bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY16-03: Enterprise-wide clinical sequencing to match patients to personalized cancer treatments
Authors: Berger Michael F. 
Published: August 2015

Abstract
Massively parallel sequencing of tumors enables the identification of oncogenomic mutations that correlate with response and resistance to targeted therapies and the prospective detection of these biomarkers in patients with cancer. At Memorial Sloan Kettering Cancer Center, we have developed and optimized a targeted sequencing panel encompassing more than 300 key cancer associated genes (MSK-IMPACT), which we have applied to prospectively profile several thousands of tumors in the clinical setting. The large-scale implementation of our clinical assay has allowed us to identify targetable mutations in patients with many types of cancer and to match patients to the most appropriate clinical trials. I will discuss general challenges and considerations involved in the establishment of an infrastructure for precision oncology at a large center, including challenges in the analysis and management of data and the clinical interpretation of genomic results. I will also present results from our molecular profiling initiative, including several cases in which they have directly influenced patient management.
Citation Format: Michael F. Berger. Enterprise-wide clinical sequencing to match patients to personalized cancer treatments. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY16-03. doi:10.1158/1538-7445.AM2015-SY16-03
Abstract SY19-01: Therapeutic network re-wiring of the DNA damage response can be used to enhance tumor killing by cytotoxic chemotherapy
Authors: Lee Michael J. , Dayma Yogesh , Heijinks Anne-Margriet , Morton Stephen W. , Dreaden Erik C. , Hammond Paula T. , Yaffe Michael B. 
Published: August 2015

Abstract
Dynamic re-wiring of signaling networks is a prominent mechanism responsible for the development of resistance to many molecular-targeted anti-cancer agents. Here we show how this same dynamic re-wiring process can be used therapeutically to enhance the response of tumors to cytotoxic anti-cancer agents. Using cell lines and murine tumor models of triple-negative breast cancer, non-small cell lung cancer, and head and neck cancer, we show that chronic inhibition of EGFR and/or FGFR driver oncogenes dramatically enhances cell death in response to topoisomerase inhibitors and platinum DNA crosslinking drugs. In marked contrast, no such sensitization is observed when the growth factor receptor inhibitors are co-administered with the cytotoxic agents. The molecular mechanism responsible for this time-dependent growth factor inhibitor-induced tumor cell sensitization was explored using a systems biology-based model of DNA damage signaling in which protein kinase activities, substrate phosphorylation, and phosphoprotein-binding events for multiple signaling pathways were quantitatively measured at densely sampled points in time, and mathematically correlated with tumor cell responses including cell cycle arrest, cytokine production, autophagy, and apoptosis. This analysis revealed that sustained EGFR/FGFR suppression unmasks an apoptotic network involving Caspase-8 that is normally suppressed by oncogene addiction, resulting in an enhanced apoptotic response to equivalent amounts of DNA damage. This discovery demonstrates that the timing interval between administration of different drugs in combination chemotherapy can have profound effects on the tumor response through the dynamic re-wiring of cell signaling pathways in real time. Finally, we take advantage of this dynamic re-wiring process by developing tumor-targeted time-staggered release nanoparticles that deliver EGFR inhibitors at early times followed by the delayed release of doxorubicin. We show that these nanoparticles cause dramatic regression of murine NSCLC and TNBC tumor xenografts in vivo, substantiating the utility of therapeutic network re-wiring for anti-cancer therapy in the clinic.
Citation Format: Michael J. Lee, Yogesh Dayma, Anne-Margriet Heijinks, Stephen W. Morton, Erik C. Dreaden, Paula T. Hammond, Michael B. Yaffe. Therapeutic network re-wiring of the DNA damage response can be used to enhance tumor killing by cytotoxic chemotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2015-SY19-01
Abstract SY20-01: Conventional chemotherapy cures people by exploiting apoptotic priming
Authors: Letai Anthony G. 
Published: August 2015

Abstract
Conventional chemotherapy has an amazing track record that is often under-appreciated in today's world of genomics and targeted pathway inhibitors. Conventional chemotherapy is responsible for curing millions of cancer patients over the past 5 decades. That is, millions of patients have presented to their doctors with an otherwise fatal malignancy, were given a finite course of chemotherapy (largely DNA and microtubule perturbing agents) and had their cancer eradicated, never to return. Perhaps as remarkable as the magnitude of the achievement of conventional chemotherapy is the magnitude of our ignorance of why it should ever work, and why it works far better in some tumors than in others. Textbook explanations rely on concepts of differential proliferation rates in cancers that are incompletely supported in the clinical literature. Successful chemotherapy treatments usually kill via the mitochondrial pathway of apoptosis. We have found that simple functional measurements of the pre-treatment state of the tumor cell can be rapidly made with BH3 profiling. These measurements demonstrate that a major, if not the major, reason for a therapeutic index for cancer chemotherapy is that chemo-sensitive cancer cells are simply more primed for apoptosis than normal cells. Moreover, apoptotic priming can be measured to make clinical predictions regarding quality of response on an individualized basis. Enhancing pretreatment priming of cancer cells with selectively acting targeted agents is a promising strategy to extend the demonstrated curative power of conventional chemotherapy.
Citation Format: Anthony G. Letai. Conventional chemotherapy cures people by exploiting apoptotic priming. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY20-01. doi:10.1158/1538-7445.AM2015-SY20-01
Abstract SY23-03: Intratumoural heterogeneity in human serous ovarian carcinoma
Authors: Stingl John P. 
Published: August 2015

Abstract
To investigate the hierarchical organization of cells within human high grade serous ovarian carcinomas (HGSOC), we used a combination of multi-parameter flow cytometry and in vitro and in vivo functional assays to interrogate the growth and differentiation properties of phenotypically distinct cell populations present within 86 freshly isolated, non-cultured HGSOC tissues. Our results indicate that 3 functionally distinct subpopulations of epithelial cells can be identified. One population expresses high levels of the epithelial cell protein EpCAM, whereas the other two populations are EpCAM-, but express podoplanin (PDPN) and variable levels of CD34. All detectable growth in vitro colony-forming cell and sphere-forming assays is restricted to the two EpCAM- cell populations, although the types of progeny the two EpCAM- subpopulations differ from one another. Xenotransplantation of lentivirally marked HGSOC cell subpopulations into immune-deficient mice reveals that in vivo engrafting ability is restricted to only EpCAM-PDPN+CD34- cells. Treatment of mice harbouring HGSOC xenografts with cisplatin reveals that non-cycling EpCAM- cells appear to have a selective survival advantage during the course of chemotherapy.
Citation Format: John P. Stingl. Intratumoural heterogeneity in human serous ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY23-03. doi:10.1158/1538-7445.AM2015-SY23-03
Abstract SY27-02: Tumour heterogeneity and therapy resistance in melanoma
Authors: Wellbrock Claudia 
Published: August 2015

Abstract
Solid tumors are structurally very complex; they consist of heterogeneous cancer cell populations, other non-cancerous cell types and a distinct extracellular matrix. Interactions of cancer cells with non-cancerous cells is well investigated, and our recent work in melanoma has demonstrated that the cellular environment that surrounds cancer cells has a major impact on the way a patient responds to MAP-kinase pathway targeting therapy.
We have shown that intra-tumor signaling within a heterogeneous tumor can have a major impact on the efficacy of BRAF and MEK inhibitors. With the increasing evidence of genetic and phenotypic heterogeneity within tumors, intra-tumor signaling between individual cancer-cell subpopulations is therefore a crucial factor that needs to be considered in future therapy approaches. Our work has identified the ‘melanocyte-lineage survival oncogene’ MITF as an important player in phenotypic heterogeneity (MITFhigh and MITFlow cells) in melanoma, and MITF expression levels are crucial for the response to MAP-kinase pathway targeted therapy. We found that ‘MITF heterogeneity’ can be caused by cell-autonomous mechanisms or by the microenvironment, including the immune-microenvironment.
We have identified various mechanisms underlying MITF action in resistance to BRAF and MEK inhibitors in melanoma. In MITFhigh expressing cells, MITF confers cell-autonomous resistance to MAP-kinase pathway targeted therapy. Moreover, it appears that in melanomas heterogeneous for MITF expression (MITFhigh and MITFlow cells), individual subpopulations of resistant and sensitive cells communicate and MITF can contribute to overall tumor-resistance through intra-tumor signaling. Finally, we have identified a novel approach of interfering with MITF action, which profoundly sensitizes melanoma to MAP-kinase pathway targeted therapy.
Citation Format: Claudia Wellbrock. Tumour heterogeneity and therapy resistance in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY27-02. doi:10.1158/1538-7445.AM2015-SY27-02
Abstract SY35-04: Arming tumor-targeting antibodies with cytokine payloads: Emerging clinical results
Authors: Neri Dario 
Published: August 2015

Abstract
Antibodies can be used to deliver bioactive molecules (drugs, cytokines, photosensitizers, radionuclides, etc.) to the tumor environment, thus sparing normal tissues. Pharmacodelivery strategies targeting certain modified extracellular matrix components, associated with the tumor neo-vasculature, is particularly attractive, because of: (i) the abundance and stability of these antigens (e.g., splice isoforms of fibronectin and tenascin-C); (ii) the dependence of cancer on new blood vessels; (iii) the accessibility of neo-vascular structures for therapeutic agents coming from the blood-stream; (iv) the fact that some extracellular matrix components are very abundant in many different cancer types, while being virtually undetectable in most normal adult tissues [Refs. 1-8].
In this lecture, I will present our experience (at a preclinical and clinical level) in the development and clinical applications of antibody-cytokine fusion proteins (“immunocytokines”) for cancer therapy applications. In particular, I will focus on pro-inflammatory immunocytokines specific to the alternatively-spliced EDA and EDB domains of fibronectin, or A1 domain of tenascin-C, used either as single agents or in combination. Immunocytokines based on IL2 or TNF as payloads are able to dramatically increase the density of certain leukocytes (e.g., T cells and NK cells) at the neoplastic site in various types of malignancies.
References:
1. Neri, D. & Bicknell, R.. Nature Rev. Cancer. 2005, 5, 436-446
2. Neri, D. & Supuran, C. Nature Rev. Drug Discov., 2011, 10, 767-777
3. Neri, D. & Pasche N. Drug Discov. Today, 2012, 17, 583-590
4. Gutbrodt, K. et al. Sci. Transl. Med., 2013, 5, 201ra118
5. Hemmerle, T. et al. Br. J. Cancer, 2013, 109, 1206-1213
6. Schwager K. et al. J. Invest. Dermatol., 2013, 133, 751-758
7. Schliemann C. et al. Blood, 2009, 113, 2275-2283
8. Halin C. et al. Nat. Biotechnol., 2002, 20, 264-269
Citation Format: Dario Neri. Arming tumor-targeting antibodies with cytokine payloads: Emerging clinical results. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY35-04. doi:10.1158/1538-7445.AM2015-SY35-04
Prognostic Significance of Short-Term Blood Pressure Variability in Acute Stroke
Authors: Manning Lisa S. , Rothwell Peter M. , Potter John F. , Robinson Thompson G. 
Published: August 2015

Background and Purpose—
Blood pressure variability (BPV) may be an important prognostic factor acutely after stroke. This review investigated the existing evidence for the effect of BPV on outcome after stroke, also considering BPV measurement techniques and definitions.

Methods—
A literature search was performed according to a prespecified study protocol. Two reviewers independently assessed study eligibility and quality. Where appropriate, meta-analyses were performed to assess the effect of BPV on poor functional outcome.

Results—
Eighteen studies from 1359 identified citations were included. Seven studies were included in a meta-analysis for the effect of BPV on functional outcome (death or disability). Systolic BPV was significantly associated with poor functional outcome: pooled odds ratio per 10-mm Hg increment, 1.2; confidence interval (1.1–1.3). A descriptive review of included studies also supports these findings, and in addition, it suggests that systolic BPV may be associated with increased risk of intracranial hemorrhage in those treated with thrombolytic therapy.

Conclusions—
This systematic review and meta-analysis suggest that greater systolic BPV, measured early from ischemic stroke or intracerebral hemorrhage onset, is associated with poor longer-term functional outcome. Future prospective studies should investigate how best to measure and define BPV in acute stroke, as well as to determine its prognostic significance.
Rapid Attentional Selection of Non-native Stimuli despite Perceptual Narrowing
Authors: Wu Rachel , Nako Rebecca , Band Jared , Pizzuto Jacquelyne , Ghoreishi Yalda , Scerif Gaia , Aslin Richard 
Published: August 2015

Abstract
Visual experiences increase our ability to discriminate environmentally relevant stimuli (native stimuli, e.g., human faces) at the cost of a reduced sensitivity to irrelevant or infrequent stimuli (non-native stimuli, e.g., monkey/ape faces)—a developmental progression known as perceptual narrowing. One possible source of the reduced sensitivity in distinguishing non-native stimuli (e.g., one ape face vs. another ape face) could be underspecified attentional search templates (i.e., working memory representations). To determine whether perceptual narrowing stems from underspecified attentional templates for non-native exemplars, this study used ERP (the N2pc component) and behavioral measures in a visual search task, where the target was either an exemplar (e.g., a specific ape face) or a category (e.g., any ape face). The N2pc component, an ERP marker of early attentional selection emerging at 200 msec poststimulus, is typically modulated by the specificity of the target and, therefore, by the attentional template—the N2pc is larger for specific items versus categories. In two experiments using both human and ape faces (i.e., native and non-native stimuli), we found that perceptual narrowing affects later response selection (i.e., manual RT and accuracy), but not early attentional selection relying on attentional templates (i.e., the N2pc component). Our ERP results show that adults deploy exemplar level attentional templates for non-native stimuli (as well as native stimuli), despite poor downstream behavioral performance. Our findings suggest that long-term previous experience with reduced exemplar level judgments (i.e., perceptual narrowing) does not appear to eliminate early attentional selection of non-native exemplars.
Semantic Relations between Visual Objects Can Be Unconsciously Processed but Not Reported under Change Blindness
Authors: Ball Felix , Bernasconi Fosco , Busch Niko A. 
Published: August 2015

Abstract
Change blindness—the failure to detect changes in visual scenes—has often been interpreted as a result of impoverished visual information encoding or as a failure to compare the prechange and postchange scene. In the present electroencephalography study, we investigated whether semantic features of prechange and postchange information are processed unconsciously, even when observers are unaware that a change has occurred. We presented scenes composed of natural objects in which one object changed from one presentation to the next. Object changes were either semantically related (e.g., rail car changed to rail) or unrelated (e.g., rail car changed to sausage). Observers were first asked to detect whether any change had occurred and then to judge the semantic relation of the two objects involved in the change. We found a semantic mismatch ERP effect, that is, a more negative-going ERP for semantically unrelated compared to related changes, originating from a cortical network including the left middle temporal gyrus and occipital cortex and resembling the N400 effect, albeit at longer latencies. Importantly, this semantic mismatch effect persisted even when observers were unaware of the change and the semantic relationship of prechange and postchange object. This finding implies that change blindness does not preclude the encoding of the prechange and postchange objects' identities and possibly even the comparison of their semantic content. Thus, change blindness cannot be interpreted as resulting from impoverished or volatile visual representations or as a failure to process the prechange and postchange object. Instead, change detection appears to be limited at a later, postperceptual stage.
New Sericosura (Pycnogonida:Ammotheidae) from deep-sea hydrothermal vents in the Southern Ocean
Authors: ARANGO CLAUDIA P. , LINSE KATRIN 
Published: August 2015

Three new species of Sericosura (Pycnogonida: Ammotheidae) are described from recently discovered hydrothermal vents in the East Scotia Ridge, Southern Ocean: Sericosura bamberi sp. nov., S. dimorpha sp. nov. and S. curva sp. nov. The eleven species known to date in the genus Sericosura are all inhabitants of chemosynthetic environments in different oceans around the world. Morphology and preliminary DNA data from the COI locus suggest the East Scotia Ridge pycnogonids have relatively close evolutionary affinities with species known from the East Pacific Rise and the Mid-Atlantic Ridge. This finding highlights the importance of Sericosura as a characteristic taxon of hydrothermal vents and the great potential of this genus for global scale ecological and evolutionary studies of hydrothermal vents fauna. The use of pycnogonid DNA data combined with recent models explaining biogeographic provinces along the mid-ocean ridge system should prove extremely useful to understanding the patterns of diversification of endemic fauna from chemosynthetic environments and from the deep-sea in general.
Impact of Victim, Offender, and Relationship Characteristics on Frequency and Timing of Intimate Partner Violence using Life History Calendar Data
Authors: Hayes Brittany E. 
Published: August 2015

Objectives: To examine whether victim, offender, and relationship characteristics increase the risk and frequency of intimate partner violence (IPV). The effect of separation length on the risk of IPV is also evaluated. Methods: Using abuse incident data ( N = 4,960) from IPV victims ( n = 497), who accessed a health-care facility over a one-year period, between-individual differences in the frequency and timing of abuse were assessed. Dependence of event times within respondents was accounted for with conditional risk set “gap time” models, which stratified participants across event number and failure order. Results: Employment of both partners and only the victim decreased the risk and frequency. Employment of only the abuser and length of separation decreased frequency but was not significantly associated with timing of abuse. Separated and non-separated respondents were not significantly different in frequency (incident risk ratio = 1.06, p > .05) and timing of abuse, (exp ( b) = 0.95, p > .05). Conclusions: By capturing the timing between abuse incidents, insight into the long-term risk of abuse is provided and accounts for selection effects. Findings call for an improvement in measuring relationship status indicators, including relationship length and time since separation. Future research should examine within-individual changes in separation and IPV risk.
Well-being, austerity and policing
Authors: Hesketh Ian , Cooper Cary L. , Ivy Jonathan 
Published: August 2015

The purpose of this paper is to deepen conceptual understanding of workplace well-being in policing, particularly personal resilience. This is a conceptual paper reviewing and discussing contemporary literature with a focus on themes congruent with personal resilience in a police setting. This paper considers well-being in the context of police work in the UK, how resilience factors impact on an individual’s working life and the implications for policing generally. People can be trained to improve their resilience by a host of activities and approaches. These skills can be used to assess their own levels of resilience, and inform how to manage others through a variety of techniques. Some resilience factors are completely out of an individual’s locus of control; but many are not. Organisations can contribute by providing training and creating environments where individuals can practice these approaches as part and parcel of their daily activity, and flourish from doing so.