bluuebunny/crossref_metadata_2025 huggingface dataset:
Microsatellite instability in Japanese female patients with triple-negative breast cancer
Authors: Kurata Kanako , Kubo Makoto , Kai Masaya , Mori Hitomi , Kawaji Hitomi , Kaneshiro Kazuhisa , Yamada Mai , Nishimura Reiki , Osako Tomofumi , Arima Nobuyuki , Okido Masayuki , Oda Yoshinao , Nakamura Masafumi
Published: January 2020

Background

It is important to identify biomarkers for triple-negative breast cancers (TNBCs). Recently, pembrolizumab, an immune checkpoint inhibitor (ICI) for programmed cell death 1 (PD-1), was approved as a treatment strategy for unresectable or metastatic tumor with high-frequency microsatellite instability (MSI-H) or mismatch repair deficiency, such as malignant melanoma, non-small cell lung cancer, renal cell cancer and urothelial cancer. In addition, results from clinical trials suggested that ICI was a promising treatment for TNBCs with accumulated mutations. However, the frequency of MSI in Japanese TNBCs still remains unclear. We aimed to analyze the presence of MSI-H in TNBCs as a biomarker for ICI therapy.

Methods

In this study, we retrospectively evaluated the MSI of 228 TNBCs using an innovative method, MSI Analysis System Version 1.2 (Promega), consisting of 5 microsatellite markers: BAT-26, NR-21, BAT-25, MONO-27 and NR-24 without a normal tissue control.

Results

Among 228 tumors, 222 (97.4%) were microsatellite stable, 4 (1.7%) low-frequency MSI and 2 (0.9%) MSI-H, respectively. Two MSI-H tumors were potentially aggressive pathologically as indicated by nuclear grade 3 and high Ki-67 (> 30%), and were classified as basal-like and non-BRCA-like, but were not consistent regarding tumor-infiltrating lymphocytes, CD8 and PD-L1 expression.

Conclusions

Although we found that MSI-H was uncommon (0.9%) in TNBCs, potential targets for ICIs exist in TNBCs. Therefore, MSI-H breast cancer patients should be picked up using not only conventional methods but also platforms for comprehensive genomic profiling.
Buddhist Ethics
Authors: Heim Maria
Published: January 2020

'Ethics' was not developed as a separate branch of philosophy in Buddhist traditions until the modern period, though Buddhist philosophers have always been concerned with the moral significance of thoughts, emotions, intentions, actions, virtues, and precepts. Their most penetrating forms of moral reflection have been developed within disciplines of practice aimed at achieving freedom and peace. This Element first offers a brief overview of Buddhist thought and modern scholarly approaches to its diverse forms of moral reflection. It then explores two of the most prominent philosophers from the main strands of the Indian Buddhist tradition – Buddhaghosa and Śāntideva – in a comparative fashion.
Toward Compatibility of the EU Trade Policy with the General Data Protection Regulation
Authors: Yakovleva Svetlana , Irion Kristina
Published: January 2020

The European Union's (EU) negotiating position on cross-border data flows, which the EU has recently included in its proposal for the World Trade Organization (WTO) talks on e-commerce, not only enshrines the protection of privacy and personal data as fundamental rights, but also creates a broad exception for a Member's restrictions on cross-border transfers of personal data. This essay argues that maintaining such a strong position in trade negotiations is essential for the EU to preserve the internal compatibility of its legal system when it comes to the right to protection of personal data under the EU Charter of Fundamental Rights (EU Charter) and the recently adopted General Data Protection Regulation (GDPR).
The electoral personalization of Italian mayors. A study of 25 years of direct election
Authors: Freschi Anna Carola , Mete Vittorio
Published: January 2020

This paper presents an analysis of the personalization of the vote in Italian municipal elections in the period 1993–2017. Considering the ability of mayoral candidates to attract more votes than those of the lists that support them, the paper outlines the socio-demographic and political characteristics of the candidates who receive the most personalized votes. Contrary to what one might expect, the most personalized candidates are the losing candidates, not the winning ones. At the same time, the candidates who present themselves as outsiders are more personalized: women; candidates at the head of civic lists; those who lead coalitions positioned at the extremes of the left/right axis; candidates supported by one or two lists. Thus, the paper shows the propensity of the Italian electorate to use the split vote to reward those candidates who present themselves as challengers, rather than the established ones, also in the more pragmatic context of local government elections. Moreover, while it is true that personalization is increasingly more important in the political and electoral context, the ability to create lists of candidates for municipal elections capable of obtaining the broad support of voters seems to count as much, if not more.
Diurnal lake-level cycles on ice shelves driven by meltwater input and ocean tidal tilt
Authors: MacAyeal Douglas R. , Willis Ian C. , Banwell Alison F. , Macdonald Grant J. , Goodsell Becky
Published: January 2020

Diurnal depth cycles of decimeter scale are observed in a supraglacial lake on the McMurdo Ice Shelf, Antarctica. We evaluate two possible causes: (1) tidal tilt of the ice shelf in response to the underlying ocean tide, and (2) meltwater input variation. We find the latter to be the most likely explanation of our observations. However, we do not rule out tidal tilt as a source of centimeter scale variations, and point to the possibility that other, larger supraglacial lake systems, particularly those on ice shelves that experience higher amplitude tidal tilts, such as in the Weddell Sea, may have depth cycles driven by ocean tide. The broader significance of diurnal cycles in meltwater depth is that, under circumstances where the ice shelf is thin, tidal-tilt amplitudes are high, and meltwater runoff rates are large, there may be associated flexure stresses that can contribute to ice-shelf fracture and destabilization. For the McMurdo Ice Shelf (~20–50 m thickness, ~ 1 m tidal amplitude and ~10 cm water-depth variations), these stresses amount to several 10's of kPa.
Body composition-derived BMI cut-offs for overweight and obesity in ethnic Indian and Creole urban children of Mauritius
Authors: Ramuth Harris , Hunma Sadhna , Ramessur Vinaysing , Ramuth Magalutcheemee , Monnard Cathriona , Montani Jean-Pierre , Schutz Yves , Joonas Noorjehan , Dulloo Abdul G.
Published: January 2020

It is increasingly recognised that the use of BMI cut-off points for diagnosing obesity (OB) and proxy measures for body fatness in a given population needs to take into account the potential impact of ethnicity on the BMI–fat % relationship in order to avoid adiposity status misclassification. This relationship was studied here in 377 Mauritian schoolchildren (200 boys and 177 girls, aged 7–13 years) belonging to the two main ethnic groups: Indian (South Asian descent) and Creole (African/Malagasy descent), with body composition assessed using an isotopic 2H dilution technique as reference. The results indicate that for the same BMI, Indians have more body fat (and less lean mass) than Creoles among both boys and girls: linear regression analysis revealed significantly higher body fat % by 4–5 units (P < 0·001) in Indians than in Creoles across a wide range of BMI (11·6–34·2 kg/m2) and body fat % (5–52 %). By applying Deurenberg’s Caucasian-based equation to predict body fat % from WHO-defined BMI thresholds for overweight (OW) and OB, and by recalculating the equivalent BMI values using a Mauritian-specific equation, it is shown that the WHO BMI cut-offs for OB and OW would need to be lowered by 4·6–5·9 units in Indian and 2·0–3·7 units in Creole children in the 7–13-year-old age group. These results have major implications for ethnic-based population research towards improving the early diagnosis of excess adiposity in this multi-ethnic population known to be at high risk for later development of type 2 diabetes and CVD.
The effects ofn-3 fatty acids from flaxseed oil on genetic and metabolic profiles in patients with gestational diabetes mellitus: a randomised, double-blind, placebo-controlled trial
Authors: Jamilian Mehri , Tabassi Zohreh , Reiner Željko , Panahandeh Ida , Naderi Fatemeh , Aghadavod Esmat , Amirani Elaheh , Taghizadeh Mohsen , Shafabakhsh Rana , Satari Mahbobeh , Mansournia Mohammad Ali , Memarzadeh Mohammad Reza , Asemi Zatollah
Published: January 2020

The present study was performed to evaluate the effects ofn-3 fatty acids from flaxseed oil on genetic and metabolic profiles in patients with gestational diabetes mellitus (GDM). This randomised, double-blind, placebo-controlled clinical trial was performed in sixty women with GDM. Participants were randomly divided into two groups to intake either 2 × 1000 mg/dn-3 fatty acids from flaxseed oil containing 400 mgα-linolenic acid in each capsule (n30) or placebo (n30) for 6 weeks.n-3 Fatty acid intake up-regulated PPAR-γ(P< 0·001) and LDL receptor (P= 0·004) and down-regulated gene expression of IL-1 (P= 0·002) and TNF-α(P= 0·001) in peripheral blood mononuclear cells of subjects with GDM. In addition,n-3 fatty acid supplementation reduced fasting plasma glucose (P= 0·001), insulin levels (P= 0·001) and insulin resistance (P< 0·001) and increased insulin sensitivity (P= 0·005) when compared with the placebo. Additionally,n-3 fatty acid supplementation was associated with a decrease in TAG (P< 0·001), VLDL-cholesterol (P< 0·001), total cholesterol (P= 0·01) and total cholesterol:HDL-cholesterol ratio (P= 0·01) when compared with placebo.n-3 Fatty acid administration was also associated with a significant reduction in high-sensitivity C-reactive protein (P= 0·006) and malondialdehyde (P< 0·001), and an increase in total nitrite (P< 0·001) and total glutathione levels (P= 0·006) when compared with the placebo.n-3 Fatty acid supplementation for 6 weeks to women with GDM had beneficial effects on gene expression related to insulin, lipid and inflammation, glycaemic control, lipids, inflammatory markers and oxidative stress.
The Buffering Effect of Character Strengths on	Depression
Authors: Lee Beatrice , Kaya Cahit , Chen Xiangli , Wu Jia-Rung , Iwanaga Kanako , Umucu Emre , Bezyak Jill , Tansey Timothy N. , Chan Fong
Published: January 2020

Abstract. The transition from high school to college can be very stressful for Turkish students because they may experience value conflicts and adjustment issues, which can trigger the development of mental health problems. Character strengths can serve as a buffer against psychopathology. The aim of the study was to examine perceived stress and negative attributional style as mediating factors between character strengths and depression among Turkish college students. Bootstrap testing approach was implemented to compute direct and indirect effects and total effect in the mediation analysis. Altogether 235 students from two Turkish universities participated in the study. The results showed that character strengths were associated with lower levels of depression and it was negatively associated with perceived stress and negative attributional style. The results also indicated that perceived stress and negative attribution style completely mediated the relationship between character strengths and depression among Turkish college students. These findings suggested the need to develop empirically supported interventions that can promote character strengths toward reducing stress, negative attributions, and depression in this population.
Source‐Independent Passive Seismic Reverse‐Time Structure Imaging With Grouping Imaging Condition: Method and Application to Microseismic Events Induced by Hydraulic Fracturing
Authors: Lin Ye , Zhang Haijiang , Chen Yukuan , Li Junlun
Published: January 2020

Seismic imaging with active seismic sources can be used to image subsurface structures such as faults, fractures, and layer interfaces with higher resolutions than tomographic methods. However, for characterizing large‐scale three‐dimensional structures, oftentimes it is too expensive and thus impractical to conduct active seismic survey. Seismic imaging using passive sources has been used to image structures through the “pseudoactive” source imaging by assuming source information is known. However, in practice there exist some uncertainties on source information including location, origin time, source time function, and radiation pattern, which can inevitably affect the final imaging result. In this study, we propose a new source‐independent passive seismic imaging method based on reverse‐time imaging with converted waves and a new imaging condition. This method uses the interference between P and S waves at conversion points for structure imaging by back‐propagating seismograms recorded by all receivers. Since no forward modeling is needed in this method, source information is not needed. A new grouping imaging condition is proposed to improve the image resolution, in which seismic receivers are divided into several groups and the separated P and S wavefields of different groups are multiplied and then stacked over time to get an image. We test the new method on both synthetic and real data sets based on a downhole microseismic system that is used for monitoring a shale gas hydraulic fracturing treatment. The results show that the proposed passive seismic imaging method does not depend on knowing source information and can achieve higher imaging resolution.
Effective delivery of Complex Innovative Design (CID) cancer trials—A consensus statement
Authors: Blagden Sarah P. , Billingham Lucinda , Brown Louise C. , Buckland Sean W. , Cooper Alison M. , Ellis Stephanie , Fisher Wendy , Hughes Helen , Keatley Debbie A. , Maignen Francois M. , Morozov Alex , Navaie Will , Pearson Sarah , Shaaban Abeer , Wydenbach Kirsty , Kearns Pamela R. ,   on behalf of the Experimental Cancer Medicine Centres (ECMC) CID trials working group, Abouzeid Christiane , Ahmed Rubina , Bailey Sue , Blewett Catherine , Campbell Helen , Cerone Maria Antonietta , Clack Glen , Cook Natalie , Ghiorghiu Serban , Halford Sarah , Johnston Andrew , Kaplan Rick , Lawson Anna , Lowe Emma , Mathews Jacqueline , Mirabile Ilaria , Osipenko Leeza , Patel Dipak , Potter Claire , Regan Aoife , Ricamara Marivic , Ringrose Carly , Rodger Joanne , Sandhu Gurcharan K. , Schiavone Francesca , Silvester Julie , Sydes Matthew R. , Weller Charles , Yiangou Angeliki
Published: January 2020

The traditional cancer drug development pathway is increasingly being superseded by trials that address multiple clinical questions. These are collectively termed Complex Innovative Design (CID) trials. CID trials not only assess the safety and toxicity of novel anticancer medicines but also their efficacy in biomarker-selected patients, specific cancer cohorts or in combination with other agents. They can be adapted to include new cohorts and test additional agents within a single protocol. Whilst CID trials can speed up the traditional route to drug licencing, they can be challenging to design, conduct and interpret. The Experimental Cancer Medicine Centres (ECMC) network, funded by the National Institute for Health Research (NIHR), Cancer Research UK (CRUK) and the Health Boards of Wales, Northern Ireland and Scotland, formed a working group with relevant stakeholders from clinical trials units, the pharmaceutical industry, funding bodies, regulators and patients to identify the main challenges of CID trials. The working group generated ten consensus recommendations. These aim to improve the conduct, quality and acceptability of oncology CID trials in clinical research and, importantly, to expedite the process by which effective treatments can reach cancer patients.
Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver
Authors: Wang Jianye , Hu Bian , Zhao Zhicong , Zhang Haiyan , Zhang He , Zhao Zhenjun , Ma Xiong , Shen Bin , Sun Beicheng , Huang Xingxu , Hou Jiajie , Xia Qiang
Published: January 2020

Endoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an antiapoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.
Raman chemical imaging of intact non-flat tablets in regular and high-confocal mode
Authors: Šašić Slobodan , Prusnick Tim
Published: January 2020

Curved and embossed surface of a tablet is Raman-imaged with API images produced by a variety of methods.
Perrhenate and pertechnetate complexation by an azacryptand in nitric acid medium
Authors: Thevenet Alexiane , Marie Cécile , Tamain Christelle , Amendola Valeria , Miljkovic Ana , Guillaumont Dominique , Boubals Nathalie , Guilbaud Philippe
Published: January 2020

Azacryptand addition in nitric acid medium for the recognition of the pertechnetate anion for extraction studies.
2.6 V aqueous symmetric supercapacitors based on phosphorus-doped TiO2 nanotube arrays
Authors: Zhang Yaxiong , Duan Shifang , Li Yan , Zhang Shengming , Wu Yin , Ma Mingyu , Tao Chunlan , Zhang Zhenxing , Qin Dongdong , Xie Erqing
Published: January 2020

P-Doped TiO2 nanotube arrays exhibit excellent electrochemical performance in an aqueous symmetric supercapacitor with a widened potential window of 2.6 V.
A subtle structural change in the distal haem pocket has a remarkable effect on tuning hydrogen peroxide reactivity in dye decolourising peroxidases fromStreptomyces lividans
Authors: Lučić Marina , Chaplin Amanda K. , Moreno-Chicano Tadeo , Dworkowski Florian S. N. , Wilson Michael T. , Svistunenko Dimitri A. , Hough Michael A. , Worrall Jonathan A. R.
Published: January 2020

A subtle positional shift of the distal haem pocket aspartate in two dye decolourising peroxidase homologs has a remarkable effect on their reactivity with H2O2.
Tubular metal organic frameworks from the curvature of 2D-honeycombed metal coordination
Authors: Bao Junhui , Wu Shanshan , Xu Xin , Huang Liping , Zhang Liwei , Kim Jehan , Zhou Xiantai , Chen Yaju , Ji Hongbing , Huang Zhegang
Published: January 2020

A tubular catalyst showed fast catalytic kinetics for CO2 conversion with a TON of 2300 and a TOF of up to 173 h−1.
Structural phase transitions coupled with prominent dielectric anomalies and dielectric relaxation in [(CH3)3NH]2[KCo(CN)6] and mixed [(CH3)3NH]2[KFexCo1−x(CN)6] double perovskite hybrids
Authors: Rok Magdalena , Zarychta Bartosz , Moskwa Marcin , Dziuk Błażej , Medycki Wojciech , Bator Grażyna
Published: January 2020

Structural phase transition and dielectric anomalies measured in pure and mixed crystals (TrMAFexCo1−x).
Chiral Ru(ii) complexes act as a potential non-viral gene carrier for directional transportation to the nucleus and cytoplasm
Authors: Wu Qiong , Zhang Shuang-Yan , Liao Si-Yan , Cao Jie-Qiong , Zheng Wen-Jie , Li Li , Mei Wen-Jie
Published: January 2020

Guanine-rich DNA sequences can spontaneously fold into four-stranded structures called G-quadruplexes (G4s). G4s have been identified extensively in the promoter regions of several proto-oncogenes, including c-myc, as well as telomeres. G4s have attracted an increasing amount of attention in the field of nanotechnology because of their use as versatile building blocks of DNA-based nanostructures. In this study, we report the self-assembly of c-myc G-quadruplex DNA controlled by a pair of chiral ruthenium(ii) complexes coordinated by 2-(4-phenyacetylenephenyl)-1H-imidazo[4,5f][1,10]phenanthroline (PBEPIP), Λ-[Ru(bpy)2(PBEPIP)](ClO4)2 (Λ-RM0627, bpy = bipyridine) and Δ-[Ru(bpy)2(PBEPIP)](ClO4)2 (Δ-RM0627). Λ-RM0627 could promote the high-order self-assembly of c-myc G-quadruplex DNA into a nanowire structure, whereas Δ-RM0627 could induce DNA condensation into G-quadruplex aggregates. Moreover, in vitro studies on human liver carcinoma HepG2 cells showed that the nanowire of c-myc G-quadruplex DNA promoted by Λ-RM0627 could be localized in the nuclei of cells, whereas the nanoparticle of c-myc G-quadruplex DNA generated by Δ-RM0627 was taken up and localized in the cytoplasm. This study provides examples of the enantioselective self-assembly of G4 DNA molecules controlled by chiral ruthenium(ii) complexes and suggests the potential applications of assembled nanostructures as non-viral DNA vectors for gene therapy.
Activating a hematite nanorod photoanode via fluorine-doping and surface fluorination for enhanced oxygen evolution reaction
Authors: Wang Chenglong , Wei Shenqi , Li Feng , Long Xuefeng , Wang Tong , Wang Peng , Li Shuwen , Ma Jiantai , Jin Jun
Published: January 2020

A high-performance hematite photoanode modified by F-treatment of both the bulk and the surface facilitates simultaneous charge separation from the interior to the interface.
Hypersensitive azobenzenes: facile synthesis of clickable and cleavable azo linkers with tunable and high reducibility
Authors: Eom Taejun , Khan Anzar
Published: January 2020

Molecular design principles of azobenzene nuclei that can be cleaved in a few seconds under mild reducing conditions are described.
Reduced strain mechanochemical activation onset in microstructured materials
Authors: Schwartz Johanna J. , Behrou Reza , Cao Bo , Bassford Morgan , Mendible Ariana , Shaeffer Courtney , Boydston Andrew J. , Boechler Nicholas
Published: January 2020

In this study, we show that mechanochemical activation in responsive materials with designed, periodic microstructures can be achieved at lower applied strains than their bulk counterparts.
Diffusion dynamics of a single collapsed homopolymer globule at the solid–liquid interface
Authors: Cai Shali , Liu Jingjing , Tian Mengting , Wang Kang , Shen Lei
Published: January 2020

A single polymer globule in a poor solvent is not as sticky as we originally thought in the presence of surfaces.
Les limites des inhibiteurs de points de contrôle immunitaire et la gestion de leur toxicité
Authors: Kostine Marie , Marabelle Aurélien , Schaeverbeke Thierry , Kfoury Maria
Published: January 2020

L’immunothérapie représente désormais un des piliers de la prise en charge du cancer, notamment avec l’arrivée des inhibiteurs de points de contrôle (checkpoint) immunitaire (ICI, immune checkpoint inhibitors). Ces anticorps thérapeutiques ciblent ces co-signaux inhibiteurs entre cellules tumorales ou cellules présentatrices d’antigènes et lymphocytes T, activant ou réactivant ainsi une immunité cellulaire T anti-tumorale. Mais la survenue d’une toxicité immunologique, qui peut concerner tous les organes, représente le facteur limitant dans le développement clinique de ces anticorps. La gestion de cette toxicité nécessite une collaboration étroite entre oncologues et spécialistes d’organe, et repose sur l’utilisation de corticoïdes et/ou d’autres immunosuppresseurs, avec l’objectif de contrôler la dysimmunité induite sans perdre l’efficacité anti-tumorale.
Rhumatologie, la multitude des options
Authors: Morel Jacques , Mulleman Denis
Published: January 2020

Le nombre d’anticorps (Ac) thérapeutiques disponibles en rhumatologie ne cesse de croître et concerne aussi bien les rhumatismes inflammatoires chroniques que les connectivites, les vascularites et, dans une moindre mesure, les pathologies osseuses et l’arthrose. Le choix d’un biomédicament repose aujourd’hui beaucoup sur les spécificités du médicament et des caractéristiques du patient. Il n’existe pas encore de véritables biomarqueurs prédictifs de réponse pour une médecine plus personnalisée. Le suivi sérique des Ac thérapeutiques et le dosage des anticorps anti-médicaments représentent un espoir pour adapter au mieux la posologie du médicament et décider d’un changement de traitement en fonction de l’activité de la maladie inflammatoire chronique.
Les anticorps monoclonaux
Authors: Diallo Béré K. , Riffard Clémence , Le Gouge Kenz , Teillaud Jean-Luc
Published: January 2020

En 2019, les anticorps monoclonaux (Acm) vont représenter un marché mondial annuel de plus de cent milliards de dollars, soit près de 90 milliards d’euros. Outre leur utilisation en clinique, les anticorps monoclonaux sont utilisés également dans de nombreux tests diagnostiques et sont toujours des outils précieux pour la recherche fondamentale et appliquée. Quarante-quatre ans après la publication de Georges Köhler et César Milstein [1], des dizaines de congrès et séminaires de toute nature sur les anticorps monoclonaux se tiennent annuellement à travers le monde. Mais 44 ans plus tard, les travaux scientifiques qui ont amené à cette publication sont peu à peu oubliés et, dans bien des esprits, les anticorps monoclonaux ne sont qu’unbusinessd’un multi-milliard euros/dollars comme un autre, déterminé par les marchés financiers et les résultats des derniers essais cliniques… Il est grand temps de rendre hommage à toute une génération de chercheurs fondamentalistes, à ces fous de science duxxe siècle, à ces chercheurs connus et souvent désormais méconnus, disséminés aux quatre coins du monde, qui ont exploré les frontières de l’inconnu d’alors et qui ont modelé et ciselé un savoir qui a débouché sur une technique d’obtention de molécules qui ont permis l’une des plus grandes révolutions thérapeutiques de ces vingt-cinq dernières années.
Les immunoconjugués en oncologie
Authors: Beck Alain , Dumontet Charles , Joubert Nicolas
Published: January 2020

Un anticorps armé (ADC,antibody-drug conjugateen anglais) est une chimiothérapie vectorisée qui résulte du greffage d’un agent cytotoxique sur un anticorps monoclonal par l’intermédiaire d’un bras espaceur judicieusement construit. Les anticorps armés ont fait des progrès considérables en 10 ans. En 2009, seul le gemtuzumab ozogamicine (Mylotarg®) était utilisé en clinique. En 2019, 4 autres ADC ont été approuvés par laFood and Drug Administrationet plus de 80 autres sont en études cliniques actives. La seconde partie de cette revue sera focalisée sur les nouvelles stratégies émergentes pour faire face aux limitations des ADC actuels et pour tenter d’élargir leur fenêtre thérapeutique. Enfin, les combinaisons avec la chimiothérapie classique ou les inhibiteurs de points de contrôles seront discutées, pour tenter de faire des anticorps armés lamagic bulletdont rêvait Paul Ehrlich.
Fan-shaped optical laser beams blow away impurities
Authors: Mandel Savannah
Published: January 2020

Researchers create a fan-shaped vortex beam that can perform optical clearing, optical shielding and optical transporting.
Structure, magnetic and thermal properties of FePt–C–BN granular films for heat assisted magnetic recording
Authors: Chen Shaohai , Shu Xinyu , Xie Qidong , Zhou Chenghang , Zhou Jing , Deng Jinyu , Guo Rui , Peng Y G , Ju G , Chen Jingsheng
Published: January 2020

The structure, magnetic and thermal properties of (FePt0.78–C0.22)–BN granular films with various BN volume concentrations are systematically studied. Compared to the FePt–C film without BN doping, the grain size distribution of the FePt grains is reduced by 50% with BN component is 10 vol.%, and the coercivity and the intrinsic switching field distributions of the film are increased 3 times and narrowed by 35%, respectively, when BN component is 6 vol.%. The improvement in magnetic properties is attributed to the enhanced chemical ordering of the FePt L10 phase. Based on the 3ω method, it is found that the relative cross-plane thermal conductivity

of the FePt–C–BN layer is more correlated to the grain size distribution of the film, which decreases to the minimum value at 10 vol.% BN. Our results indicate that a certain amount of BN doping can improve the comprehensive performance of the FePt–C–BN granular films, making it a promising candidate for heat assisted magnetic recording.
Transverse momentum spectra of J/ψ produced in collisions over an energy range from 17.4 GeV to 13 TeV
Authors: Chen Ya-Hui , Ma Yu-Gang , Ma Guo-Liang , Chen Jin-Hui
Published: January 2020

Transverse momentum spectra of inclusive J/ψ mesons produced in particle–particle, particle–nucleus and nucleus–nucleus collisions over a center-of-mass energy range from 17.4 GeV to 13 TeV are analyzed by a multi-component Schwinger mechanism. The model results are found to fit the experimental data measured by the ALICE, CDF, D0, HERA-B, E789, NA50, E705, LHCb and PHENIX Collaborations. We extract the distribution of minimum distance between the partons which form the charmonium

c

c

¯

. Moreover, the energy and rapidity dependent free parameters in Schwinger mechanism are obtained. The parameter related to string tension is found to increase with the increase of energy and to decrease with the increase of rapidity and centrality.
Modeling and plasma characteristics of high-power direct current discharge
Authors: Chen Lei , Cui Suihan , Tang Wei , Zhou Lin , Li Tijun , Liu Liangliang , An Xiaokai , Wu Zhongcan , Ma Zhengyong , Lin Hai , Tian Xiubo , Fu Ricky KY , Chu Paul K , Wu Zhongzhen
Published: January 2020

To obtain both high ionization and high deposition rate, a modified global model for a continuous high-power DC magnetron sputtering (C-HPMS) is established by considering the continuous generation of the hot electrons and the high temperature caused by continuous high-power discharge. The results show that the plasma density is on the order of 1019 m−3 for power densities of only 183 W cm−2 (Al) and 117 W cm−2 (Cu). The ionization rate exceeds 90% of high-power impulse magnetron sputtering (HiPIMS) (peak power density of 564 W cm−2) for a DC power density of 180 W cm−2, and the total diffusion fluxes of the two targets are 26 (Al) and 30 (Cu) times that of conventional HiPIMS, leading to very high deposition rates. The work provides a theoretical basis for the realization of C-HPMS and gives an enlightenment to the development of deposition equipment for continuous high-power discharges.
Heat and mass transfer analysis of MHD peristaltic flow through a complaint porous channel with variable thermal conductivity
Authors: Vaidya H , Rajashekhar C , Manjunatha G , Prasad K V , Makinde O D , Vajravelu K
Published: January 2020

The MHD peristaltic motion of Bingham fluid through a uniform channel is examined under the influence of long wavelength and small Reynolds number. The impact of variable thermal conductivity, convective heat transfer, porous boundaries, and wall properties are considered. The semi-analytical technique is utilized to solve the governing nonlinear temperature equation. The effects of different parameters on the physiological quantities of interest are captured with the assistance of MATLAB programming. The assessment reveals that an ascent in a magnetic parameter reduces the velocity field. Further, an increment in the estimation of variable thermal conductivity upgrades the temperature profiles. Besides, the trapped bolus is a function of a porous parameter, and an increase in porous parameter will have the proportional increment in the other parameter.
Generalized Riesz systems and orthonormal sequences in Krein spaces
Authors: Bagarello Fabio , Kużel Sergiusz
Published: January 2020

We analyze special classes of bi-orthogonal sets of vectors in Hilbert and in Krein spaces, and their relations with generalized Riesz systems. In this way, the notion of the first/second type sequences is introduced and studied. We also discuss their relevance in some concrete quantum mechanical system driven by manifestly non self-adjoint Hamiltonians.
DORN1/P2K1 and purino-calcium signalling in plants: making waves with extracellular ATP
Authors: Matthus Elsa , Sun Jian , Wang Limin , Bhat Madhura G , Mohammad-Sidik Amirah B , Wilkins Katie A , Leblanc-Fournier Nathalie , Legué Valérie , Moulia Bruno , Stacey Gary , Davies Julia M
Published: January 2020

Background and Aims

Extracellular ATP governs a range of plant functions, including cell viability, adaptation and cross-kingdom interactions. Key functions of extracellular ATP in leaves and roots may involve an increase in cytosolic free calcium as a second messenger (‘calcium signature’). The main aim here was to determine to what extent leaf and root calcium responses require the DORN1/P2K1 extracellular ATP receptor in Arabidopsis thaliana. The second aim was to test whether extracellular ATP can generate a calcium wave in the root.

Methods

Leaf and root responses to extracellular ATP were reviewed for their possible links to calcium signalling and DORN1/P2K1. Leaves and roots of wild type and dorn1 plants were tested for cytosolic calcium increase in response to ATP, using aequorin. The spatial abundance of DORN1/P2K1 in the root was estimated using green fluorescent protein. Wild type roots expressing GCaMP3 were used to determine the spatial variation of cytosolic calcium increase in response to extracellular ATP.

Key Results

Leaf and root ATP-induced calcium signatures differed markedly. The leaf signature was only partially dependent on DORN1/P2K1, while the root signature was fully dependent. The distribution of DORN1/P2K1 in the root supports a key role in the generation of the apical calcium signature. Root apical and sub-apical calcium signatures may operate independently of each other but an apical calcium increase can drive a sub-apical increase, consistent with a calcium wave.

Conclusion

DORN1 could underpin several calcium-related responses but it may not be the only receptor for extracellular ATP in Arabidopsis. The root has the capacity for a calcium wave, triggered by extracellular ATP at the apex.
Neural Patterns are More Similar across Individuals during Successful Memory Encoding than during Failed Memory Encoding
Authors: Koch Griffin E , Paulus John P , Coutanche Marc N
Published: January 2020

After experiencing the same episode, some people can recall certain details about it, whereas others cannot. We investigate how common (intersubject) neural patterns during memory encoding influence whether an episode will be subsequently remembered, and how divergence from a common organization is associated with encoding failure. Using functional magnetic resonance imaging with intersubject multivariate analyses, we measured brain activity as people viewed episodes within wildlife videos and then assessed their memory for these episodes. During encoding, greater neural similarity was observed between the people who later remembered an episode (compared with those who did not) within the regions of the declarative memory network (hippocampus, posterior medial cortex [PMC], and dorsal Default Mode Network [dDMN]). The intersubject similarity of the PMC and dDMN was episode-specific. Hippocampal encoding patterns were also more similar between subjects for memory success that was defined after one day, compared with immediately after retrieval. The neural encoding patterns were sufficiently robust and generalizable to train machine learning classifiers to predict future recall success in held-out subjects, and a subset of decodable regions formed a network of shared classifier predictions of subsequent memory success. This work suggests that common neural patterns reflect successful, rather than unsuccessful, encoding across individuals.
High Detection Rate of Copy Number Variations Using Capture Sequencing Data: A Retrospective Study
Authors: Sun Yu , Ye Xiantao , Fan Yanjie , Wang Lili , Luo Xiaomei , Liu Huili , Gao Xueren , Gong Zhuwen , Wang Yu , Qiu Wenjuan , Zhang Huiwen , Han Lianshu , Liang Lili , Ye Hui , Xiao Bing , Gu Xuefan , Yu Yongguo
Published: January 2020

Background

Capture sequencing (CS) is widely applied to detect small genetic variations such as single nucleotide variants or indels. Algorithms based on depth comparison are becoming available for detecting copy number variation (CNV) from CS data. However, a systematic evaluation with a large sample size has not been conducted to evaluate the efficacy of CS-based CNV detection in clinical diagnosis.

Methods

We retrospectively studied 3010 samples referred to our diagnostic laboratory for CS testing. We used 68 chromosomal microarray analysis–positive samples (true set [TS]) and 1520 reference samples to build a robust CS-CNV pipeline. The pipeline was used to detect candidate clinically relevant CNVs in 1422 undiagnosed samples (undiagnosed set [UDS]). The candidate CNVs were confirmed by an alternative method.

Results

The CS-CNV pipeline detected 78 of 79 clinically relevant CNVs in TS samples, with analytical sensitivity of 98.7% and positive predictive value of 49.4%. Candidate clinically relevant CNVs were identified in 106 UDS samples. CNVs were confirmed in 96 patients (90.6%). The diagnostic yield was 6.8%. The molecular etiology includes aneuploid (n = 7), microdeletion/microduplication syndrome (n = 40), and Mendelian disorders (n = 49).

Conclusions

These findings demonstrate the high yield of CS-based CNV. With further improvement of our CS-CNV pipeline, the method may have clinical utility for simultaneous evaluation of CNVs and small variations in samples referred for pre- or postnatal analysis.
Impact of sex hormone-binding globulin on the human phenome
Authors: Arathimos Ryan , Millard Louise A C , Bell Joshua A , Relton Caroline L , Suderman Matthew
Published: January 2020

Background: Sex hormone-binding globulin (SHBG) is a circulating glycoprotein and a regulator of sex hormone levels, which has been shown to influence various traits and diseases. The molecular nature of SHBG makes it a feasible target for preventative or therapeutic interventions. A systematic study of its effects across the human phenome may uncover novel associations. Methods: We used a Mendelian randomization phenome-wide association study (MR-pheWAS) approach to systematically appraise the potential functions of SHBG while reducing potential biases such as confounding and reverse causation common to the literature. We searched for potential causal effects of SHBG in UK Biobank (N = 334 977) and followed-up our top findings using two-sample MR analyses to evaluate whether estimates may be biased due to horizontal pleiotropy. Results: Results of the MR-pheWAS across over 21 000 outcome phenotypes identified 12 phenotypes associated with genetically elevated SHBG after Bonferroni correction for multiple testing. Follow-up analysis using two-sample MR indicated the associations of increased natural log SHBG with higher impedance of the arms and whole body, lower pulse rate, lower bone density, higher odds of hip replacement, lower odds of high cholesterol or cholesterol medication use and higher odds of gallbladder removal. Conclusions: Our systematic MR-pheWAS of SHBG, which was comprehensive to the range of phenotypes available in UK Biobank, suggested that higher circulating SHBG affects the body impedance, bone density and cholesterol levels, among others. These phenotypes should be prioritized in future studies aiming to investigate the biological effects of SHBG or develop targets for therapeutic intervention.
Opioid Use and Chronic Infections: The Value of Addressing the Syndemic in Correctional Settings Via Telemedicine Guidance and Broader Use of Long-Acting Medications
Authors: Krsak Martin , Montague Brian T , Trowbridge Paul , Johnson Steven C , Binswanger Ingrid A
Published: January 2020

In the United States, we are experiencing linked epidemics (a syndemic) of substance use disorders (SUDs) and infections associated with drug use, including unsafe injecting and unsafe sex in exchange for drugs or money. Current drug laws, together with risk-taking behavior among persons with SUDs, contribute to disproportionately high prevalences of these conditions in correctional settings. Detection and treatment of diseases with a high impact on public health are best addressed in the settings where such conditions are most prevalent (ie, jails and prisons for SUDs and chronic infections). The effectiveness, safety, cost of care. and public health impact of these conditions can be improved by means of broader screening and expanded access to specialty consultations through telemedicine/telehealth, along with broader use of long-acting medications for the treatment of human immunodeficiency virus and SUDs. Expanding telemedicine/telehealth, first for specialties which do not require advanced technology (eg, infectious diseases, addictions), can eventually lead to further advancements in correctional healthcare.
Does BERT need domain adaptation for clinical negation detection?
Authors: Lin Chen , Bethard Steven , Dligach Dmitriy , Sadeque Farig , Savova Guergana , Miller Timothy A
Published: January 2020

Introduction

Classifying whether concepts in an unstructured clinical text are negated is an important unsolved task. New domain adaptation and transfer learning methods can potentially address this issue.

Objective

We examine neural unsupervised domain adaptation methods, introducing a novel combination of domain adaptation with transformer-based transfer learning methods to improve negation detection. We also want to better understand the interaction between the widely used bidirectional encoder representations from transformers (BERT) system and domain adaptation methods.

Materials and Methods

We use 4 clinical text datasets that are annotated with negation status. We evaluate a neural unsupervised domain adaptation algorithm and BERT, a transformer-based model that is pretrained on massive general text datasets. We develop an extension to BERT that uses domain adversarial training, a neural domain adaptation method that adds an objective to the negation task, that the classifier should not be able to distinguish between instances from 2 different domains.

Results

The domain adaptation methods we describe show positive results, but, on average, the best performance is obtained by plain BERT (without the extension). We provide evidence that the gains from BERT are likely not additive with the gains from domain adaptation.

Discussion

Our results suggest that, at least for the task of clinical negation detection, BERT subsumes domain adaptation, implying that BERT is already learning very general representations of negation phenomena such that fine-tuning even on a specific corpus does not lead to much overfitting.

Conclusion

Despite being trained on nonclinical text, the large training sets of models like BERT lead to large gains in performance for the clinical negation detection task.
The Optimal Treatment for Partial Thickness Burns: A Cost-Utility Analysis of Skin Allograft vs. Topical Silver Dressings
Authors: Sheckter Clifford C , Meyerkord Nickolas L , Sinskey Yunna L , Clark Pariss , Anderson Katarina , Van Vliet Michael
Published: January 2020

Introduction

Partial thickness burns not undergoing surgical excision are treated with topical silver products including silver sulfadiazine (SSD) and Mepilex Ag. Skin allograft is a more costly alternative that acts as definitive wound coverage until autogenous epithelialization. Economic constraints and the movement toward value-based care demand cost and outcome justification prior to adopting more costly products.

Methods

A cost-utility analysis was performed comparing skin allograft to SSD and Mepilex Ag using decision tree analysis. The base case modeled a superficial partial thickness 20% total body surface area burn. Utilities were derived from expert opinion on the basis of personal experience. Costs were derived from 2019 Medicare payments. Quality adjusted life years were calculated using rollback method assuming standard life expectancies in the United States. Probabilistic sensitivity analysis was performed to asses model robustness.

Results

The incremental costs of skin allograft to Mepilex Ag and SSD were $907.71 and $1257.86, respectively. The incremental quality adjusted life year (QALY) gains from allograft over Mepilex Ag and SSD were 0.011 and 0.016. This yielded an incremental cost-utility ratio for allograft vs. Mepilex Ag of $84,189.29/QALY compared with an incremental cost-utility ratio of $79,684.63/QALY for allograft vs. SSD. Assuming willingness-to-pay thresholds of $100,000/QALY, probabilistic sensitivity analysis demonstrated that allograft was cost effective to Mepilex Ag in 62.1% of scenarios, and cost effective to SSD in 64.9% of simulations.

Conclusion

Skin allograft showed greater QALYs compared with topical silver dressings at a higher cost. Depending on willingness-to-pay thresholds, skin allograft may be a considered a cost-effective treatment of partial-thickness burns.
The Molecular Analysis for Therapy Choice (NCI-MATCH) Trial: Lessons for Genomic Trial Design
Authors: Flaherty Keith T , Gray Robert , Chen Alice , Li Shuli , Patton David , Hamilton Stanley R , Williams Paul M , Mitchell Edith P , Iafrate A John , Sklar Jeffrey , Harris Lyndsay N , McShane Lisa M , Rubinstein Larry V , Sims David J , Routbort Mark , Coffey Brent , Fu Tony , Zwiebel James A , Little Richard F , Marinucci Donna , Catalano Robert , Magnan Rick , Kibbe Warren , Weil Carol , Tricoli James V , Alexander Brian , Kumar Shaji , Schwartz Gary K , Meric-Bernstam Funda , Lih Chih-Jian , McCaskill-Stevens Worta , Caimi Paolo , Takebe Naoko , Datta Vivekananda , Arteaga Carlos L , Abrams Jeffrey S , Comis Robert , O’Dwyer Peter J , Conley Barbara A ,   for the NCI-MATCH Team
Published: January 2020

Background

The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology.

Methods

Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA–targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial.

Results

At interim analysis, accrual was robust, tumor biopsies were safe (<1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround).

Conclusions

The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.