expenditure promotes weight regain more than 90% of the time. Using mice with impaired hypothalamic leptin signaling as a model of early-onset hyperphagia and obesity, we explored whether this unfavorable response to weight loss could be circumvented by early intervention. Early-onset obesity was associated with impairments in the structure and function of brown adipose tissue mitochondria, which were ameliorated by weight loss at any age. Although decreased sympathetic tone in weight-reduced adults resulted in net reductions in brown adipose tissue thermogenesis and energy expenditure that promoted rapid weight regain, this was not the case when dietary interventions were initiated at weaning. Enhanced energy expenditure persisted even after mice were allowed to resume overeating, leading to lasting reductions in adiposity. These findings reveal a time window when dietary interventions can produce metabolic improvements that are stably maintained.