bluuebunny/crossref_metadata_2025 huggingface dataset:
Nieuw licht op de arbeidsrechtelijke omkeringsregel?
Authors: Oskam Veneta
Published: July 2018

Nieuw licht op de arbeidsrechtelijke omkeringsregel? HR 6 april 2018, ECLI:NL:HR:2018:536

Bij beantwoording van de vraag of causaal verband aanwezig is tussen de asbestblootstelling en het ontstaan van mesothelioom, en of ter vaststelling hiervan de arbeidsrechtelijke omkeringsregel moet worden toegepast, is – overeenkomstig de arresten HR 7 juni 2013, ECLI:NL:HR:2013:BZ1717 (SVB/Van der Wege) en ECLI:HR:2013:BZ1721 (Lansink/Ritsma) – van belang dat het verband tussen de gezondheidsschade en de arbeidsomstandigheden niet te onzeker dan wel te onbepaald dient te zijn. De Hoge Raad bekrachtigt het oordeel van het hof dat de enkele blootstelling aan asbest onvoldoende is om toepassing te geven aan de omkeringsregel. De in de eerdergenoemde arresten vastgestelde regels gelden ook bij schade als gevolg van mesothelioom. Ook hier kan het causaal verband te onzeker of te onbepaald zijn wanneer de werknemer ook buiten de werkzaamheden aan asbest blootgesteld is geweest. Daarom komt, gelet op hetgeen in het algemeen bekend is omtrent de ziekte mesothelioom en haar oorzaak, betekenis toe aan (1) de duur en de intensiteit van de blootstelling bij deze werkgever, en in voorkomend geval (2) de duur en de intensiteit van andere blootstelling(en) aan asbest gedurende de latentieperiode en (3) de verhouding tussen (1) en (2).
De Hoge Raad en de uitleg van de opzetclausule: een antwoord op alle vragen?
Authors: de Vries M.
Published: July 2018

De Hoge Raad en de uitleg van de opzetclausule: een antwoord op alle vragen?

In deze annotatie staat het arrest van de Hoge Raad van 13 april 2018 centraal. Daarin buigt Nederlands hoogste rechtscollege zich voor het eerst over de opzetclausule 2000. Deze clausule is in veel aansprakelijkheidsverzekeringen voor particulieren (AVP) opgenomen, maar de uitleg daarvan staat ter discussie. De Hoge Raad ziet dan ook aanleiding om met het oog op de rechtseenheid enkele fundamentele overwegingen te wijden aan de uitleg van deze opzetclausule.
Data analysis of information system TURAWA in the aspect of data mining methods
Authors: Szafrański Bolesław , Zieja Mirosław , Wójcik Jarosław , Murawski Krzysztof
Published: July 2018

The article is devoted to the analysis of data coming from the operation process and collected in computer system TURAWA, which focuses on supporting the management of flight safety in the Polish Air Force. The Armed Forces are equipped with a system, which collects and processes data concerning the whole air crew, all performed flights and all aircraft. The increasing opportunities in obtaining data and the continuous development of data mining methods allow to extract information never been known before, which, together with conclusions obtained from the data analysis, will help to improve the level of flight safety.
Impacto de un estilo de vida activo sobre la memoria emocional
Authors: Bossio Maximiliano , Justel Nadia
Published: July 2018

ResumenEl ejercicio aeróbico y de resistencia se ha relacionado con la promoción de la salud física, además en los últi­mos años se han investigado sus beneficios a nivel cogni­tivo. En base a ello, el objetivo de este trabajo fue eva­luar el posible efecto de tener un estilo de vida activo sobre la memoria emocional. Participaron del estudio 48 adultos de edad temprana y media (rango: 18-58 años) que llevaron a cabo un auto-reporte mediante el Cuestio­nario Internacional de Actividad Física dando cuenta de la cantidad y tipo de actividad física realizada en una semana habitual o típica, es decir aquella sostenida du­rante los últimos tres meses de sus vidas. Para evaluar la memoria emocional los participantes observaron una serie de imágenes positivas, negativas y neutras seleccio­nadas del Sistema Internacional de Imágenes Afectivas. Luego se evaluó cuántas imágenes recordaban y recono­cían (tanto de modo inmediato como diferido). Se halló que los sujetos que poseían un nivel alto de actividad física en su vida diaria recordaban inmediatamente más estímulos de valencia positiva que aquellos con niveles moderados y bajos. Además, este grupo obtuvo mejores resultados en la evaluación de reconocimiento inmediato. Por tanto, incorporar a la actividad física y deportiva como un estilo de vida, mostraría tener efectos favorables en la memoria de estímulos visuales vinculados a emo­ciones positivas.AbstractAerobic and resistance exercise has been related to phys­i­cal health promotion, besides in the last years its effects at a cognitive level has been investigated. Based on that, the aim of the current work was to evaluate the possible effect of having an active life style on emotional memory. Forty-eight adults of early and middle age par­ticipated (range: 18-58 years old) who complete a report through the Inter­national Physical Activity Questionnaire about the amount and type of physical activity performed in a typical or reg­ular week, i.e. a week sustained in the last three months of their lives. To evaluate emotional memory participants watched positive, negative and neu­tral images selected from the International Affective Picture System. Then, how many images they recall and recognize was evaluated (immediate and deferred measures). Participants that had a high level of physical activity in their lives remember immediately more posi­tive images than those participants with a low or moder­ate level of activity. Besides, this group obtained better results in the immediate recognition measure. Thus, in­corporate physical activity as a life style shows benefits in the emotional positive memory.
O Ensino Superior Artístico de Belas Artes: perspectivas e dilemas
Authors:   Escola Superior de Educação de Paula Frassinetti, Oliveira Sandra Mónica Figueiredo
Published: July 2018

Pensar o ensino superior artístico de belas artes atualmente é pensar as circunstâncias do contexto ecológico da formação dos estudantes e também na forma de trabalhar dos professores, tendo em conta as evidências resultantes quer do meio artístico, quer da sociedade atual, quer dos pressupostos enumerados pela política educativa vigente. Assim este artigo pretende refletir sobre as perspectivas de ensino-aprendizagem no ensino superior artístico de belas artes, através da percepção dos docentes, perspectivando o futuro. Este trabalho privilegia uma abordagem metodológica mista cujos objetivos passam por: compreender como os professores se percebem enquanto profissionais; que dilemas vivem atualmente e como perspectivam a formação no ensino superior artístico de belas artes. As conclusões emergentes do estudo evidenciam a necessidade de uma reforma curricular ensino superior artístico de belas artes, visando a inovação dos processos de formação.
O sistema TRIPS como instrumento de poder das corporações transnacionais na sociedade globalizada
Authors: Klein Junior Paulo , Olsson Giovanni
Published: July 2018

O estudo objetiva compreender o sistema TRIPS como instrumento de poder das corporações transnacionais na sociedade globalizada. Essa temática constitui uma questão contemporânea, uma vez que retrata situações em curso na sociedade internacional. A sociedade internacional, devido a vários fatores, sendo o mais destacado o fenômeno rede, tornou-se complexa, enfraquecendo o poderio estatal em detrimento do surgimento dos novos atores. As corporações internacionais detêm grandes poderes, e sua influência molda o globo de acordo com seus interesses. O acordo TRIPS, como exemplo de estudo, foi capitaneado pelo lobby realizado pelas corporações para consolidarem seus monopólios sobre a propriedade intelectual. Isso trouxe consequências negativas, mas que podem ser revertidas ou, ao menos, suavizadas. A metodologia utilizada na presente pesquisa consiste no método dedutivo, pela técnica de pesquisa bibliográfica.
Financiamento de startups: aspectos econômicos dos investimentos de alto risco e mecanismos jurídicos de controle
Authors: Fonseca Victor Cabral , Domingues Juliana Oliveira
Published: July 2018

Empresas nascentes inovadoras – conhecidas como startups – operam em situação de incerteza e risco. Este contexto decorre de características recorrentes destas empresas, como o oferecimento de produtos ou serviços inovadores, falta de experiência, pouco tempo de existência, porte, etc. Diante deste cenário, é possível encontrar diversos problemas enfrentados por tais empresas, capazes de afastar investidores, como assimetria informacional, custos de transação elevados e relações de agência; por outro lado, investidores enxergam alto potencial de retorno para o capital aportado em startups. Como tais problemas são minimizados pelos investidores típicos de startups, como venture capital ou investidores-anjo? O objetivo deste artigo é analisar quais são os problemas enfrentados no investimento em startups sob uma ótica de Law and Economics e Law and Finance e, assim, estudar o desenvolvimento de mecanismos jurídicos de controle, que objetivam garantir maior proteção do investidor e mitigar seus riscos.
Análise econômica do direito e propriedade intelectual: a contribuição de Posner & Landes
Authors: Magnino Rosa Portilho Raphaela , Da Silva Sant´Anna Leonardo
Published: July 2018

Este artigo tem por escopo trazer à colação a abordagem da Análise Econômica do Direito sobre o ramo jurídico da Propriedade Intelectual. Nesse diapasão, opta-se por apresentar um estudo panorâmico acerca da metodologia econômica valendo-se dos estudos de Richard A. Posner como marco teórico. Além de apresentar os principais postulados que sustentam a perspectiva em comento, o primeiro capítulo cumpre o papel de demonstrar suas raízes no paradigma utilitarista. O segundo capítulo, por conseguinte, leva a investigação para o ramo específico da Propriedade Intelectual, apresentando as matrizes teóricas mais usadas para sua justificação, bem como o estudo de Posner e William Landes sobre tal ramo jurídico nos parâmetros da abordagem econômica. Importa observar, finalmente, que o presente trabalho se perfaz segundo a metodologia da pesquisa qualitativa e análise de conteúdo.
Perspectivas da gestão do saneamento básico no Brasil: prestação indireta e deficiências setoriais
Authors: Nohara Irene Patrícia , Postal Júnior Jairo
Published: July 2018

No Brasil, o saneamento básico, conjunto de procedimentos que visam propiciar aos habitantes de determinada região uma situação higiênica saudável, está longe de ser universalizado. Na região Norte, pesquisas apontam que 54,51% da população encontra-se servida de água impoluta para consumo, sendo que mais de 100 milhões de brasileiros não têm acesso a uma rede de esgoto. Muito embora a Lei do Saneamento Básico preveja como diretriz nacional para a política pública de saneamento a universalização de acesso, a ausência de articulação efetiva entre entes federativos para a melhor prestação do serviço à população contribui para que grande parte dos cidadãos se encontrem alijados de condição mínimas de higiene. No modelo de administração gerencial adotado pelo Brasil a partir da década de 1990, em que o Estado recebe papel fiscalizatório predominante, concedendo à iniciativa privada grande parte dos serviços públicos, verifica-se uma tendência contemporânea à privatização em sentido lato das atividade inerentes ao saneamento básico. A partir da análise concernente a este modelo de gestão, baseando-se no método hipotético-dedutivo, buscar-se-á a identificação das insuficiências da política nacional de saneamento ambiental, com o escopo de formulação de propostas que tendam a garantir a melhor implementação dos projetos de governo nesta área.
Resenha: “Sapiens: uma breve história da humanidade”, de Yuval Noah Harari
Authors: Rossi Amélia Do Carmo Sampaio
Published: July 2018

Nesta obra o autor Yuval Harari, historiador, doutor em História pela Universidade de Oxford, professor da Universidade Hebraica de Jerusalém e especializado em história mundial, nos leva de maneira muito leve, interessante e também polêmica, pela história da passagem e evolução da espécie humana pelo planeta Terra. Importante notar que a perspectiva do autor não é apenas e exclusivamente histórica, mas uma combinação interdisciplinar entre história, biologia, antropologia, economia e considerações filosóficas como a ideia de felicidade e a ideia de justiça. Esta característica deixa a leitura enriquecida e extremamente agradável, pela gama de informações, mas também pelo senso refinado de humor crítico do autor.
Noncoding RNA-nucleated heterochromatin spreading is intrinsically labile and requires accessory elements for epigenetic stability
Authors: Greenstein R A , Jones Stephen K , Spivey Eric C , Rybarski James R , Finkelstein Ilya J , Al-Sady Bassem
Published: July 2018

The heterochromatin spreading reaction is a central contributor to the formation of gene-repressive structures, which are re-established with high positional precision, or fidelity, following replication. How the spreading reaction contributes to this fidelity is not clear. To resolve the origins of stable inheritance of repression, we probed the intrinsic character of spreading events in fission yeast using a system that quantitatively describes the spreading reaction in live single cells. We show that spreading triggered by noncoding RNA-nucleated elements is stochastic, multimodal, and fluctuates dynamically across time. This lack of stability correlates with high histone turnover. At the mating type locus, this unstable behavior is restrained by an accessory cis-acting element REIII, which represses histone turnover. Further, REIII safeguards epigenetic memory against environmental perturbations. Our results suggest that the most prevalent type of spreading, driven by noncoding RNA-nucleators, is epigenetically unstable and requires collaboration with accessory elements to achieve high fidelity.
UBE3A-mediated p18/LAMTOR1 ubiquitination and degradation regulate mTORC1 activity and synaptic plasticity
Authors: Sun Jiandong , Liu Yan , Jia Yousheng , Hao Xiaoning , Lin Wei ju , Tran Jennifer , Lynch Gary , Baudry Michel , Bi Xiaoning
Published: July 2018

Accumulating evidence indicates that the lysosomal Ragulator complex is essential for full activation of the mechanistic target of rapamycin complex 1 (mTORC1). Abnormal mTORC1 activation has been implicated in several developmental neurological disorders, including Angelman syndrome (AS), which is caused by maternal deficiency of the ubiquitin E3 ligase UBE3A. Here we report that Ube3a regulates mTORC1 signaling by targeting p18, a subunit of the Ragulator. Ube3a ubiquinates p18, resulting in its proteasomal degradation, and Ube3a deficiency in the hippocampus of AS mice induces increased lysosomal localization of p18 and other members of the Ragulator-Rag complex, and increased mTORC1 activity. p18 knockdown in hippocampal CA1 neurons of AS mice reduces elevated mTORC1 activity and improves dendritic spine maturation, long-term potentiation (LTP), as well as learning performance. Our results indicate that Ube3a-mediated regulation of p18 and subsequent mTORC1 signaling is critical for typical synaptic plasticity, dendritic spine development, and learning and memory.
Habitat use, preference, and utilization distribution of two crane species (Genus: Grus) in Huize National Nature Reserve, Yunnan–Guizhou Plateau, China
Authors: Kong Dejun , Luo Weixiong , Liu Qiang , Li Zhuoqing , Huan Guoyue , Zhang Jianjun , Yang Xiaojun
Published: July 2018

Understanding the habitat use and spatial distribution of wildlife can help conservationists determine high-priority areas and enhance conservation efforts. We studied the wintering habitat use, preference, and utilization distribution of two crane species, that is, the black-necked crane (Grus nigricollis, Przevalski, 1876) and common crane (Grus grus, Linnaeus, 1758), in Huize National Natural Reserve, Yunnan–Guizhou Plateau, southwestern China. Line transects indicated that anthropogenic farmland habitat was highly utilized and was positively selected by both crane species (>90% of flocks observed for both species). Black-necked cranes preferred marshland in spring (February and March) but avoided grassland during the entire wintering period, whereas common cranes avoided both marshland and grassland throughout the entire period. The two cranes species had communal nightly roosting sites and separate daily foraging sites. Black-necked cranes were distributed within two km (1.89 ± 0.08 km) of the roosting site, covering an area of 283.84 ha, with the core distribution area encompassing less than 100 ha. In contrast, common cranes were distributed far from the roosting site (4.38 ± 0.11 km), covering an area of 558.73 ha, with the core distribution area encompassing 224.81 ha. Thus, interspecies competition may have influenced the habitat preference and spatial distribution divergence of these two phylogenetically related species. This study should help guide habitat management as well as functional zoning development and adjustment in the future. Based on our results, we recommend restoration of additional wetlands, retention of large areas of farmland, and protection of areas that cranes use most frequently.
Microarray gene expression profiling in colorectal (HCT116) and hepatocellular (HepG2) carcinoma cell lines treated withMelicope ptelefolialeaf extract reveals transcriptome profiles exhibiting anticancer activity
Authors: Kabir Mohammad Faujul , Mohd Ali Johari , Haji Hashim Onn
Published: July 2018

Background

We have previously reported anticancer activities ofMelicope ptelefolia(MP) leaf extracts on four different cancer cell lines. However, the underlying mechanisms of actions have yet to be deciphered. In the present study, the anticancer activity of MP hexane extract (MP-HX) on colorectal (HCT116) and hepatocellular carcinoma (HepG2) cell lines was characterized through microarray gene expression profiling.

Methods

HCT116 and HepG2 cells were treated with MP-HX for 24 hr. Total RNA was extracted from the cells and used for transcriptome profiling using Applied Biosystem GeneChip™ Human Gene 2.0 ST Array. Gene expression data was analysed using an Applied Biosystems Expression Console and Transcriptome Analysis Console software. Pathway enrichment analyses was performed using Ingenuity Pathway Analysis (IPA) software. The microarray data was validated by profiling the expression of 17 genes through quantitative reverse transcription PCR (RT-qPCR).

Results

MP-HX induced differential expression of 1,290 and 1,325 genes in HCT116 and HepG2 cells, respectively (microarray data fold change, MA_FC ≥ ±2.0). The direction of gene expression change for the 17 genes assayed through RT-qPCR agree with the microarray data. In both cell lines, MP-HX modulated the expression of many genes in directions that support antiproliferative activity. IPA software analyses revealed MP-HX modulated canonical pathways, networks and biological processes that are associated with cell cycle, DNA replication, cellular growth and cell proliferation. In both cell lines, upregulation of genes which promote apoptosis, cell cycle arrest and growth inhibition were observed, while genes that are typically overexpressed in diverse human cancers or those that promoted cell cycle progression, DNA replication and cellular proliferation were downregulated. Some of the genes upregulated by MP-HX include pro-apoptotic genes (DDIT3, BBC3, JUN), cell cycle arresting (CDKN1A, CDKN2B), growth arrest/repair (TP53, GADD45A) and metastasis suppression (NDRG1). MP-HX downregulated the expression of genes that could promote anti-apoptotic effect, cell cycle progression, tumor development and progression, which include BIRC5, CCNA2, CCNB1, CCNB2, CCNE2, CDK1/2/6, GINS2, HELLS, MCM2/10 PLK1, RRM2 and SKP2. It is interesting to note that all six top-ranked genes proposed to be cancer-associated (PLK1, MCM2, MCM3, MCM7, MCM10 and SKP2) were downregulated by MP-HX in both cell lines.

Discussion

The present study showed that the anticancer activities of MP-HX are exerted through its actions on genes regulating apoptosis, cell proliferation, DNA replication and cell cycle progression. These findings further project the potential use of MP as a nutraceutical agent for cancer therapeutics.
Mechanical/thermal sensitivity and superficial temperature in the stump of long-term tail-docked dairy cows
Authors: Troncoso Renata J. , Herzberg Daniel E. , Meneses Constanza S. , Müller Heine Y. , Werner Marianne P. , Bustamante Hedie
Published: July 2018

Background

Tail docking of dairy cows is a painful procedure that affects animal welfare level. The aims of this study were first to evaluate the response to mechanical and thermal stimulation, and second to determine the superficial temperature of the stump of tail-docked dairy cows.

Methods

One hundred and sixty-four dairy cows were enrolled. From these, 133 cows were assigned to the tail-docked (TD) group and 31 cows were selected as control animals. The following sensory assessments to evaluate pain in tail-docked cows were performed. Sensitivity of the tail region in both groups of animals was evaluated using a portable algometer. Cold and heat sensitivity assessment was performed using a frozen pack (0 °C) and warm water (45 °C), respectively. Pinprick sensitivity was evaluated using a Wartenberg neurological pinwheel. Superficial temperature was evaluated using a thermographic camera. All sensory assessments and superficial temperature were evaluated in the ventral surface of the tail stump (TD) and tail (C).

Results

Pressure pain threshold was lower in TD cows (5.97 ± 0.19 kg) compared to control cows (11.75 ± 0.43 kg). Heat and cold sensitivity was higher in the TD cows compared to control cows with 29% and 23% of TD cows responding positively, respectively. Similarly, after pinprick sensitivity test was performed, 93% of TD cows elicited a positive response to stimulation. Tail-docked cows had lower superficial temperature (26.4 ± 0.27 °C) compared to control cows (29.9 ± 0.62 °C).

Discussion

Pressure pain threshold values in both groups of animals were higher than those previously reported for TD pigs, sows and cows. In contrast, pinprick stimulation evaluates the presence of punctate mechanical hyperalgesia/allodynia, usually related to traumatic nerve injury, and this association may reveal that it is possible that these animals developed a disorder associated to the development of a tail stump neuroma and concurrent neuropathic pain, previously reported in TD lambs, pigs and dogs. Thermal sensitivity showed that TD cows responded positively to heat and cold stimulation. These findings suggest that long-term TD cows could be suffering hyperalgesia/allodynia, which may be indicative of chronic pain. Lower superficial temperature in the stump may be associated to sympathetic fiber sprouting in the distal stump, which can lead to vasoconstriction and lower surface temperatures. Further studies are needed in order to confirm neuroma development and adrenergic sprouting.
Trematodon (Bryopsida: Bruchiaceae) in Australia: unravelling the conundrum
Authors: Ramsay Helen P. , Seppelt Rodney D , Downing Alison J
Published: July 2018

Following a critical re-examination and evaluation of Australian taxa of the genus Trematodon, three species formerly considered endemic, T. baileyi Broth., T. brachyphyllus Müll. Hal., and T. longescens Müll. Hal., together with the New Caledonian endemic T. longifolius Broth. & Paris in Broth., are illustrated for the first time and reduced to synonyms of T. longicollis Michx.
Transcription factor ABI3 auto‐activates its own expression during dehydration stress response
Authors: Bedi Sonia , Nag Chaudhuri Ronita
Published: July 2018

The transcription factor abscisic acid insensitive 3 (ABI3) has recently been shown to mediate the dehydration stress response in nonseed and seed plants by regulation of several downstream genes. Here, we show how ABI3 autoregulates its transcription in response to dehydration stress signalling. Autoactivation is primarily through the Sph/RY element CATGCA present at the promoter region of ABI3. Along with other known cis‐elements found at the ABI3 promoter, CATGCA remains occluded by nucleosomes during transcription repression. The nucleosomes tend to reposit during active transcription and are associated with several histone modifications, such as H3K9 and K27 acetylations and H3K4 trimethylation. This work thus, reveals the genetic and epigenetic essentials required for expression of the ABI3 gene, a crucial factor regulating dehydration stress signalling in Arabidopsis thaliana.
Application of Multifunctional Nanomaterials in Radioprotection of Healthy Tissues
Authors: Xie Jiani , Wang Chengyan , Zhao Feng , Gu Zhanjun , Zhao Yuliang
Published: July 2018

Radiotherapy has been extensively used in clinic for malignant tumors treatment. However, a severe challenge of it is that the ionizing radiation needed to kill tumors inevitably causes damage to surrounding normal tissues. Although some of the molecular radioprotective drugs, such as amifostine, have been used as clinical adjuvants to radio‐protect healthy tissues, their shortcomings such as short systemic circulation time and fast biological clearing from the body largely hinder the sustained bioactivity. Recently, with the rapid development of nanotechnology in the biological field, the multifunctional nanomaterials not only establish powerful drug delivery systems to improve the molecular radioprotective drugs' biological availability, but also open a new route to develop neozoic radioprotective agents because some nanoparticles possess intrinsic radioprotective abilities. Therefore, considering these overwhelming superiorities, this review systematically summarizes the advances in healthy tissue radioprotection applications of multifunctional nanomaterials. Furthermore, this review also points out a perspective of nanomaterial designs for radioprotection applications and discusses the challenges and future outlooks of the nanomaterial‐mediated radioprotection.
N‐Alkylation of Fulleropyrrolidines by Aminomethylation Reaction of Ketones/Arylboronic Acids
Authors: Huang Cheng , Huang Gang , Wang Hui‐Juan , Li Fa‐Bao , Wang Zhen , Huang Yongshun , Liu Li , Liu Chao‐Yang
Published: July 2018

N‐alkylation of fulleropyrrolidines in the presence of polyformaldehyde and p‐toluenesulfonic acid was systematically investigated. With the addition of ketones/arylboronic acids, a series of novel N‐alkyl fulleropyrrolidines were formed. Nevertheless, in the absence of ketones/arylboronic acids, scarce N‐methyl fulleropyrrolidines were obtained with the aid of benzyl alcohol. Possible reaction pathways for the formation of N‐alkyl fulleropyrrolidines were proposed to elucidate the above reaction process.

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Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies
Authors: Savona Michael R. , Kolibaba Kathryn , Conkling Paul , Kingsley Edwin C. , Becerra Carlos , Morris John C. , Rifkin Robert M. , Laille Eric , Kellerman Amy , Ukrainskyj Stacey M. , Dong Qian , Skikne Barry S.
Published: July 2018

CC‐486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC‐486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC‐486 300 mg once‐daily for 21 days of repeated 28‐day cycles. Median age was 71 years (range: 53‐93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC‐486 treatment cycles was 4 (range: 1‐32). The most common treatment‐emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3‐4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC‐486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on‐study. No baseline gene mutation was predictive of response/nonresponse. CC‐486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics.

KEY POINTS

The safety profile of oral CC‐486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal.

Extended (21‐day/cycle) CC‐486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.
Can Shareholders Hold Directors Liable for Failing to Address Social Issues?
Authors: Resnick Stephanie , Fuller John C.
Published: July 2018

Stephanie Resnick is office managing partner of Fox Rothschild LLP's Philadelphia office and chair of the Directors' & Officers' Liability & Corporate Governance Practice Group. John C. Fuller is an attorney with Fox Rothschild's Directors' & Officers' Liability & Corporate Governance Practice Group. In this article, they discuss the liabilities that boards and their leaders face if they fail to adequately address marquee social issues impacting their organizations.
The Hard and Critical Work of School Board Governance
Authors: Elsbernd Cindy
Published: July 2018

Cindy Elsbernd is the vice chair of the Des Moines Public Schools board of directors in Des Moines, Iowa; a member of the second cohort of the IPGA Policy Governance Proficiency Program; founder and director of Iowa Kidstrong Inc.; the program manager for the United Way of Central Iowa's Well Kids Coalition; and an independent contractor with the Iowa Association of School Boards' Board Development Cadre. In this article, she discusses the application of Policy Governance principles in a school board setting.
Economic evaluation of smoking cessation in Ontario's regional cancer programs
Authors: Djalalov Sandjar , Masucci Lisa , Isaranuwatchai Wanrudee , Evans William , Peter Alice , Truscott Rebecca , Cameron Erin , Mittmann Nicole , Rabeneck Linda , Chan Kelvin , Hoch Jeffrey S.
Published: July 2018

Quitting smoking after a diagnosis of cancer results in greater response to treatment and decreased risk of disease recurrence and second primary cancers. The objective of this study was to evaluate the potential cost‐effectiveness of two smoking cessation approaches: the current basic smoking cessation program consisting of screening for tobacco use, advice, and referral; and a best practice smoking cessation program that includes the current basic program with the addition of pharmacological therapy, counseling, and follow‐up. A Markov model was constructed that followed 65‐year‐old smokers with cancer over a lifetime horizon. Transition probabilities and mortality estimates were obtained from the published literature. Costs were obtained from standard costing sources in Ontario and reports. Probabilistic and deterministic sensitivity analyses were conducted to address parameter uncertainties. For smokers with cancer, the best practice smoking cessation program was more effective and more costly than the basic smoking cessation program. The incremental cost‐effectiveness ratio of the best practice smoking cessation program compared to the basic smoking cessation program was $3367 per QALY gained and $5050 per LY gained for males, and $2050 per QALY gained and $4100 per LY gained for females. Results were most sensitive to the hazard ratio of mortality for former and current smokers, the probability of quitting smoking through participation in the program and smoking‐attributable costs. The study results suggested that a best practice smoking cessation program could be a cost‐effective option. These findings can support and guide implementation of smoking cessation programs.
Effects of thoracic radiotherapy timing and duration on progression‐free survival in limited‐stage small cell lung cancer
Authors: Zhao Shen , Zhou Ting , Ma Shuxiang , Zhao Yuanyuan , Zhan Jianhua , Fang Wenfeng , Yang Yunpeng , Hou Xue , Zhang Zhonghan , Chen Gang , Zhang Yaxiong , Huang Yan , Zhang Li
Published: July 2018

Concurrent chemoradiotherapy (CRT) has been recommended and applied widely as the standard treatment for limited‐stage small cell lung cancer (LS‐SCLC). However, controversies remain regarding the optimal timing and treatment duration of thoracic radiotherapy (TRT), and their effects on patient survival. To evaluate prognostic values of TRT timing and duration on progression‐free survival (PFS) in LS‐SCLC and their dependence on TRT fractionation and clinicopathological characteristics, we retrospectively analyzed 197 LS‐SCLC patients receiving CRT from 2000 to 2016 at Sun Yat‐sen University Cancer Center. Based on the optimal cut‐off values of TRT timing and duration generated by Cutoff Finder, patients were divided into early TRT/late TRT group and short TRT/long TRT group respectively. Univariate and multivariate Cox analysis were performed to assess correlations of TRT timing, duration, fractionation, and clinicopathological characteristics with PFS. Univariate analysis revealed that early‐initiated TRT (P = 2.54 × 10−4) and short TRT (P = .001) significantly correlated with longer PFS. Their PFS benefits persisted in patients receiving hyperfractionated TRT and etoposide‐cisplatin (EP) chemotherapy, but were less prominent in those receiving once‐daily TRT and non‐EP chemotherapy. Multivariate analysis further identified early initiated TRT (P = .004) and short TRT (P = .017) as independent prognostic factors for longer PFS in LS‐SCLC. Our study confirmed that early‐initiated TRT and short TRT had positive prognostic roles in LS‐SCLC, especially in patients receiving hyperfractionated TRT and etoposide‐cisplatin chemotherapy. TRT fractionation was not an independent prognostic factor in LS‐SCLC.
Coexpression of CD5 and CD43 predicts worse prognosis in diffuse large B‐cell lymphoma
Authors: Ma Xiao‐bo , Zhong Yan‐ping , Zheng Yan , Jiang Jing , Wang Yin‐ping
Published: July 2018

Both CD5 and CD43 are expressed on the surface of B lymphocytes of definite phase and associated with the adverse outcome in diffuse large B‐cell lymphoma (DLBCL). However, the relationship between CD5 and CD43 expression and the prognostic value of CD5/CD43 coexpression in DLBCL are unknown. We herein determined the correlation between CD5 and CD43 expression, as separate factors or in combination, with the clinicopathological features and survival of 200 patients with DLBCL receiving standard chemotherapy with or without rituximab. Among these DLBCL patients, CD5 expression, CD43 expression, and CD5/CD43 coexpression were detected in 18 (9%), 57 (27%), and 10 (5%) patients, respectively, and all were positively correlated with advanced age and nongerminal cell type. CD5‐positive and CD43‐positive DLBCL patients had poorer event‐free survival (EFS, P < 0.001) and overall survival (OS, P < 0.001) than CD5‐negative and CD43‐negative patients, respectively. CD5/CD43 coexpression was correlated with a significantly worse prognosis than CD5 or CD43 expression alone. Univariate analysis showed that CD5 expression, CD43 expression, and CD5/CD43 coexpression were all adverse prognostic factors for DLBCL patient survival, and CD5/CD43 coexpression was associated with a greater relative risk for recurrence and death than either CD5 or CD43 expression alone. Multivariate analysis demonstrated that CD5/CD43 coexpression was an independent prognostic factor for EFS (P < 0.001) and OS (P < 0.001) in DLBCL. In conclusion, our data indicate that DLBCL patients with CD5/CD43 coexpression represent a specific subgroup with a significantly worse prognosis than those expressing either marker alone.
Cancer of unknown primary—Epidemiological trends and relevance of comprehensive genomic profiling
Authors: Binder Carmen , Matthes Katarina Luise , Korol Dimitri , Rohrmann Sabine , Moch Holger
Published: July 2018

Background

Cancer of unknown primary (CUP) is a distinct clinicopathological entity with poor prognosis, frequently resistant to chemotherapy. Comprehensive genomic profiling (CGP) by next‐generation sequencing potentially identifies novel treatment options for CUP patients. The objective of this study was to determine incidence and survival trends and to discuss the value of CGP in CUP patients.

Methods

Age‐standardized incidence rates (ASR) per 100 000 were calculated for 2935 CUP patients from 1981 to 2014 using cancer registry data of the canton of Zurich, Switzerland. Kaplan–Meier survival curves were estimated for sex, age, and histological groups. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HR). A literature review was conducted to assess the current use of CGP in CUP patients.

Results

ASR of CUP increased from 10.3 to 17.6 between 1981 and 1997 and decreased to 5.8/100 000 in 2014. Mean overall survival remained stable. Mortality was significantly lower for patients with squamous cell carcinoma (HR 0.48 [95% CI, 0.41‐0.57]) and neuroendocrine carcinoma (0.75 [0.63‐0.88]) and higher for unclassified neoplasms (1.25 [1.13‐1.66]) compared to adenocarcinomas. The literature review identified 10 studies using CGP of CUP tissue. Clinically relevant mutations were identified in up to 85% of CUP patients, of which 13%‐64% may benefit from currently available drugs.

Conclusions

CUP incidence decreased probably due to improved diagnostics, but mortality did not improve over the last 34 years. CGP testing may help to identify molecular signatures in CUP patients and enable targeted treatment.
Chemical Constituents from Chloranthus anhuiensis and Their Cytotoxic Activities
Authors: Zhu Hui‐Lin , Qu Wei , Zhang Jie , Guo Er‐Yan , Du Tao , Liu Wen‐Yuan , Cao Wen‐Yuan , Feng Feng , Xu Jian
Published: July 2018

Three hiherto unknown phenylpropanoid compounds, namely (7S,8R)‐1‐(1‐ethoxy‐2‐hydroxypropyl)‐2‐methoxy‐3,4‐(methylenedioxy)benzene (1), (7S,8S)‐1‐(1‐ethoxy‐2‐hydroxypropyl)‐2‐methoxy‐3,4‐(methylenedioxy)benzene (2), and (7S,8R)‐1‐(1‐methoxy‐2‐hydroxypropyl)‐2‐methoxy‐3,4‐(methylenedioxy)benzene (3), along with 12 known compounds (4 – 15) were obtained from the extract of whole plant of Chloranthus anhuiensis. Among them, 7 and 13 were obtained from nature for the first time. The structures of these natural compounds were characterized by extensive spectroscopic analysis and calculated electronic circular dichroism (ECD) data. Furthermore, their cytotoxic and neuroprotective activities were evaluated using MDA‐MB‐231, 4T1, HepG2, and PC12 cell lines. Compounds 8 and 13 exhibited moderate cytotoxic activities against MDA‐MB‐231 cell line with the IC50 values of 39.7 and 25.8 μm, respectively. And all the isolated compounds have no neuroprotective activities.
Identification of a BRCA2 mutation in a Turkish family with early‐onset breast cancer
Authors: Celik Elifnaz , Ermis Tekkus Kubra , Akcay Izzet Mehmet , Alkurt Sal Gizem , Ezberci Fikret , Dinler Doganay Gizem , Doganay Levent
Published: July 2018

Key Clinical Message

We used a multi‐gene panel testing to identify the germline variants in a mother‐daughter pair with early‐onset breast cancer, and detected one pathogenic protein‐truncating variant in BRCA2. Our results highlight the importance of genetic testing in identifying the pathogenic mutation running in cancer families.
Heterocyclization and Spirocyclization Processes Based on Domino Reactions of N‐Tosylhydrazones and Boronic Acids Involving Intramolecular Allylborylations of Nitriles
Authors: Plaza Manuel , Parisotto Stefano , Valdés Carlos
Published: July 2018

Polycyclic molecules featuring all‐carbon quaternary bridgehead centers were synthesized through domino cyclizations between N‐tosylhydrazones and boronic acids. Variations of the general cascade have been applied for the preparation of 3‐quinuclidinones and related alkaloid‐like scaffolds through transannular heterocyclizations. Moreover, the employment of 3‐cyanopropyl and 4‐cyanobutylboronic acids and α,β‐unsaturated N‐tosylhydrazones led to spirocycles through unprecedented formal [n+1] cyclizations, including the stereoselective spirocyclization of the Hajos–Parrish ketone. The common feature of all the new reactions described is the creation of an all‐carbon quaternary center by formation of two Csp3−C bonds on the hydrazonic carbon atom. DFT‐based calculations suggested the occurrence of cascade processes, which involve a diazo compound carboborylation followed by a 1,3‐borotropic rearrangement on an intermediate allylboronic acid and a novel bora‐aza‐ene cyclization.
Non‐coronary predictors of elevated high‐sensitive cardiac troponin T (hs‐cTnT) levels in an unselected emergency patient cohort
Authors: Berger Manfred , Emir Meryem , Brünnler Tanja , Rockmann Felix , Lehmann Ralf
Published: July 2018

Background

Aim of this study was to evaluate the predictors of hs‐cTnT in a non‐ACS patient cohort admitted to the emergency department.

Hypothesis

Atrial fibrillation and hypertension may not always be sufficient for elevation for hs‐cTnT.

Methods

We performed a retrospective, single center study encompassing in total 1003 patients. Individuals were retrospectively divided in ACS‐ and non‐ACS patients by two independent investigators reviewing the medical records. In order to identify predictors of hs‐cTnT elevation hazard ratios were calculated for age, gender, vital signs, cardiovascular risk factors, LVEF, serum levels of CRP, hemoglobin, and creatinine. Elevation of hs‐cTnT was defined by exceeding 14 ng/L (upper reference limit [URL]).

Results

About 987 patients were included while 25 patients were excluded because of missing data. 307 patients (31.4%) met the current guideline requirements of diagnosing an ACS, whereas 671 patients (68.6%) were hospitalized with excluded ACS. In the multivariate analysis age, anemia, CRP, creatinine, and reduced systolic left ventricular ejection fraction were independent predictors of elevated troponin T levels in the non‐ACS group. However, hypertensive systolic blood pressure, atrial fibrillation and tachycardia were not predictive for Troponin T elevation in non‐ACS patients in this multivariate analysis.

Conclusions

In an unselected, non‐ACS patient cohort age, chronic renal failure, inflammatory state, and reduced left ventricular systolic function were associated with hs‐cTnT levels above the upper reference limit. Rather, often supposed predictors as atrial fibrillation, hypertension, and tachycardia cannot sufficiently explain increased hs‐cTnT in our study. Hence, further studies are needed to assess whether isolated hypertension, tachycardia, or atrial fibrillation sufficiently explain elevated hs‐cTnT.
Strong cytoskeleton activity on millisecond timescales upon particle binding revealed by ROCS microscopy
Authors: Jünger Felix , Rohrbach Alexander
Published: July 2018

Cells change their shape within seconds, cellular protrusions even on subsecond timescales enabling various responses to stimuli of approaching bacteria, viruses or pharmaceutical drugs. Typical response patterns are governed by a complex reorganization of the actin cortex, where single filaments and molecules act on even faster timescales. These dynamics have remained mostly invisible due to a superposition of slow and fast motions, but also due to a lack of adequate imaging technology. Whereas fluorescence techniques require too long integration times, novel coherent techniques such as ROCS microscopy can achieve sufficiently high spatiotemporal resolution. ROCS uses rotating back‐scattered laser light from cellular structures and generates a consistently high image contrast at 150 nm resolution and frame rates of 100 Hz—without fluorescence or bleaching. Here, we present an extension of ROCS microscopy that exploits the principles of dynamic light scattering for precise localization, visualization and quantification of the cytoskeleton activity of mouse macrophages. The locally observed structural reorganization processes, encoded by dynamic speckle patterns, occur upon distinct mechanical stimuli, such as soft contacts with optically trapped beads. We find that a substantial amount of the near‐membrane cytoskeleton activity takes place on millisecond timescales, which is much faster than reported ever before.
GLP‐1 neurons form a local synaptic circuit within the rodent nucleus of the solitary tract
Authors: Card J. Patrick , Johnson Aaron L. , Llewellyn‐Smith Ida J. , Zheng Huiyuan , Anand Rishi , Brierley Daniel I. , Trapp Stefan , Rinaman Linda
Published: July 2018

Glutamatergic neurons that express pre‐proglucagon (PPG) and are immunopositive (+) for glucagon‐like peptide‐1 (i.e., GLP‐1+ neurons) are located within the caudal nucleus of the solitary tract (cNTS) and medullary reticular formation in rats and mice. GLP‐1 neurons give rise to an extensive central network in which GLP‐1 receptor (GLP‐1R) signaling suppresses food intake, attenuates rewarding, increases avoidance, and stimulates stress responses, partly via GLP‐1R signaling within the cNTS. In mice, noradrenergic (A2) cNTS neurons express GLP‐1R, whereas PPG neurons do not. In this study, confocal microscopy in rats confirmed that prolactin‐releasing peptide (PrRP)+ A2 neurons are closely apposed by GLP‐1+ axonal varicosities. Surprisingly, GLP‐1+ appositions were also observed on dendrites of PPG/GLP‐1+ neurons in both species, and electron microscopy in rats revealed that GLP‐1+ boutons form asymmetric synaptic contacts with GLP‐1+ dendrites. However, RNAscope confirmed that rat GLP‐1 neurons do not express GLP‐1R mRNA. Similarly, Ca2+ imaging of somatic and dendritic responses in mouse ex vivo slices confirmed that PPG neurons do not respond directly to GLP‐1, and a mouse crossbreeding strategy revealed that <1% of PPG neurons co‐express GLP‐1R. Collectively, these data suggest that GLP‐1R signaling pathways modulate the activity of PrRP+ A2 neurons, and also reveal a local “feed‐forward” synaptic network among GLP‐1 neurons that apparently does not use GLP‐1R signaling. This local GLP‐1 network may instead use glutamatergic signaling to facilitate dynamic and potentially selective recruitment of GLP‐1 neural populations that shape behavioral and physiological responses to internal and external challenges.
Stimuli‐Responsive Lanthanide‐Based Smart Luminescent Materials for Optical Encoding and Bio‐applications
Authors: Yang Yiwei , Su Pingru , Tang Yu
Published: July 2018

Lanthanide based luminescent materials have attracted extensive attention in a wide range of fields including chemistry, biology and logic due to the narrow emission band, long decay time of the excited state, low auto‐fluorescence background and excellent photostability. More interestingly, stimuli‐responsive lanthanide‐based luminescent materials have exhibited enormous application prospects in optical encoding and bio‐applications. In this review, we summarize these aspects of the development of stimuli‐responsive smart lanthanide luminescent materials by sorting the stimuli into several categories, including photo‐, pH‐, thermo‐ and molecule‐responsive. These unique stimuli‐responsive properties endow these materials with great potential in enriching code library and expanding data storage. Additionally, these properties have also been studied widely for bio‐applications, including drug release, imaging biosensing, cell adhesion, and cancer therapy. Based on these two aspects, we highlight the recent progress of lanthanide‐based smart luminescent materials.