bluuebunny/crossref_metadata_2025 huggingface dataset:
Sectoral Estimates of Informality: A New Method and Application for the Turkish Economy
Authors: Elgin Ceyhun , Sezgin Muhammed Burak
Published: December 2017

In this paper, we use results of a novel survey covering 1,000 firms from 16 different sectors of the Turkish economy along with a two‐sector dynamic general equilibrium model to measure the extent of informality in these sectors. Moreover, we also evaluate the effects of two different policy tools on informality, namely, income taxes and tax enforcement. Our results show that while both are effective policy tools in dealing with informality, tax enforcement is a relatively more efficient tool and tax becomes quite ineffective at lower levels of informality.
De‐constitutionalisation and majority rule: A democratic vision for Europe
Authors: Scharpf Fritz W.
Published: December 2017

European integration has long relied on the democratic legitimacy of its Member States without paying much attention to the increasing importance of its multilevel governing processes. At this time, however, Europe is caught in the intersection of multiple crises, all of which—Brexit as well as the euro crisis, the refugee crisis as well as the crises in Europe's relations with its Eastern and Southern ‘near abroad’—are challenging the effectiveness as well as the democratic legitimacy of government on European and national levels. These dual challenges are connected: Democratic legitimacy presupposes effective governing and problem‐solving capacity. Hence the failure of output legitimacy may undermine or even destroy the possibility of input legitimacy—a risk for which the fate of the Weimar Republic remains a most disturbing memento. At the same time, however, the lack of input legitimacy in the present European context will constrain and may ultimately destroy the effectiveness of measures based on non‐accountable supranational authority.
An Experimental Study of the Internal Consistency of Judgments Made in Bookmark Standard Setting
Authors: Clauser Brian E. , Baldwin Peter , Margolis Melissa J. , Mee Janet , Winward Marcia
Published: December 2017

Validating performance standards is challenging and complex. Because of the difficulties associated with collecting evidence related to external criteria, validity arguments rely heavily on evidence related to internal criteria—especially evidence that expert judgments are internally consistent. Given its importance, it is somewhat surprising that evidence of this kind has rarely been published in the context of the widely used bookmark standard‐setting procedure. In this article we examined the effect of ordered item booklet difficulty on content experts’ bookmark judgments. If panelists make internally consistent judgments, their resultant cut scores should be unaffected by the difficulty of their respective booklets. This internal consistency was not observed: the results suggest that substantial systematic differences in the resultant cut scores can arise when the difficulty of the ordered item booklets varies. These findings raise questions about the ability of content experts to make the judgments required by the bookmark procedure.
From Private Practice to Academia: Integrating social and political advocacy into every MFT Identity
Authors: Goodman Jessica M. , Morgan Amy A. , Hodgson Jennifer L. , Caldwell Benjamin E.
Published: December 2017

While advocacy was essential to establishing the field of marriage and family therapy, at present a social and political advocacy skill set is lacking for the typical marriage and family therapist (MFT). This article reviews the importance of being active in social and political advocacy and highlights the attributes of MFTs’ professional identity that uniquely position us for success in these areas. Other mental health fields’ pedagogical approaches to training and education are explored, and recommendations are made for how MFTs can begin to increase their competency in advocacy. Ideas for incorporating advocacy into a professional identity are presented for MFTs at every level of professional experience. Finally, the concept self‐of‐the‐advocate is introduced and discussed.
Who is telecaring whom? Exploring the total social organisation of care work in an Italian municipality
Authors: Wilson Rob , Baines Sue , Martin Mike , Richter Paul , McLoughlin Ian , Maniatopoulos Gregory
Published: December 2017

Telecare’ refers to the use of digital or information and communication technologies (ICTs) to facilitate health and social care delivery to individuals in their homes. This article explores the phenomenon by foregrounding its interconnections with work activities, paid and unpaid. It draws on research as a part of the design and deployment of a set of telecare innovations for older people in an Italian municipality. The project was conceived at the outset in terms of formal inter‐ relationships between functions and components of technical systems. Technical setbacks, however, were resolved only by enrolling the active support of groups and individuals (including civil society organisations and older people). By situating a telecare intervention conceptually within the ‘total social organisation of labour’ (TSOL), we provide an analysis that contributes to understanding how a socio‐technical infrastructural approach to telecare reveals ways to improve our understanding of how formal and informal care systems interact.
Soft law in the Paris Climate Agreement: Strength or weakness?
Authors: Lawrence Peter , Wong Daryl
Published: December 2017

In the lead‐up to the Paris Agreement, and in reactions to it since its adoption, there has been a narrative which emphasizes the perceived advantages of key mitigation obligations in the Agreement being non‐binding or ‘soft’ law. Central to these advantages is the idea that soft law obligations were a precondition for United States, China and wider participation in the Agreement, and also desirable in terms of flexibility. This article challenges the soft law narrative, arguing that the Paris Agreement's use of non‐binding ‘nationally determined contributions’ has come at a cost in terms of likely effectiveness. Empirical studies comparing hard (binding) and soft law obligations in terms of compliance and effectiveness are equivocal, but precision of obligations and effective non‐compliance mechanisms are essential. Moreover, when States have a strong political will to change behaviour, treaty instruments containing hard obligations have been considered to be more likely to be effective (e.g., ozone agreements, World Trade Organization agreements and arms control treaties). The development of the transparency, review and non‐compliance elements of the Paris Agreement is essential, but is no substitute for strong political will to reduce emissions. In addition, it is crucial to muster the political will to ratchet up the Paris mitigation commitments and transform them from soft to hard obligations. The article assesses options for doing this, including a Conference of the Parties decision and a political declaration.
Trouble in the air: Recent developments under the 1979 Convention on Long‐Range Transboundary Air Pollution
Authors: Byrne Adam
Published: December 2017

The 1979 Geneva Convention on Long‐Range Transboundary Air Pollution (CLRTAP) is a significant regional treaty under which eight protocols have been developed. The Convention offers a case study on the legal and political challenges that can occur when addressing air pollution. This article explores the recent history of the CLRTAP regime, drawing on the conceptual lens of regime effectiveness. First, the article considers how the legal framework has been modernized over the past decade to reflect changes in the sources and effects of air pollution. This has predominantly occurred through amendments to the 1999 Protocol to Abate Acidification, Eutrophication and Ground‐Level Ozone, the 1998 Protocol on Persistent Organic Pollutants and the 1998 Protocol on Heavy Metals, which were negotiated in 2009–2012. The amendments are an important point in the regime's history, as they set more stringent pollution limits. Particular attention is paid to their prospective entry into force and their broader impact on European law. Second, the geographic coverage of the legal instruments has long been an issue of concern, with a number of former Soviet Union States choosing to not participate in the pollution‐specific protocols. The article reviews efforts to boost participation through the creation in 2011 of a coordinating group to promote action in the countries of Eastern Europe, the Caucasus and Central Asia. Third, the article explores recent developments in compliance and inventory adjustments under the Gothenburg Protocol, as a demonstration of how the system approaches changes in scientific knowledge on the sources and levels of air pollution, and how this affects compliance.
Free Will, Foreknowledge, and Future‐Dependent Beliefs
Authors: van Riel Raphael
Published: December 2017

Recently, a time‐honored assumption has resurfaced in some parts of the free will debate: (A) if past divine beliefs or past truths about what we do depend on what we do, then these beliefs and truths are, in a sense, up to us; hence, we are able to act otherwise, despite the existence of past truths or past divine beliefs about our future actions. In this paper, I introduce and discuss a novel incompatibilist argument that rests on (A). This argument is interesting in itself, for it is independent of a number of assumptions about the nature of God that have played an essential role in the classical defense of incompatibilism about divine foreknowledge and human free will. Moreover, the argument enables us to identify a difficulty compatibilists encounter when employing (A) to block incompatibilism.
PANENTHEISM, NEUTRAL MONISM, AND ADVAITA VEDANTA
Authors: Silberstein Michael
Published: December 2017

It is argued that when it comes to the hard problem of consciousness neutral monism beats out the competition. It is further argued that neutral monism provides a unique route to a novel type of panentheism via Advaita Vedanta Hinduism.
Enfermedades reumáticas en Colombia: quince años de investigaciones psicológicas
Authors: Gómez Acosta César Andrés , Vinaccia Alpi Stéfano , Quiceno Sierra Japcy Margarita
Published: December 2017

El objetivo de esta revisión es analizar las principales investigaciones psicosociales que se han llevado a cabo en Colombia con pacientes reumáticos. Por un lado, se evalúan los estudios desarrollados con pacientes de artritis reumatoide, lupus eritematoso sistémico y fibromialgia; por otro, se analizan los procesos de evaluación y de intervención que se han desarrollado en el área. Se le da relevancia a la descripción de los resultados alcanzados en cada estudio. Por último, se analizan los resultados encontrados en las investigaciones colombianas. 
Quantitative Computational Fluid Dynamics Analyses of Particle Deposition in a Heavy-Duty Subsonic Axial Compressor
Authors: Aldi Nicola , Casari Nicola , Dainese Devid , Morini Mirko , Pinelli Michele , Spina Pier Ruggero , Suman Alessio
Published: December 2017

Solid particle ingestion is one of the principal degradation mechanisms in the compressor and turbine sections of gas turbines. In particular, in industrial applications, the microparticles not captured by the air filtration system can cause deposits on blading and, consequently, result in a decrease in compressor performance. In the literature, there are some studies related to the fouling phenomena in transonic compressors, but in industrial applications (heavy-duty compressors, pump stations, etc.), the subsonic compressors are widespread. It is highly important for the manufacturer to gather information about the fouling phenomenon related to this type of compressor. This paper presents three-dimensional (3D) numerical simulations of the microparticle ingestion (0.15–1.50 μm) in a multistage (i.e., eight stage) subsonic axial compressor, carried out by means of a commercial computational fluid dynamic (CFD) code. Particles of this size can follow the main air flow with relatively little slip, while being impacted by flow turbulence. It is of great interest to the industry to determine which zones of the compressor blades are impacted by these small particles. Particle trajectory simulations use a stochastic Lagrangian tracking method that solves the equations of motion separately from the continuous phase. The adopted computational strategy allows the evaluation of particle deposition in a multistage axial compressor thanks to the use of a mixing plane approach to model the rotor/stator interaction. The compressor numerical model and the discrete phase model are set up and validated against the experimental and numerical data available in the literature. The number of particles and sizes is specified in order to perform a quantitative analysis of the particle impacts on the blade surface. The blade zones affected by particle impacts and the kinematic characteristics (velocity and angle) of the impact of micrometric and submicrometric particles with the blade surface are shown. Both blade zones affected by particle impact and deposition are analyzed. The particle deposition is established by using the quantity called sticking probability (SP), adopted from the literature. The SP links the kinematic characteristics of particle impact on the blade with the fouling phenomenon. The results show that microparticles tend to follow the flow by impacting on the compressor blades at full span. The suction side (SS) of the blade is only affected by the impacts of the smallest particles. Particular fluid dynamic phenomena, such as corner separations and clearance vortices, strongly influence the impact location of the particles. The impact and deposition trends decrease according to the stages. The front stages appear more affected by particle impact and deposition than the rear ones.
Erratum: “Static Performance Characteristics and Rotordynamic Coefficients for a Four-Pad Ball-in-Socket Tilting Pad Journal Bearing” [ASME J. Eng. Gas Turbines Power, 2009, 131(6), p. 062502; DOI: 10.1115/1.3098376]
Authors: Harris Joel , Childs Dara
Published: December 2017

The following erratum has been written to alert readers to unreliable data contained in the referenced paper.
Complete Genome Sequence of Bacillus altitudinis P-10, a Potential Bioprotectant against Xanthomonas oryzae pv. oryzae, Isolated from Rice Rhizosphere in Java, Indonesia
Authors: Budiharjo Anto , Jeong Haeyoung , Wulandari Dyah , Lee Soohyun , Ryu Choong-Min
Published: December 2017

Bacillus altitudinis
P-10 was isolated from the rhizosphere of rice grown in an organic rice field and provides strong antagonism against the bacterial blight caused by
Xanthomonas oryzae
pv. oryzae in rice. Herein, we provide the complete genome sequence and a possible explanation of the antibiotic function of the P-10 strain.
CRITICAL CONTACT RATE FOR VECTOR–HOST–PATHOGEN OSCILLATION INVOLVING CO-FEEDING AND DIAPAUSE
Authors: ZHANG XUE , WU XIAOTIAN , WU JIANHONG
Published: December 2017

We consider the dynamic vector–host–pathogen interaction motivated by tick-borne diseases such as tick-borne encephalitis and Lyme disease. We stratify the vector population in terms of the stage before and after the vector’s contact with hosts when co-feeding transmission may take place, and we also consider the case where vector development may involve two time lags due to normal development and diapause. We derive threshold conditions for disease persistence and for nonlinear oscillations in the vector population and in the diseased vector and host populations. Our objective here is to use a simple mechanistic dynamic model to show that diapause and co-feeding transmission may generate periodic and irregular oscillations even when seasonal variations of the environmental conditions are ignored. These oscillations are not necessary in synchrony with the seasonality of vector development, and hence complicated oscillatory patterns of vector-borne disease dynamics in the field and surveillance observations should be expected.
Remanufacturing Strategy Considering Green Consumers and Environmental Policy Guidance
Authors: Zhu Yujiao , Gao Liang
Published: December 2017

Low carbon production, as one kind of eco-friendly process, has received widespread attention from demand, supply and government side. Meanwhile, the structure of the marketplace is subtly changed as the emergence of the green consumers. In this work, we build consumer’s utility model considering both the new product and remanufactured product to investigate the price strategy for manufacturer and the effect of environmental policy for government. For the manufacturer, the model can serve as a decision-supporting to plan the price strategy of the remanufactured product. Our findings indicate that the price strategy depends on the green segment size and the price strategy made by a profit-driven manufacturer may not be the better choice for the environment. For the environmental policy makers, when the government implements the cap-and-trade mechanism, our findings show that the carbon price should not be set too low or too high. Only an appropriate carbon price can unify the economic and environmental incentives of the manufacturer, and then make the environmental policy meaningful.
Characterization of an Atmospheric-Pressure Argon Plasma Generated by 915 MHz Microwaves Using Optical Emission Spectroscopy
Authors: Miotk Robert , Hrycak Bartosz , Jasiński Mariusz , Mizeraczyk Jerzy
Published: December 2017

The paper presents the investigations of an atmospheric-pressure argon plasma generated at 915 MHz microwaves using the optical emission spectroscopy (OES). The 915 MHz microwave plasma was inducted and sustained in a waveguide-supplied coaxial-line-based nozzleless microwave plasma source. The aim of presented investigations was to estimate parameters of the generated plasma, that is, excitation temperature of electrons Texc, temperature of plasma gas Tg, and concentration of electrons ne. Assuming that excited levels of argon atoms are in local thermodynamic equilibrium, Boltzmann method allowed in determining the Texc temperature in the range of 8100–11000 K. The temperature of plasma gas Tg was estimated by comparing the simulated spectra of the OH radical to the measured one in LIFBASE program. The obtained Tg temperature ranged in 1200–2800 K. Using a method based on Stark broadening of the Hβ line, the concentration of electrons ne was determined in the range from 1.4 × 1015 to 1.7 × 1015 cm−3, depending on the power absorbed by the microwave plasma.
Abstract A04: Cross-species analysis identifies MUS81, a structure-specific endonuclease, as a novel synthetic lethal interaction with PARP
Authors: Bailey Melanie L. , O'Neil Nigel J. , Hieter Philip
Published: December 2017

Recently, the inhibition of poly ADP-ribose polymerase, or PARP, in BRCA-mutated cells has been exploited as a therapeutic strategy for cancer due to the strong PARP/BRCA synthetic lethal relationship. Evidence suggests this lethality is likely due to DNA repair defects; however, details of this mechanism remain unclear. To this end, we sought to identify a larger spectrum of genes whose mutation renders cells sensitive to PARP inhibition. Using the model organism Caenorhabditis elegans, we developed an in vivo variomics approach to screen mutated C. elegans strains for sensitivity to the PARP inhibitor olaparib. Multiple sensitive strains contained mutations in either mus-81 or eme-1, two genes that form a heterodimeric DNA endonuclease complex involved in both stalled fork cleavage in replication and Holliday junction resolution in homologous recombination repair. Further investigation revealed that olaparib treatment caused somatic proliferation defects and anaphase bridges in mus-81 mutants.

We found the MUS81/PARP genetic interaction from C. elegans to be conserved in human cells. Compared to MUS81 wild-type cell lines, MUS81 knockout cells showed a significant decrease in proliferation after exposure to PARP inhibitor and had characteristics distinct from olaparib-treated BRCA2 knockout cells. Surprisingly, cells that were lacking MUS81 and treated with PARP inhibitor showed a lack of apoptosis, dramatic increase in tetraploidy and higher incidence of anaphase bridges in mitosis. Using cross-species approaches, we have identified a new PARP synthetic lethal interaction that is conserved in human cells. Our results suggest that MUS81 protection after PARP inhibitor treatment is functionally distinct from other homologous recombination repair genes and provides further insights into the mechanism behind PARP inhibitor-induced selective tumor cell killing.

Citation Format: Melanie L. Bailey, Nigel J. O’Neil, Philip Hieter. Cross-species analysis identifies MUS81, a structure-specific endonuclease, as a novel synthetic lethal interaction with PARP [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A04.
Abstract A16: Discovery and functional characterization of essential pathways in KRAS mutant cancers
Authors: Ku Angel A. , Bandyopadhyay Sourav
Published: December 2017

KRAS oncogenes are present in 30% of all human cancers and are required for tumor development and maintenance and although clearly important efforts to target KRAS mutant tumors remains a major challenge. Several systematic approaches have been made to target these RAS-dependent cancers through small molecule screening and genome-scale RNAi screens to identify KRAS Synthetic Lethal (SL) genes. We applied and network based approached to integrate published KRAS SL screen data to uncover protein networks enriched with KRAS SL genes. We are using these proteins networks to generate a KRAS genetic interaction map (E-MAP) using combinatorial RNAi to identify candidate drug combinations, which may be useful to treat KRAS mutant cancers. Our network analysis revealed a dozen protein networks enriched with KRAS SL genes. Our pilot RNAi screen revealed that KRAS mutant tumors are sensitive to PAPR inhibition. Furthermore our isogenic models reveal that KRAS mutant cells harbor active DNA repair pathways in the absence of DNA damaging agents and are likely suffering from replication stress. A combinatorial RNAi screen revealed a KRAS specific synthetic lethal interaction with PARP inhibitors and knock down of MEK-ERK pathway genes. Our results suggest that PARP inhibitions have some efficacy in treating KRAS mutant tumors undergoing replication stress single agents and potentially combined with inhibitors of MEK-ERK signaling. Future studies are underway to determine if PAPR inhibitors are effective in cancer cell in vitro and in vivo models.

Citation Format: Angel A. Ku, Sourav Bandyopadhyay. Discovery and functional characterization of essential pathways in KRAS mutant cancers [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A16.
Abstract A29: Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression
Authors: Ogiwara Hideaki , Sasaki Mariko , Oike Takahiro , Higuchi Saito , Tominaga Yuichi , Kohno Takashi
Published: December 2017

Loss-of-function mutations in the CBP/CREBBP gene, which encodes a histone acetyltransferase (HAT), are present in a variety of human tumors, including lung, bladder, gastric, and hematopoietic cancers. Consequently, development of a molecular targeting method capable of specifically killing CBP-deficient cancer cells would greatly improve cancer therapy. Functional screening of synthetic-lethal genes in CBP-deficient cancers identified the CBP paralog p300/EP300. Ablation of p300 in CBP-knockout and -deficient cancer cells induced G1/S cell-cycle arrest, followed by apoptosis. Genome-wide gene expression analysis revealed that MYC is a major factor responsible for the synthetic lethality. Indeed, p300 ablation in CBP-deficient cells caused downregulation of MYC expression via reduction of histone acetylation in its promoter, and this lethality was rescued by exogenous MYC expression. The p300-HAT inhibitor C646 specifically suppressed the growth of CBP-deficient lung and hematopoietic cancer cells in vitro and in vivo; thus p300 is a promising therapeutic target for treatment of CBP-deficient cancers.

Citation Format: Hideaki Ogiwara, Mariko Sasaki, Takahiro Oike, Saito Higuchi, Yuichi Tominaga, Takashi Kohno. Targeting p300 addiction in CBP-deficient cancers causes synthetic lethality by apoptotic cell death due to abrogation of MYC expression [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A29.
Abstract B31: miRNAs regulated cancer metastasis in esophageal squamous cell carcinoma
Authors: Kano Masayuki , Matsubara Hisahiro , Masahiko Takahashi
Published: December 2017

MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs and negatively regulate gene expression through base pairing of 3' UTRs of the target genes. Over the past decade, much of important evidences have been obtained to clarify that miRNAs are unusual expressed in human malignancies and could act as OncomiRs or Tumor suppressive miRs.

Esophageal squamous cell carcinoma (ESCC) is one of the most malignant cancers of the gastrointestinal tract. Especially, metastatic recurrences after esophagectomy for ESCC bears unfortunately prognosis and little exists for treatment strategy. Clarification of molecular indicators of the origin cellular deregulation in ESCC have been important objective for cancer research in ESCC.

Recently, increasing number of studies have demonstrated the involvement of miRNAs in cancer metastasis. Especially, many studies have shown that microRNAs could target genes playing a role in epithelia-mesenchymal-transition (EMT), a cellular transformation process that allows cancer cells to acquire motility and invasiveness. EMT is considered an essential step driving the early phase of cancer metastasis.

We search for miRNAs in ESCC using the miRNA expression signatures and gain-of-function analysis. It is revealed that 3 miRNAs (miR-145, miR-133a and miR-133b) inhibit cell proliferation and cell invasion. These miRNAs, which have conserved sequences in the 3' UTR of FSCN1, inhibited FSCN1 expression. The identification of tumor-suppressive miRNAs, miR-145, miR-133a and miR-133b, directly control oncogenic FSCN1 gene. These signal pathways of ESCC could provide new insights into potential mechanisms of ESCC carcinogenesis.

FSCN1 is actin bundling protein, which is concerned with cancer invadopodia ,which is the phenomenon regarding cancer cell invasion into surrounding tissue. We focused on MMP14 and examined the gene expression of MMP14 in ESCC tissues and patient survival. FSCN1 and MMP14 were evaluated by immunohistochemistry and quantitative PCR, and microRNA (miR)-133a was also

evaluated by PCR in surgical ESCC specimens. The roles of FSCN1, MMP14 and miR-133a were established in ESCC cells. The relationship between the expressions of miR-133 and MMP14 is strongly negative correlation. miR-145 and miR-133 play a chief role in cancer invasion and metastasis, which control invadopodia associated proteins.

The combined expression of FSCN1 and MMP14 is associated with a poor prognosis, and miR-133a, which regulates their mRNAs, can serve as a strong tumour suppressor of ESCC.

Citation Format: Masayuki Kano, Hisahiro Matsubara, Takahashi Masahiko. miRNAs regulated cancer metastasis in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B31.
Abstract IA05: Massively parallel search for synthetic lethal vulnerabilities using CRISPRi and CRISPRa
Authors: Weissman Jonathan
Published: December 2017

While the catalog of mammalian transcripts and their expression levels in different cell types and disease states is rapidly expanding, our understanding of their function lags behind. We present a robust technology enabling systematic investigation of the cellular consequences of repressing or inducing individual transcripts. We identify rules for specific targeting of transcriptional repressors (CRISPRi), typically achieving 90-99% knockdown with minimal off-target effects, and activators (CRISPRa) to endogenous genes via endonuclease-deficient Cas9. Together they enable modulation of gene expression over a ~1000-fold range. Using these rules, we construct and validate genome-scale CRISPRi and CRISPRa libraries that enable systematic analysis of gene function including both essential and nonessential as well as long noncoding RNAs. Our results establish CRISPRi and CRISPRa as powerful tools that provide rich and complementary information for mapping complex pathways. We have now adpated this approach to allow the largescale analysis of double knockdowns. This enables the systematic search for synthetic lethal interactions that will inform the rational design of combination drug therapies.

Citation Format: Jonathan Weissman. Massively parallel search for synthetic lethal vulnerabilities using CRISPRi and CRISPRa [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA05.
Abstract IA08: Systematic interrogation of cancer dependencies
Authors: Hahn William C.
Published: December 2017

Although we now have a draft view of the genetic alterations that occur in human cancer, the number of mutations found at low frequency and the molecular heterogeneity of most cancers makes identifying genes that contribute to cancer phenotypes challenging. Determining the function of genes altered in cancer genomes is essential to develop new therapeutic approaches. To complement these genome characterization studies, we have used genome scale gain and loss of function approaches to identify genes required for cell survival and transformation. Specifically, we have performed systematic studies to interrogate rare alleles found altered in cancer genomes and used advances in synthetic gene synthesis to prospectively interrogate all possible alleles of known cancer genes. In parallel, we have performed both genome scale RNAi and CRISRP-Cas9 screens in more than 500 cell lines to identify differentially essential genes and the context that specifies gene dependency. This approach now permits us to identify and classify cancer dependencies.

These studies allow us to begin to define a global cancer dependencies map.

Citation Format: William C. Hahn. Systematic interrogation of cancer dependencies [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA08.
Abstract IA13: A novel KRAS specific vulnerability in the nutrient stress response
Authors: Sweet-Cordero Alejandro
Published: December 2017

Oncogenic KRAS has multiple effects on cellular functions. A relatively poorly understood role of oncogenic KRAS is in regulation of nutrient stress. As a strategy to identify new KRAS-specific tumor vulnerabilities, we sought to explore the role of oncogenic KRAS in mediating the response to nutrient stress. A key observation is that the gene expression signature of oncogenic KRAS is markedly different in standard tissue culture conditions compared to more physiologic levels of glutamine. Glutamine is a key nutrient for tumor cells that supports nucleotide and amino acid biosynthesis, replenishes TCA cycle intermediates and contributes to redox metabolism. We identified oncogenic KRAS as an important regulator of the response to glutamine deprivation in non-small cell lung cancer (NSCLC). A significant fraction of the gene expression signature mediated by KRAS in low glutamine is mediated by activation of ATF4. Activation of the ATF4 stress response pathway is dependent on PI3K and expression of NRF2 downstream of oncogenic KRAS in NSCLC. Through this mechanism, KRAS alters amino acid uptake and metabolism and sustains mTORC1 signaling during nutrient stress. We identified regulation of asparagine synthetase (ASNS) as a key effect of oncogenic KRAS signaling via ATF4 during glutamine deprivation. Preliminary data indicates that simultaneous blockade of PI3K and ASNS may be a useful therapeutic strategy in lung cancer. Our studies underscore an important role for KRAS in metabolism of NSCLC and identify a need for further studies that evaluate KRAS vulnerabilities under conditions of nutrient stress.

Citation Format: Alejandro Sweet-Cordero. A novel KRAS specific vulnerability in the nutrient stress response [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA13.
Abstract PR14: MEK inhibitors block growth of Ataxia Telangiectasia Mutated (ATM) mutant lung tumors
Authors: Cruz Ferran Fece de la , Smida Michal , Nijman Sebastian
Published: December 2017

Introduction: Lung cancer is the leading cause of cancer death worldwide. In the past decade, deep sequencing projects have shed light on the molecular drivers commonly found altered in NSCLC. As a result, the first molecularly targeted agents have been approved for the treatment of tumors presenting activating oncogenic events in EGFR or EML4/ALK. However, the translation into therapies for tumors presenting loss-of-function mutations has proven challenging and constitutes an unexplored and promising field.

In order to narrow the gap between cancer genomics and effective treatments for tumors harboring mutations in well-defined tumor suppressor genes (such as PTEN, BRG1 or ATM), we have developed a genetically tractable lung cancer cell model. Focusing on lung adenocarcinoma, we have engineered a panel of isogenic cell lines capturing the molecular heterogeneity found in patients. This panel has been screened against a collection of drugs, comprising classical chemotherapeutics and kinase inhibitors, providing a comprehensive evaluation for hundreds of gene-drug interactions.

Results: The screen confirmed known or highly expected interactions, proving the robustness of our approach. Among the unexpected and most relevant hits, we have found that ATM-deficient cells are exquisitely sensitive to drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Extensive validation in ATM mutant patient-derived lung cancer cell lines has confirmed the synthetic lethal interaction between ATM and MEK in vitro and in vivo.

Mechanistically, the interaction may not be directly associated with the major role of ATM in DNA damage signaling. Rather, we have observed a deregulation of the crosstalk between the MAPK and AKT/mTOR signaling pathways as a consequence of ATM deficiency, resulting in an increased dependency on MEK kinase activity for cell survival.

Perspectives: Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma (5- 10%) but directly targeting these with drugs remains challenging. MEK inhibitors are currently being tested in clinical trials for efficacy in KRAS or BRAF mutant lung cancer. However, these mutations alone do not adequately predict response to MEK inhibition. Our findings indicate that including ATM mutation status in lung cancer as a mechanistic biomarker for MEK inhibitors can improve patient stratification. Ultimately, extending the applicability of these drugs beyond KRAS or BRAF mutant tumors.

Citation Format: Ferran Fece de la Cruz, Michal Smida, Sebastian Nijman. MEK inhibitors block growth of Ataxia Telangiectasia Mutated (ATM) mutant lung tumors [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR14.
Abstract PR15: Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma
Authors: Thompson Jordan M. , Nguyen Quy H. , Singh Manpreet , Pavesic Matthew W. , Nesterenko Irina , Nelson Luke J. , Liao Alicia , Razorenova Olga V.
Published: December 2017

Clear cell renal cell carcinoma (CC-RCC) is the most lethal of all genitourinary cancers. The functional loss of the von Hippel-Lindau (VHL) gene occurs in 90% of CC-RCC, driving cancer progression. The objective of this study was to identify chemical compounds that are synthetically lethal with VHL deficiency in CC-RCC. An annotated chemical library, the library of pharmacologically active compounds (LOPAC), was screened in parallel on VHL-deficient RCC4 cells and RCC4VHL cells with re-introduced VHL. The ROCK inhibitor, Y-27632, was identified and validated for selective targeting of VHL-deficient CC-RCC in multiple genetic backgrounds by clonogenic assays. Downregulation of ROCK1 by small interfering RNA (siRNA) selectively reduced the colony forming ability of VHL-deficient CC-RCC, thus mimicking the effect of Y-27632 treatment, whereas downregulation of ROCK2 had no effect. In addition, three other ROCK inhibitors, RKI 1447, GSK 429286, AT13148 selectively targeted VHL-deficient CC-RCC. Importantly, we found that mammalian target of rapamycin (mTOR) inhibitor Everolimus synergized with ROCK inhibitor RKI 1447 in targeting VHL-deficient cells. Accordingly, AT13148, an AGC kinase inhibitor blocking S6 kinase (S6K, downstream target of mTOR) in addition to ROCK1&2, showed the most strong synthetic lethality effect out of all ROCK inhibitors tested. CC-RCC treatment with ROCK inhibitors is cytotoxic and cytostatic based on bromodeoxyuridine (BrdU) assay, propidium iodide (PI) staining and growth curves, and blocks cell migration based on transwell assay. On the one hand, knockdown of hypoxia-inducible factor (HIF) β in the VHL-deficient CC-RCC had a protective effect against Y-27632 treatment, mimicking VHL reintroduction. On the other hand, CC-RCCVHL cells were sensitized to Y-27632 treatment in hypoxia (2% O2). These results suggest that synthetic lethality between ROCK inhibition and VHL deficiency is dependent on HIF activation. Moreover, HIF1α or HIF2α overexpression in CC-RCCVHL cells is sufficient to sensitize them to ROCK inhibition. Finally, Y-27632 treatment inhibited growth of subcutaneous 786-OT1 CC-RCC tumors in mice. Thus, ROCK inhibitors represent potential therapeutics for VHL-deficient CC-RCC.

Citation Format: Jordan M. Thompson, Quy H. Nguyen, Manpreet Singh, Matthew W. Pavesic, Irina Nesterenko, Luke J. Nelson, Alicia Liao, Olga V. Razorenova. Rho-associated kinase 1 inhibition is synthetically lethal with von Hippel-Lindau deficiency in clear cell renal cell carcinoma [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR15.
The Association of Circulating MiR-29b and Interleukin-6 with Subclinical Atherosclerosis
Authors: Huang Yu-qing , Li Jie , Chen Ji-yan , Zhou Ying-ling , Cai An-ping , Huang Cheng , Feng Ying-qing
Published: December 2017

Background/Aims: Although it is widely acknowledged that atherosclerosis is mainly a chronic inflammatory process, in which both miR-29b and interleukin-6 (IL-6) play multifaceted roles, the association between miR-29b and IL-6 remains unknown. The aim of the present study was to explore the relationship between miR-29b and IL-6 and to test whether circulating levels of miR-29b and IL-6 could predict atherosclerosis. Methods: A total of 170 participants were divided into two groups according to carotid intima-media thickness (CIMT): study group (CIMT ≥ 0.9mm) and control group (CIMT < 0.9mm). Levels of circulating miR-29b and IL-6 were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. The association of miR-29b and IL-6 levels with CIMT was assessed using Spearman correlation analysis and multiple linear regression analysis. Results: The study group showed higher miR-29b levels (31.61 ± 3.05 vs. 27.91 ± 1.71 Ct, p < 0.001) and IL-6 levels (3.40 ± 0.67 vs. 2.99 ± 0.37 pg/ml, p < 0.001), compared with the control group. CIMT was positively correlated with miR-29b (r = 0.587, p < 0.001) and IL-6 (r = 0.410, p < 0.001), and miR-29b levels were also correlated with IL-6 (r = 0.242, p = 0.001). Multiple linear regression analysis also showed that CIMT was positively correlated with miR-29b and IL-6. After adjustment for age, body mass index, systolic blood pressure, total cholesterol and C-reactive protein, CIMT was still closely correlated with miR-29b and IL-6. The combination of miR-29b and IL-6 (AUC = 0.901, p < 0.001) offered a better predictive index for atherosclerosis than either miR-29b (AUC = 0.867, p < 0.001) or IL-6 (AUC = 0.747, p < 0.001) alone. Conclusion: Circulating levels of miR-29b and IL-6 may be independently correlated with subclinical atherosclerosis, and may serve as novel biomarkers for the identification of atherosclerosis.
Invocations of the Blood of Christ in Greek Magical Amulets
Authors: Chepel Elena
Published: December 2017

The author analyses the meaning and function of the invocations of the blood of Christ in Greek magical amulets by exploring their theological and liturgical contexts and the points of contact between the discourse of the church leaders and the language of ‘Christian magic’. The apotropaic power of the blood of Christ, to which the magical texts appeal, is rooted in the Christian teaching, promoted by the Fathers. It is argued that the special attitude to the blood of Christ reflected in the magical texts is to be explained by its soteriological connotations, which could be borrowed by the producers of the amulets from sermons preached in the church as well as from liturgical contexts of both baptism and eucharist.
Concept of Genetic Transmission of the ‘Essence of Salvation’ in Ethiopian Church and Its Reminiscence in Islam
Authors: Frantsouzoff Serge A.
Published: December 2017

The 68th chapter of the Ethiopian dynastic treatise Kəbrä nägäśt ‘the Nobility of the Kings’ is of considerable interest due to the occurrence of the term mädḫänit interpreted either as ‘Savior’ (in the feminine!) or as ‘Salvation’. The contents of that chapter is focused on a specific ‘essence of Salvation’ (‘ənqwä baḥrəy, literally ‘mother-of-pearl’) created ‘in the abdomen of Adam’ and transmitted from generation to generation. It should be noted that in medieval Ethiopian Christian theology the term baḥrəy ‘pearl’ denoted the Second Hypostasis represented in the unity of His nature. A parallel to such a concept of ‘Salvation’ transfer was found in Islamic tradition, viz. in legends about the emission of light from ‘Abdallāh, Muḥammad’s father, which gave evidence of his engagement in procreation of a future prophet. Similar ideas appeared to influence the early Shī‘ite doctrine.
Little Known Aspects of Veneration of the Old Testament Sabbath in Medieval Ethiopia
Authors: Gusarova Ekaterina V.
Published: December 2017

The Church of Ethiopia did observe both the Old Testament or the Jewish Sabbath and its Christian counterpart. This practice became one of the distinctive features of the Ethiopian Christianity. In various periods of its history the problem of veneration of the Jewish Sabbath provoked a lasting controversy among the country’s clergy. It was under the reign of the King Zär’a Ya‘ǝqob (1434-1468) that the observance of both Sabbaths became the officially accepted by the Ethiopian Church and the State. However, some evidences of this custom can be traced for many centuries before. Following the Confession of faith of the King Claudius (1540-1559), the priority was given to the celebration of Sunday. The author of the article was fortunate to discover several cases of the preferential veneration of Sunday during a military campaign of 1781, described in the chronicle of the King Täklä Giyorgis I.
Gender, Catholicism, and Communism in 1950s Shanghai (1950年代上海的性别、天主教与共产主义)
Authors: Mariani Paul P.
Published: December 2017

In the 1950s, Shanghai witnessed a conflict between the Chinese Communist Party (ccp) and the Shanghai Catholic community. The ccp wanted this community to break ties with the pope and form an “independent” Catholic Church that would fall under the authority of the Chinese government. Many Catholics in Shanghai soon resisted what they perceived to be the unjust religious policies of the ccp. One of the “backbone elements” of Catholic resistance in Shanghai was young women. This study investigates how three young Catholic women dealt with the ccp’s encroaching religious policies. All three came from similar backgrounds and they all initially formed part of the Catholic resistance to ccp religious policies during the early 1950s. Afterward their trajectories differed dramatically due to the particular way in which the Communist revolution intervened in the life of each woman. This study thus illuminates the contested area of religious faith, state power, and gender in the early years of the People’s Republic of China.

上世纪五十年代，上海见证了中共与上海天主教会之间的冲突。中共命令上海天主教会断绝与教宗的联系，成为一个听命于中国政府的“独立”教会。上海的许多天主教徒很快就起来抵制这些他们视为不公正的宗教政策。反抗运动中的许多“骨干分子”是年轻女信徒。本文探究了三位年轻的女天主教信徒如何应对当时中共侵权的宗教政策。她们有相似的生活背景，并都在50年代初期参与了抵制中共宗教政策的运动。但是因为中共革命介入她们生命的不同方式，她们之后的人生轨迹大相径庭。这项研究因此阐述了在中华人民共和国初期，宗教信仰、国家政权与性别之间充满张力的互动。
A synopsis of the Neotropical genus Protoneura (Odonata: Coenagrionidae)
Authors: ELLENRIEDER NATALIA VON , GARRISON ROSSER W.
Published: December 2017

A synopsis of the Neotropical genus Protoneura is presented, including an identification key to its 22 species accompanied by illustrations of diagnostic characters, and characterizations, diagnoses, and distribution maps for all species. A lectotype is designated for P. peramans Calvert in Skinner, 1902.