bluuebunny/crossref_metadata_2025 huggingface dataset:
Integración de tecnologías energéticamente eficientes en sistemas de climatización operados con energía térmica
Authors: Cardona Gil Jorge , Gallego Orrego Jorge Humberto , Isaza Roldán César Alejandro , Torres Salazar Renato , López Chejne Daniel A.
Published: January 2020

Con el artículo se pretende mostrar el desarrollo de un proyecto demostrativo y educativo de un sistema de climatización operado con energía solar, en el cual se usan tecnologías complementarias energéticamente eficientes que potencien su desempeño dentro del bloque de registro de la Universidad Pontificia Bolivariana (UPB), así mismo potenciar la investigación, desarrollo e inversión para conseguir una alta penetración de tecnologías de climatización eficiente y limpia. El desarrollo se ha dividido en 4 grandes fases, que inician con la simulación del sistema de refrigeración, en el cual se ha utilizado el software TRNSYS®; dimensionamiento y diseño básico del sistema de refrigeración; búsqueda y selección de equipos p.e. bombas; máquina de absorción, colectores solares, entre otros; diseño de detalle de un sistema de climatización con energía solar térmica, en el cual se hace uso de un equipo de enfriamiento de agua por absorción, paneles radiantes y enfriador evaporativo indirecto. Entre los resultados obtenidos se encuentra el dimensionamiento y diseño detallado del sistema y la adquisición del equipo de absorción y enfriamiento evaporativo soportados en un diseño simulado al emplear los softwares TRNSYS® y MATLAB®. Lo anterior permitió determinar los niveles de carga adecuados para cada uno de los equipos involucrados en el sistema, además de asegurar los parámetros de calidad de potencia para atender los requerimientos de energía eléctrica y aire acondicionado.
Survival Analysis of the Clinical Episodes of Stroke Using Data from Western Delta Region of Nigeria
Authors: Ekerikevwe K. I.
Published: January 2020

This study is designed to investigate the epidemiology of stroke burden in Western Delta Region of Nigeria. To achieve this, statistical tools were used to analyze and interpret the prevalence of this diseases in the study area- with focus on the medical records (case files) of hundred and twenty-one (221) patients who suffered from stroke and were seen at selected government hospitals in the region, from 2003- 2016. The clinical episodes (CEs) of stroke for the patients who were admitted during acute care period (without discharge against medical advice) and were then assessed for various investigations and treatment interventions and long term care were obtained and statistically studied. The Kaplan-Meier survival estimator shows the survival rate to be 75% in 2003 and 25% in 2016. The year 2009 recorded the highest CEs (28) with survival function (0.23) and 2014 the lowest (4) with survival function (0.11). These have implications for all stakeholders in health matters in the study area. The study recommends an organized effort from both the government and the private sector to tackle the rising stroke burden in Western Delta Region of Nigeria.
Studi Alterasi, Mineralisasi Dan Inklusi Fluida Prospek Hidrotermal (Pb-Zn-Cu±Au-Ag) Kubah Kulonprogo Bagian Selatan, Jawa Tengah
Authors: Fadlin Fadlin , Hajar Sulystiawan Isnu , Adi Prasetyo Luthfi
Published: January 2020

Ore potential especially base metals, gold and silver in the Kulonprogo Mountains have been a discussion of Indonesian geologists for a long time, until now its prospects as economic value has not been found, which made it a challenge to conduct an intensive and detailed study. This study is conducted to understand the mineralization-alteration characteristics and the deposit fluid of the study area. The method used in this study is a surface geological mapping, laboratory analysis such as mineragraphy, X-ray diffraction, ore geochemistry (Atomic Absorption Spectrometry-fire assay) and fluid inclusion. Alteration zone of the study area is divided into prophylitic, advanced argilic, argilic and silicification. Vein texture that develop in the study area is a massive quartz, stock work, and vuggy quartz which has NE-SW orientation, while the sulphide mineral abundance which found are enargite, pyrite, chalcopyrite, sphalerite, malachite, and molybdenite, occur in quartz veins or disseminated in gangue rock. Ore geochemistry AAS-fire assay of five vein samples show Au and the highest Ag content shown in sample 3 (Au:3.8. g/t, Ag:10 g/t). Fluid inclusion analysis results show homogenization temperature value (Th) which is 293,4-322,4o C, melting temperature (Tm) is -5,22o C until -6,3o C with average salinity value 10,58-12,89 wt,%NaCl equivalent. Hydrothermal fluid evolution of the study area is at the mixing with cooler phase and less saline fluids. Fluid is estimated from magmatic water that slowly mixed with meteoric water which is shown by the cooling temperature and salinity value. Based on alteration, mineralization, vein texture, ore geochemistry and fluid inclusion data results, therefore the deposit type at the study area is an intermediate epithermal sulphidation (IS).Keyword: alteration-mineralization, intermediate epithermal sulphidation, fluid inclusion, Kulonprogo Dome.
Santolaya Machetti, Pablo: «Manual de procedimiento electoral» (Recensión)
Authors: Pajares Montolío Emilio J.
Published: January 2020

Recensión sobre la obra: Pablo Santolaya Machetti. Manual de procedimiento electoral, Madrid, Ministerio Del Interior-Secretaría General Técnica, 1993.
Sistemas de información parlamentaria y nuevas tecnologías
Authors: Maciá Mateo
Published: January 2020

Reflexión sobre los sistemas de información parlamentaria y las nuevas tecnologías.
Control de constitucionalidad : primacía y límites del Derecho comunitario europeo : casos italiano y español
Authors: Ruiz-Rico Ruiz Gerardo , Burkhardt Gemma
Published: January 2020

SUMARIO: I. Italia-1.1. Evolución de la Jurisprudencia constitucional italiana hacia el principio de primacía del derecho comunitario- I. 2. Reservas o contralímites a la primacía del Derecho comunitario sobre el Derecho interno de los Estados.-I.3. La ejecución de las Directivas comunitarias por las entidades regionales según la doctrina de la jurisprudencia constitucional.-II España- II.1. Evolución de la jurisprudencia constitucional española hacia el principio de primacía del Derecho Comunitario.-II.2 Reservas o contralímites a la primacía del Derecho Comunitario sobre el Derecho interno de los Estados.-II.3. La ejecución de las Directivas comunitarias por las entidades regionales según la jurisprudencia constitucional -III. Conclusiones.
Los archivos históricos de las Comunidades Europeas
Authors: Maciá Gómez Mateo
Published: January 2020

SUMARIO: 1. Creación.-2. Fondos y acceso.-3. Bibliografía.
Efektifitas Akupresur Terhadap Derajat Restless Leg Syndrome Pada Pasien Yang Menjalani Hemodialisis
Authors: Surya Defrima Oka , Desnita Ria
Published: January 2020

Komplikasi yang sering dialami oleh pasien gagal ginjal terminal yang menjalani hemodialisis adalah Restless Leg Syndrome (RLS). RLS terjadi karena penurunan fungsi neuron dopaminergik diensafalik A11. Akupresur dapat menstimulasi reseptor sensori dan fungsi saraf otonom sehingga menimbulkan vasoaktif neuropeptida calcitonin gene-related peptide dan substansi p yang berdampak pada peningkatan aliran darah dan memperbaiki fungsi neuron dopaminergik diensafalik A11. Tujuan penelitian adalah untuk mengetahui efektifitas akupresur terhadap derajat RLS pada pasien hemodialisis. Desain penelitian adalah quasi experiment menggunakan pendekatan pre dan post with control group design. Penelitian ini terdiri dari kelompok intervensi dan kelompok kontrol. Teknik pengambilan sampel adalah consecutive sampling dengan besar sampel 15 orang kelompok kontrol dan 15 orang kelompok intervensi. Instrumen yang digunakan adalah Kuesioner International Restless Leg Syndrome Scale. Hasil penelitian dianalisis menggunakan Paired T-Test dengan derajat kepercayaan 95%. Hasil penelitian menunjukkan akupresur efektif menurunkan derajat restless leg syndrome pada pasien hemodialisis pada kelompok intervensi (p=0,001). Disimpulkan bahwa akpresur efektif dalam menurunkan derajata restless leg syndrome pada pasien hemodialisis. Diharapkan perawat dapat menerapkan terapi akupresur pada pasien yang menjalani hemodialisis khususnya pasien yang mengalami restless leg syndrome.
Computing the Affective-Aesthetic Potential of Literary Texts
Authors: Jacobs Arthur M. , Kinder Annette
Published: January 2020

In this paper, we compute the affective-aesthetic potential (AAP) of literary texts by using a simple sentiment analysis tool called SentiArt. In contrast to other established tools, SentiArt is based on publicly available vector space models (VSMs) and requires no emotional dictionary, thus making it applicable in any language for which VSMs have been made available (>150 so far) and avoiding issues of low coverage. In a first study, the AAP values of all words of a widely used lexical databank for German were computed and the VSM’s ability in representing concrete and more abstract semantic concepts was demonstrated. In a second study, SentiArt was used to predict ~2800 human word valence ratings and shown to have a high predictive accuracy (R2 > 0.5, p < 0.0001). A third study tested the validity of SentiArt in predicting emotional states over (narrative) time using human liking ratings from reading a story. Again, the predictive accuracy was highly significant: R2adj = 0.46, p < 0.0001, establishing the SentiArt tool as a promising candidate for lexical sentiment analyses at both the micro- and macrolevels, i.e., short and long literary materials. Possibilities and limitations of lexical VSM-based sentiment analyses of diverse complex literary texts are discussed in the light of these results.
Effects of Slaughter Age on Muscle Characteristics and Meat Quality Traits of Da-Heng Meat Type Birds
Authors: Li Jingjing , Yang Chaowu , Peng Han , Yin Huadong , Wang Yan , Hu Yaodong , Yu Chunlin , Jiang Xiaosong , Du Huarui , Li Qingyun , Liu Yiping
Published: January 2020

Due to the increasing demand for producing chickens with high meat quality, there is a need to determine its mode of action on chicken meat quality traits across a wider age spectrum. In this study, five groups of 200 male Da-Heng meat type birds were reared until slaughter age of 60, 90, 120, 150, 180 days old and breast muscle performance, meat quality traits, and myofiber characteristics were evaluated. The larger body weight and breast weight of chicken are based on larger myofiber diameter and area, less myofiber density for the older birds than younger birds. There was an age effect on all meat quality traits of chicken breast muscle (p < 0.05). Older chickens often presented a higher pH, lower drip loss, higher shear force, darker, and redder breast meat. The correlation coefficients showed that myofiber characteristics played an important role in breast pH values, drip loss, and meat color (p < 0.05). Besides, significant correlations were also found between meat quality traits (p < 0.05). Further studies are needed to explore the biochemical character and potential molecular mechanism of chicken breast muscle to determine the factors that causes these age-related differences in meat quality in the current study.
Quality of Eggs and Albumen Technological Properties as Affected by Hermetia Illucens Larvae Meal in Hens’ Diet and Hen Age
Authors: Secci Giulia , Bovera Fulvia , Parisi Giuliana , Moniello Giuseppe
Published: January 2020

The impact on the egg quality and the albumen technological properties were here evaluated as affected by diet and hen age (A) of 162 Hy-line Brown hens. Three isoproteic and isoenergetic diets were formulated respecting the requirements for Hy-line hens: the control diet (C) based on conventional protein sources, and other two where vegetable proteins were substituted at 25% (HI25) and 50% (HI50) by partially defatted Hermetia illucens larva meal (HI). Ten eggs collected from each group at the hen ages of 20, 27, and 35 weeks were evaluated. The eggshell percentage and thickness were significantly reduced in the HI50 eggs (11.93% and 476 µm, respectively) compared to the C (12.34%, 542 µm) and HI25 (12.54%, 516 µm). The aging lowered (p = 0.05) the protein and increased (p < 0.001) water contents of the eggs. Although the foam capacity of the HI50 albumen was halved than the C group (p < 0.05), it was unaffected by the aging. Additionally, this did not impair the volume and the textural properties of a batter (angel cake) in which it was included. On the opposite, the textural characteristics of the cake made by the oldest hens (i.e., 35 wk-old) were compromised. In conclusion, the diet and hen age differently affected egg quality and its technological properties, which could be positive to obtain eggs to destine directly to the market or to the egg industry.
Parenteral Cu Supplementation of Late-Gestating and Lactating Iberian Red Deer Hinds Fed a Balanced Diet Reduces Somatic Cell Count and Modifies Mineral Profile of Milk
Authors: Pérez Serrano Martina , García Andrés José , Landete-Castillejos Tomás , Cappelli Jamil , Gómez José Ángel , Hidalgo Francisco , Gallego Laureano
Published: January 2020

This study describes the effects that Cu supplementation of late-gestating and lactating females (hinds) of Iberian red deer fed a balanced diet have on milk production, composition, and somatic cell count (SCC). Experimental hinds (n = 9) were subcutaneously injected every 42 days with Cu (0.83 mg Cu/kg body weight) from day 202 of gestation until the end of lactation (week 18). Control hinds (n = 8) were injected with a physiological saline solution with the same volume and at the same frequency as the experimental group. Copper supplementation decreased the SCC from 1.64 to 1.36 log 10/mL (p = 0.003) and modified the milk mineral profile. In particular, milk from hinds supplemented with Cu had more Ca (p = 0.02), Mg (p = 0.06), and K (p = 0.03) than milk from control hinds. However, Cu supplementation did not influence the Cu content of milk. Therefore, it can be concluded that Cu supplementation of hinds fed a balanced diet from late-gestation to the end of lactation could be a good strategy to reduce SCC and modify the mineral profile of milk increasing its Ca content.
Solving the Graph Problem on the Maximal Clique Problem on the P-Systems with Mitochondria Enzymes Layer
Authors: Lumban Gaol Ford , Matsuo Tokuro
Published: January 2020

P systems with mitochondria enzymes layer computing is a recent version of P systems; it integrates a new feature inspired from the enzymes gate of a natural cell to the cell-like P systems. The model of a computational layer is well known as a problem of Non-Deterministic (NP-complete) in polynomial time. In this paper, we propose a P systems with enzymes to solve one of the most NP-hard problems, which is the determination of the maximal clique in a given undirected graph. In this context, the evolution strategy proposed is based on using objects under the control of enzymes placed on layers.
A Numerical Investigation of the Berg Feature on Uranus as a Vortex-Driven System
Authors: LeBeau Raymond , Farmer Kevin , Sankar Ramanakumar , Hadland Nathan , Palotai Csaba
Published: January 2020

The Berg cloud feature in the atmosphere of Uranus was first identified as a persistent grouping of clouds located just off the bright South Polar Collar at a latitude of around −34 degrees. Ongoing observations of this feature through the 1990s and 2000s suggested that the feature was oscillating in location by a few degrees in latitude for several years, and then unexpectedly began to drift towards the equator, which continued over the final 4 years until the cloud dissipated. One possible explanation for such a persistent drifting cloud is that it is a cloud-vortex system, in which an unseen vortex drives the creation of the cloud and the motions of the vortex control the cloud location. To explore this possibility, a series of vortices are studied numerically using the Explicit Planetary Isentropic Coordinate General Circulation Model (EPIC GCM). The evolution of these test vortices are simulated to examine their drift rates and the potential for cloud formation. The results indicate that conditions on Uranus could result in an equatorward drifting vortex over a range of latitudes and that significant cloud formation could occur, potentially obscuring observations of the vortex.
An Integrated Wind Risk Warning Model for Urban Rail Transport in Shanghai, China
Authors: Han Zhihui , Tan Jianguo , Grimmond C. S. B. , Ma Bingxin , Yang Tongxiao , Weng Chunhui
Published: January 2020

The integrated wind risk warning model for rail transport presented has four elements: Background wind data, a wind field model, a vulnerability model, and a risk model. Background wind data uses observations in this study. Using the wind field model with effective surface roughness lengths, the background wind data are interpolated to a 30-m resolution grid. In the vulnerability model, the aerodynamic characteristics of railway vehicles are analyzed with CFD (Computational Fluid Dynamics) modelling. In the risk model, the maximum value of three aerodynamic forces is used as the criteria to evaluate rail safety and to quantify the risk level under extremely windy weather. The full model is tested for the Shanghai Metro Line 16 using wind conditions during Typhoon Chan-hom. The proposed approach enables quick quantification of real-time safety risk levels during typhoon landfall, providing sophisticated warning information for rail vehicle operation safety.
Fine-Scale Modeling of Individual Exposures to Ambient PM2.5, EC, NOx, and CO for the Coronary Artery Disease and Environmental Exposure (CADEE) Study
Authors: Breen Michael , Chang Shih Ying , Breen Miyuki , Xu Yadong , Isakov Vlad , Arunachalam Saravanan , Carraway Martha Sue , Devlin Robert
Published: January 2020

Air pollution epidemiological studies often use outdoor concentrations from central-site monitors as exposure surrogates, which can induce measurement error. The goal of this study was to improve exposure assessments of ambient fine particulate matter (PM2.5), elemental carbon (EC), nitrogen oxides (NOx), and carbon monoxide (CO) for a repeated measurements study with 15 individuals with coronary artery disease in central North Carolina called the Coronary Artery Disease and Environmental Exposure (CADEE) study. We developed a fine-scale exposure modeling approach to determine five tiers of individual-level exposure metrics for PM2.5, EC, NOx, and CO using outdoor concentrations, on-road vehicle emissions, weather, home building characteristics, time-locations, and time-activities. We linked an urban-scale air quality model, residential air exchange rate model, building infiltration model, global positioning system (GPS)-based microenvironment model, and accelerometer-based inhaled ventilation model to determine residential outdoor concentrations (Cout_home, Tier 1), residential indoor concentrations (Cin_home, Tier 2), personal outdoor concentrations (Cout_personal, Tier 3), exposures (E, Tier 4), and inhaled doses (D, Tier 5). We applied the fine-scale exposure model to determine daily 24 h average PM2.5, EC, NOx, and CO exposure metrics (Tiers 1–5) for 720 participant-days across the 25 months of the CADEE study. Daily modeled metrics showed considerable temporal and home-to-home variability of Cout_home and Cin_home (Tiers 1–2) and person-to-person variability of Cout_personal, E, and D (Tiers 3–5). Our study demonstrates the ability to apply an urban-scale air quality model with an individual-level exposure model to determine multiple tiers of exposure metrics for an epidemiological study, in support of improving health risk assessments.
Breastfeeding Duration Is Associated with Regional, but Not Global, Differences in White Matter Tracts
Authors: Bauer Christopher E. , Lewis James W. , Brefczynski-Lewis Julie , Frum Chris , Schade Margeaux M. , Haut Marc W. , Montgomery-Downs Hawley E.
Published: January 2020

Extended breastfeeding through infancy confers benefits on neurocognitive performance and intelligence tests, though few have examined the biological basis of these effects. To investigate correlations with breastfeeding, we examined the major white matter tracts in 4–8 year-old children using diffusion tensor imaging and volumetric measurements of the corpus callosum. We found a significant correlation between the duration of infant breastfeeding and fractional anisotropy scores in left-lateralized white matter tracts, including the left superior longitudinal fasciculus and left angular bundle, which is indicative of greater intrahemispheric connectivity. However, in contrast to expectations from earlier studies, no correlations were observed with corpus callosum size, and thus no correlations were observed when using such measures of global interhemispheric white matter connectivity development. These findings suggest a complex but significant positive association between breastfeeding duration and white matter connectivity, including in pathways known to be functionally relevant for reading and language development.
Deep Brain Stimulation of the Pedunculopontine Tegmental Nucleus Renders Neuroprotection through the Suppression of Hippocampal Apoptosis: An Experimental Animal Study
Authors: Praveen Rajneesh Chellappan , Hsieh Tsung-Hsun , Chen Shih-Ching , Lai Chien-Hung , Yang Ling-Yu , Chin Hung-Yen , Peng Chih-Wei
Published: January 2020

The core objective of this study was to determine the neuroprotective properties of deep brain stimulation of the pedunculopontine tegmental nucleus on the apoptosis of the hippocampus. The pedunculopontine tegmental nucleus is a prime target for Parkinson′s disease and is a crucial component in a feedback loop connected with the hippocampus. Deep brain stimulation was employed as a potential tool to evaluate the neuroprotective properties of hippocampal apoptosis. Deep brain stimulation was applied to the experimental animals for an hour. Henceforth, the activity of Caspase-3, myelin basic protein, Bcl-2, BAX level, lipid peroxidation, interleukin-6 levels, and brain-derived neurotrophic factor levels were evaluated at hours 1, 3 and 6 and compared with the sham group of animals. Herein, decreased levels of caspases activity and elevated levels of Bcl-2 expressions and inhibited BAX expressions were observed in experimental animals at the aforementioned time intervals. Furthermore, the ratio of Bcl-2/BAX was increased, and interleukin -6, lipid peroxidation levels were not affected by deep brain stimulation in the experimental animals. These affirmative results have explained the neuroprotection rendered by hippocampus apoptosis as a result of deep brain stimulation. Deep brain stimulation is widely used to manage neuro-motor disorders. Nevertheless, this novel study will be a revelation for a better understanding of neuromodulatory management and encourage further research with new dimensions in the field of neuroscience.
Speech Intelligibility During Clinical and Low Frequency
Authors: Sidtis John J. , Van Lancker Sidtis Diana , Ramdhani Ritesh , Tagliati Michele
Published: January 2020

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an effective and widely used tool in the treatment of Parkinson’s disease (PD). STN-DBS has varied effects on speech. Clinical speech ratings suggest worsening following STN-DBS, but quantitative intelligibility, perceptual, and acoustic studies have produced mixed and inconsistent results. Improvements in phonation and declines in articulation have frequently been reported during different speech tasks under different stimulation conditions. Questions remain about preferred STN-DBS stimulation settings. Seven right-handed, native speakers of English with PD treated with bilateral STN-DBS were studied off medication at three stimulation conditions: stimulators off, 60 Hz (low frequency stimulation—LFS), and the typical clinical setting of 185 Hz (High frequency—HFS). Spontaneous speech was recorded in each condition and excerpts were prepared for transcription (intelligibility) and difficulty judgements. Separate excerpts were prepared for listeners to rate abnormalities in voice, articulation, fluency, and rate. Intelligibility for spontaneous speech was reduced at both HFS and LFS when compared to STN-DBS off. On the average, speech produced at HFS was more intelligible than that produced at LFS, but HFS made the intelligibility task (transcription) subjectively more difficult. Both voice quality and articulation were judged to be more abnormal with DBS on. STN-DBS reduced the intelligibility of spontaneous speech at both LFS and HFS but lowering the frequency did not improve intelligibility. Voice quality ratings with STN-DBS were correlated with the ratings made without stimulation. This was not true for articulation ratings. STN-DBS exacerbated existing voice problems and may have introduced new articulatory abnormalities. The results from individual DBS subjects showed both improved and reduced intelligibility varied as a function of DBS, with perceived changes in voice appearing to be more reflective of intelligibility than perceived changes in articulation.
Formalized Computer-Aided Handwriting Psychology: Validation and Integration into Psychological Assessment
Authors: Chernov Yury , Caspers Claudia
Published: January 2020

In contrast to traditional researches that involve a manual, non-quantitative, and subjective way of performing handwriting analysis, in the current research, a special computer-aided method of revised handwriting analysis is used. It includes the detection of personality traits via manual quantitative registration of handwriting signs and their automated quantitative evaluation. This method is based on a mathematical–statistical model that integrates multiple international publications on the evaluation of handwriting signs. The first aim is the validation of the revised method against the 16 Personality Factor Questionnaire Revised (16PF-R), which is performed as a self-report personality test by test persons and was developed and researched empirically by Raymond B. Cattell et al. A second aim is the development of an integrated model for assessment including handwriting analysis: when both methods come to the same result on a certain scale, then the construct can be accepted with higher reliability; in contrast, when results are contradictory, they should be regarded as a limitation of each method and raise awareness in the researchers, as these contradictions are a precious source of additional information regarding the complexity, ambiguity, and context specificity of personality traits.
Clofarabine Improves Relapse-Free Survival of Acute Myeloid Leukemia in Younger Adults with Micro-Complex Karyotype
Authors: Fenwarth Laurène , Duployez Nicolas , Thomas Xavier , Boissel Nicolas , Geffroy Sandrine , Marceau-Renaut Alice , Caillot Denis , Raffoux Emmanuel , Lemasle Emilie , Marolleau Jean-Pierre , Berthon Céline , Cheok Meyling H. , Peyrouze Pauline , Pigneux Arnaud , Vey Norbert , Celli-Lebras Karine , Terré Christine , Preudhomme Claude , Dombret Hervé
Published: January 2020

Acute myeloid leukemia (AML) encompasses heterogeneous entities with dismal outcomes. Intermediate and unfavorable-risk AML represent the most difficult-to-treat entities. We recently reported the benefit of the clofarabine-based consolidation (CLARA) regimen compared to the standard high-dose cytarabine (HDAC) regimen in younger AML patients. Here, we aimed at assessing the clinical significance of single-nucleotide polymorphism (SNP)-array alterations and their interactions with chemotherapy regimens. A SNP-array was successfully performed in 187 out of the 221 intent-to-treat patients (CLARA arm: n = 92 patients, HDAC arm: n = 95 patients). The CLARA regimen did not significantly improve relapse-free survival (RFS) among patients who displayed a complex karyotype when compared to the HDAC regimen (4-year RFS (4y-RFS): 36.4% vs. 18.8%, respectively; p = 0.134). Defining micro-complex karyotypes from at least four SNP-array lesions enabled us to refine and enlarge the subset of adverse patients. In such patients, the CLARA regimen significantly improved RFS compared to the HDAC regimen (4y-RFS: 44.4% vs. 13.8%, respectively; p = 0.004). From our study cohort, 8% of patients displayed TP53 mutations, which were associated with an impaired RFS (4y-RFS: 20.0% vs 43.7%; p = 0.029). In a multivariate analysis, micro-complex karyotypes remained the sole poor prognostic factor in the HDAC arm (hazard ratio (HR) = 2.324 (95% confidence interval (CI) = 1.337–4.041), p = 0.003). The SNP array represents a powerful and reproductive approach to refine adverse AML patients that may benefit from alternative consolidation regimens.
Impact of FAK Expression on the Cytotoxic Effects of CIK Therapy in Triple-Negative Breast Cancer
Authors: Pan Mei-Ren , Wu Cheng-Che , Kan Jung-Yu , Li Qiao-Lin , Chang Shu-Jyuan , Wu Chun-Chieh , Li Chung-Liang , Ou-Yang Fu , Hou Ming-Feng , Yip Hon-Kan , Luo Chi-Wen
Published: January 2020

Triple-negative breast cancer (TNBC) is a special subtype of breast cancer in which several common diagnostic biomarkers are lost. Due to the loss of expression of receptors, treatment options for TNBC are limited. Therefore, finding safe and effective treatments for patients with TNBC is a major objective for clinicians. Previous studies suggested that cytokine-induced killer (CIK) cells may be beneficial for patients with a variety of tumor types. However, CIK therapy is not effective for all patients. In this study, we found that focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase that regulates several cellular functions in different cells, has the potential to regulate tumor cells sensitized to CIK cells. Knockdown of FAK expression in TNBC cells or the treatment of TNBC cells with a FAK inhibitor followed by coculture with CIK cells increases death of TNBC cells, suggesting that FAK plays important roles in sensitizing tumor cells to CIK cells. This phenomenon could be regulated by a FAK-programmed death-ligand 1 (PD-L1)-related mechanism. Overall, our findings provide new insights into the cytotoxic effect of CIK cell therapy in TNBC treatment, and show that CIK cell therapy combined with FAK inhibitors may be a novel therapeutic strategy for patients with TNBC.
Molecular Profiling of Atypical Tenosynovial Giant Cell Tumors Reveals Novel Non-CSF1 Fusions
Authors: Vougiouklakis Theodore , Shen Guomiao , Feng Xiaojun , Hoda Syed T. , Jour George
Published: January 2020

Tenosynovial giant cell tumor (TGCT) is a benign neoplasm characterized by recurrent fusions involving the colony-stimulating factor 1 (CSF1) gene and translocation partners including collagen type VI alpha 3 chain (COL6A3) or S100 calcium-binding protein A10 (S100A10). Herein, we report three atypical TGCT cases with very unusual morphology comprising areas with increased cellular atypia, mitotic activity, and worrisome features that harbor unique non-CSF1 gene fusions. Anchored multiplex PCR (AMP) for next-generation sequencing utilizing a customized panel targeting 86 cancer-related genes was performed, and it identified novel non-CSF1-driven gene fusions: NIPBL-ERG, FN1-ROS1, and YAP1-MAML2. Screening of three control TGCTs with conventional morphology found translocations involving CSF1, with partner genes COL6A3, FN1, and newly identified KCNMA1. All novel fusions were further validated by reverse transcriptase-PCR (RT-PCR) and Sanger sequencing. Late and multiple local recurrences occurred in the atypical TGCTs, while no recurrences were reported in the conventional TGCTs. Our findings reveal that atypical TGCTs harbor gene fusions not implicating CSF1 and suggest that non-CSF1 fusions potentially confer greater propensity to recurrences and local aggressiveness while indicating the presence of alternate pathogenic mechanisms that warrant further investigation.
Protein Oxidative Damage in UV-Related Skin Cancer and Dysplastic Lesions Contributes to Neoplastic Promotion and Progression
Authors: Tramutola Antonella , Falcucci Susanna , Brocco Umberto , Triani Francesca , Lanzillotta Chiara , Donati Michele , Panetta Chiara , Luzi Fabiola , Iavarone Federica , Vincenzoni Federica , Castagnola Massimo , Perluigi Marzia , Di Domenico Fabio , De Marco Federico
Published: January 2020

The ultraviolet (UV) component of solar radiation is the major driving force of skin carcinogenesis. Most of studies on UV carcinogenesis actually focus on DNA damage while their proteome-damaging ability and its contribution to skin carcinogenesis have remained largely underexplored. A redox proteomic analysis of oxidized proteins in solar-induced neoplastic skin lesion and perilesional areas has been conducted showing that the protein oxidative burden mostly concerns a selected number of proteins participating to a defined set of functions, namely: chaperoning and stress response; protein folding/refolding and protein quality control; proteasomal function; DNA damage repair; protein- and vesicle-trafficking; cell architecture, adhesion/extra-cellular matrix (ECM) interaction; proliferation/oncosuppression; apoptosis/survival, all of them ultimately concurring either to structural damage repair or to damage detoxication and stress response. In peri-neoplastic areas the oxidative alterations are conducive to the persistence of genetic alterations, dysfunctional apoptosis surveillance, and a disrupted extracellular environment, thus creating the condition for transformant clones to establish, expand and progress. A comparatively lower burden of oxidative damage is observed in neoplastic areas. Such a finding can reflect an adaptive selection of best fitting clones to the sharply pro-oxidant neoplastic environment. In this context the DNA damage response appears severely perturbed, thus sustaining an increased genomic instability and an accelerated rate of neoplastic evolution. In conclusion UV radiation, in addition to being a cancer-initiating agent, can act, through protein oxidation, as a cancer-promoting agent and as an inducer of genomic instability concurring with the neoplastic progression of established lesions.
An Outcome Assessment of a Single Institution’s Longitudinal Experience with Uveal Melanoma Patients with Liver Metastasis
Authors: Seedor Rino S. , Eschelman David J. , Gonsalves Carin F. , Adamo Robert D. , Orloff Marlana , Amjad Anjum , Sharpe-Mills Erin , Chervoneva Inna , Shields Carol L. , Shields Jerry A. , Mastrangelo Michael J. , Sato Takami
Published: January 2020

There is no FDA-approved treatment for metastatic uveal melanoma (UM) and overall outcomes are generally poor for those who develop liver metastasis. We performed a retrospective single-institution chart review on consecutive series of UM patients with liver metastasis who were treated at Thomas Jefferson University Hospital between 1971–1993 (Cohort 1, n = 80), 1998–2007 (Cohort 2, n = 198), and 2008–2017 (Cohort 3, n = 452). In total, 70% of patients in Cohort 1 received only systemic therapies as their treatment modality for liver metastasis, while 98% of patients in Cohort 2 and Cohort 3 received liver-directed treatment either alone or with systemic therapy. Median Mets-to-Death OS was shortest in Cohort 1 (5.3 months, 95% CI: 4.2–7.0), longer in Cohort 2 (13.6 months, 95% CI: 12.2–16.6) and longest in Cohort 3 (17.8 months, 95% CI: 16.6–19.4). Median Eye Tx-to-Death OS was shortest in Cohort 1 (40.8 months, 95% CI: 37.1–56.9), and similar in Cohort 2 (62.6 months, 95% CI: 54.6–71.5) and Cohort 3 (59.4 months, 95% CI: 56.2–64.7). It is speculated that this could be due to the shift of treatment modalities from DTIC-based chemotherapy to liver-directed therapies. Combination of liver-directed and newly developed systemic treatments may further improve the survival of these patients.
Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro
Authors: Freund Eric , Liedtke Kim-Rouven , Miebach Lea , Wende Kristian , Heidecke Amanda , Kaushik Nagendra Kumar , Choi Eun Ha , Partecke Lars-Ivo , Bekeschus Sander
Published: January 2020

Colorectal carcinoma is among the most common types of cancers. With this disease, diffuse scattering in the abdominal area (peritoneal carcinosis) often occurs before diagnosis, making surgical removal of the entire malignant tissue impossible due to a large number of tumor nodules. Previous treatment options include radiation and its combination with intraperitoneal heat-induced chemotherapy (HIPEC). Both options have strong side effects and are often poor in therapeutic efficacy. Tumor cells often grow and proliferate dysregulated, with enzymes of the protein kinase family often playing a crucial role. The present study investigated whether a combination of protein kinase inhibitors and low-dose induction of oxidative stress (using hydrogen peroxide, H2O2) has an additive cytotoxic effect on murine, colorectal tumor cells (CT26). Protein kinase inhibitors from a library of 80 substances were used to investigate colorectal cancer cells for their activity, morphology, and immunogenicity (immunogenic cancer cell death, ICD) upon mono or combination. Toxic compounds identified in 2D cultures were confirmed in 3D cultures, and additive cytotoxicity was identified for the substances lavendustin A, GF109203X, and rapamycin. Toxicity was concomitant with cell cycle arrest, but except HMGB1, no increased expression of immunogenic markers was identified with the combination treatment. The results were validated for GF109203X and rapamycin but not lavendustin A in the 3D model of different colorectal (HT29, SW480) and pancreatic cancer cell lines (MiaPaca, Panc01). In conclusion, our in vitro data suggest that combining oxidative stress with chemotherapy would be conceivable to enhance antitumor efficacy in HIPEC.
Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment
Authors: Titov Aleksei , Valiullina Aygul , Zmievskaya Ekaterina , Zaikova Ekaterina , Petukhov Alexey , Miftakhova Regina , Bulatov Emil , Rizvanov Albert
Published: January 2020

Chimeric antigen receptor (CAR) immunotherapy is one of the most promising modern approaches for the treatment of cancer. To date only two CAR T-cell products, Kymriah® and Yescarta®, have been approved by the Food and Drug Administration (FDA) for the treatment of lymphoblastic leukemia and B-cell lymphoma. Administration of CAR T-cells to control solid tumors has long been envisaged as one of the most difficult therapeutic tasks. The first two clinical trials conducted in sarcoma and neuroblastoma patients showed clinical benefits of CAR T-cells, yet multiple obstacles still hold us back from having accessible and efficient therapy. Why did such an effective treatment for relapsed and refractory hematological malignancies demonstrate only relatively modest efficiency in the context of solid tumors? Is it due to the lucky selection of the “magic” CD19 antigen, which might be one of a kind? Or do lymphomas lack the immunosuppressive features of solid tumors? Here we review the existing knowledge in the field of CAR T-cell therapy and address the heterogeneity of solid tumors and their diverse strategies of immunoevasion. We also provide an insight into prospective developments of CAR T-cell technologies against solid tumors.
Whole Genome Sequencing of Spontaneously Occurring Rat Natural Killer Large Granular Lymphocyte Leukemia Identifies JAK1 Somatic Activating Mutation
Authors: Wang T. Tiffany , Yang Jun , Dighe Shubha , Schmachtenberg Matthew W. , Leigh Nathan T. , Farber Emily , Onengut-Gumuscu Suna , Feith David J. , Ratan Aakrosh , Loughran Thomas P. , Olson Thomas L.
Published: January 2020

Large granular lymphocyte (LGL) leukemia arises spontaneously in elderly Fischer (F344) rats. This rodent model has been shown to emulate many aspects of the natural killer (NK) variant of human LGL leukemia. Previous transplantation of leukemic material into young F344 rats resulted in several strains of rat NK (RNK) primary leukemic cells. One strain, RNK-16, was adapted into the RNK-16 cell line and established as an aggressive NK-LGL leukemia model. Whole genome sequencing of the RNK-16 cell line identified 255,838 locations where the RNK16 had an alternate allele that was different from F344, including a mutation in Jak1. Functional studies showed Jak1 Y1034C to be a somatic activating mutation that mediated increased STAT signaling, as assessed by phosphoprotein levels. Sanger sequencing of Jak1 in RNK-1, -3, -7, and -16 found only RNK-16 to harbor the Y1034C Jak1 mutation. In vivo studies revealed that rats engrafted with RNK-16 primary material developed leukemia more rapidly than those engrafted with RNK-1, -3, and -7. Additionally, ex vivo RNK-16 spleen cells from leukemic rats exhibited increased STAT1, STAT3, and STAT5 phosphorylation compared to other RNK strains. Therefore, we report and characterize a novel gain-of-function Jak1 mutation in a spontaneous LGL leukemia model that results in increased downstream STAT signaling.
High-Throughput Label-Free Isolation of Heterogeneous Circulating Tumor Cells and CTC Clusters from Non-Small-Cell Lung Cancer Patients
Authors: Zeinali Mina , Lee Maggie , Nadhan Arthi , Mathur Anvya , Hedman Casey , Lin Eric , Harouaka Ramdane , Wicha Max , Zhao Lili , Palanisamy Nallasivam , Hafner Mathias , Reddy Rishindra , Kalemkerian Gregory , Schneider Bryan , Hassan Khaled , Ramnath Nithya , Nagrath Sunitha
Published: January 2020

(1) Background: Circulating tumor cell (CTC) clusters are emerging as clinically significant harbingers of metastases in solid organ cancers. Prior to engaging these CTC clusters in animal models of metastases, it is imperative for technology to identify them with high sensitivity. These clusters often present heterogeneous surface markers and current methods for isolation of clusters may fall short. (2) Methods: We applied an inertial microfluidic Labyrinth device for high-throughput, biomarker-independent, size-based isolation of CTCs/CTC clusters from patients with metastatic non-small-cell lung cancer (NSCLC). (3) Results: Using Labyrinth, CTCs (PanCK+/DAPI+/CD45−) were isolated from patients (n = 25). Heterogeneous CTC populations, including CTCs expressing epithelial (EpCAM), mesenchymal (Vimentin) or both markers were detected. CTCs were isolated from 100% of patients (417 ± 1023 CTCs/mL). EpCAM− CTCs were significantly greater than EpCAM+ CTCs. Cell clusters of ≥2 CTCs were observed in 96% of patients—of which, 75% were EpCAM−. CTCs revealed identical genetic aberrations as the primary tumor for RET, ROS1, and ALK genes using fluorescence in situ hybridization (FISH) analysis. (4) Conclusions: The Labyrinth device recovered heterogeneous CTCs in 100% and CTC clusters in 96% of patients with metastatic NSCLC. The majority of recovered CTCs/clusters were EpCAM−, suggesting that these would have been missed using traditional antibody-based capture methods.
Csf1 Deficiency Dysregulates Glial Responses to Demyelination and Disturbs CNS White Matter Remyelination
Authors: Wylot Bartosz , Mieczkowski Jakub , Niedziolka Sylwia , Kaminska Bozena , Zawadzka Malgorzata
Published: January 2020

Remyelination, a highly efficient central nervous system (CNS) regenerative process, is performed by oligodendrocyte progenitor cells (OPCs), which are recruited to the demyelination sites and differentiate into mature oligodendrocytes to form a new myelin sheath. Microglia, the specialized CNS-resident phagocytes, were shown to support remyelination through secretion of factors stimulating OPC recruitment and differentiation, and their pharmacological depletion impaired remyelination. Macrophage colony-stimulating factor (Csf1) has been implicated in the control of recruitment and polarization of microglia/macrophages in injury-induced CNS inflammation. However, it remains unclear how Csf1 regulates a glial inflammatory response to demyelination as well as axonal survival and new myelin formation. Here, we have investigated the effects of the inherent Csf1 deficiency in a murine model of remyelination. We showed that remyelination was severely impaired in Csf1-/- mutant mice despite the fact that reduction in monocyte/microglia accumulation affects neither the number of OPCs recruited to the demyelinating lesion nor their differentiation. We identified a specific inflammatory gene expression signature and found aberrant astrocyte activation in Csf1-/- mice. We conclude that Csf1-dependent microglia activity is essential for supporting the equilibrium between microglia and astrocyte pro-inflammatory vs. regenerative activation, demyelinated axons integration and, ultimately, reconstruction of damaged white matter.
The Singularity of the Drosophila Male Germ Cell Centriole: The Asymmetric Distribution of Sas4 and Sas6
Authors: Persico Veronica , Migliorini Massimo , Callaini Giuliano , Riparbelli Maria Giovanna
Published: January 2020

Drosophila spermatocytes have giant centrioles that display unique properties. Both the parent centrioles maintain a distinct cartwheel and nucleate a cilium-like region that persists during the meiotic divisions and organizes a structured sperm axoneme. Moreover, the parent centrioles are morphologically undistinguishable, unlike vertebrate cells in which mother and daughter centrioles have distinct structural features. However, our immunofluorescence analysis of the parent centrioles in mature primary spermatocytes revealed an asymmetric accumulation of the typical Sas4 and Sas6 proteins. Notably, the fluorescence intensity of Sas4 and Sas6 at the daughter centrioles is greater than the intensity found at the mother ones. In contrast, the centrioles of wing imaginal disc cells display an opposite condition in which the loading of Sas4 and Sas6 at the mother centrioles is greater. These data underlie a subtle asymmetry among the parent centrioles and point to a cell type diversity of the localization of the Sas4 and Sas6 proteins.
Involvement of the Gap Junction Protein, Connexin43, in the Formation and Function of Invadopodia in the Human U251 Glioblastoma Cell Line
Authors: Chepied Amandine , Daoud-Omar Zeinaba , Meunier-Balandre Annie-Claire , Laird Dale W. , Mesnil Marc , Defamie Norah
Published: January 2020

The resistance of glioblastomas to treatments is mainly the consequence of their invasive capacities. Therefore, in order to better treat these tumors, it is important to understand the molecular mechanisms which are responsible for this behavior. Previous work suggested that gap junction proteins, the connexins, facilitate the aggressive nature of glioma cells. Here, we show that one of them—connexin43 (Cx43)—is implicated in the formation and function of invadopodia responsible for invasion capacity of U251 human glioblastoma cells. Immunofluorescent approaches—combined with confocal analyses—revealed that Cx43 was detected in all the formation stages of invadopodia exhibiting proteolytic activity. Clearly, Cx43 appeared to be localized in invadopodia at low cell density and less associated with the establishment of gap junctions. Accordingly, lower extracellular matrix degradation correlated with less mature invadopodia and MMP2 activity when Cx43 expression was decreased by shRNA strategies. Moreover, the kinetics of invadopodia formation could be dependent on Cx43 dynamic interactions with partners including Src and cortactin. Interestingly, it also appeared that invadopodia formation and MMP2 activity are dependent on Cx43 hemichannel activity. In conclusion, these results reveal that Cx43 might be involved in the formation and function of the invadopodia of U251 glioblastoma cells.