bluuebunny/crossref_metadata_2025 huggingface dataset:
Par3DNet: Using 3DCNNs for Object Recognition on Tridimensional Partial Views
Authors: Gomez-Donoso Francisco , Escalona Felix , Cazorla Miguel
Published: May 2020

Deep learning-based methods have proven to be the best performers when it comes to object recognition cues both in images and tridimensional data. Nonetheless, when it comes to 3D object recognition, the authors tend to convert the 3D data to images and then perform their classification. However, despite its accuracy, this approach has some issues. In this work, we present a deep learning pipeline for object recognition that takes a point cloud as input and provides the classification probabilities as output. Our proposal is trained on synthetic CAD objects and is able to perform accurately when fed with real data provided by commercial sensors. Unlike most approaches, our method is specifically trained to work on partial views of the objects rather than on a full representation, which is not the representation of the objects as captured by commercial sensors. We trained our proposal with the ModelNet10 dataset and achieved a 78.39 % accuracy. We also tested it by adding noise to the dataset and against a number of datasets and real data with high success.
Practices of Remembrance: The Experiences of Artists and Curators in the Centenary Commemoration of World War I
Authors: Baxter Katherine Isobel
Published: May 2020

The centenary of World War One was marked in the UK by an unprecedented national investment in the creative arts as a vehicle for remembrance. This scale of funding for commemorative arts, not least under a government whose mantra had been economic “austerity”, demonstrates the importance that the nation-state placed on remembrance and on engaging the public in acts of memory through the arts. In the aftermath of the centenary, funding bodies have commissioned evaluations of this programming. These evaluations have focused on audiences reached, organisations benefitted, and social transformation. What remain occluded by the reports are the experiences of the artists themselves and the curators with whom they worked. In this article I explore the personal and affective experiences of several artists and curators whose work contributed to this national programme of remembrance. I ask: to what extent did artists and curators consciously engage with prior artistic responses to World War One? How did the context of collective commemoration and memory-making inform their practice and the works produced? What did their involvement in this programme of national remembrance make them feel? What were the narratives of the war they wanted to tell? To begin to answer these questions, I draw on a series of one-to-one interviews conducted with a number of artists and curators who were involved in commemorative projects in the UK and overseas.
Molecular Distributions and Compound-Specific Stable Carbon Isotopic Compositions of Plant Wax n-Alkanes in Marine Aerosols along a North–South Transect in the Arctic–Northwest Pacific Region
Authors: Kim Jung-Hyun , Park Jiyeon , Kim Sol-Bin , Shin Kyung-Hoon , Kim Sookwan , Gim Yeontae
Published: May 2020

A geographical source of n-alkanes in marine aerosols was assessed along a North–South transect in the Arctic–Northwest Pacific region. Marine aerosol samples were collected during the ARA08 cruise with the R/V Araon between 28 August and 28 September 2017. We investigated molecular distributions of n-alkanes (homologous series of C16 to C34) and compound-specific stable carbon isotopes (δ13C) of n-C27, n-C29, and n-C31. Unresolved complex mixtures (UCM) showed a latitudinal trend from the Arctic Ocean to the northwest Pacific Ocean, highlighting an increasing influence of the plume of polluted air exported from East Asian countries. The anthropogenic input was further evidenced by high U/R ratios (>5) and low CPI17–23 (0.6–1.4). The occurrence of high molecular weight (HMW) n-alkanes with high CPI27–31 (>3) indicated the biogenic input of terrestrial higher plant leaf waxes in all studied samples. The δ13C of HMW n-alkanes was influenced by both the relative contributions from the C3/C4 plant sources and from fossil fuel combustions. The back-trajectory analyses provided evidence that changes in molecular distributions and δ13C of n-alkanes were due to the long-range atmospheric transport of anthropogenic and biogenic organic materials from North American and East Asian countries to the Arctic Ocean and the remote northwest Pacific Ocean, respectively.
The Change Characteristics and Interactions of Soil Moisture and Temperature in the Farmland in Wuchuan County, Inner Mongolia, China
Authors: Zhang Ziyuan , Pan Zhihua , Pan Feifei , Zhang Jun , Han Guolin , Huang Na , Wang Jialin , Pan Yuying , Wang Zizhong , Peng Ruiqi
Published: May 2020

Soil moisture and temperature are both significant factors for crop growth and development. They are also the main influencing factors of regional climate change. In the context of climate change, the relationship between soil moisture and soil temperature is not only important for explaining the mechanism of moisture and temperature interaction, but also provides scientific suggestions for agricultural production. Since the accurate measurement of soil moisture and temperature is difficult, their relationship remains poorly understood. Here, based on real-time field observation in a potato field in Wuchuan County, Inner Mongolia, China, the change characteristics of soil moisture and temperature under different water level treatments were analyzed, and their relationships were disclosed. The results show that there was an inverse proportional relationship between soil moisture and temperature. With an increase of soil moisture, soil temperature decreased. The basic relation between soil moisture and temperature took the form of reciprocal functions (Q = 4.2 × 103 V × (0.2 + W) × ΔT). The decline of soil moisture in the farmland will increase the soil temperature and has a negative impact on land–atmosphere interactions. The results can provide important insight into regional climate change mechanisms.
Estimations of the Mexicali Valley (Mexico) Mixing Height
Authors: Salcido Alejandro , Celada-Murillo Ana-Teresa , Carreón-Sierra Susana , Castro Telma , Peralta Oscar , Salcido-González Rogelio-Sebastián , Hernández-Flores Nicasio , Tamayo-Flores Gustavo-Adolfo , Martínez-Flores Marco-Antonio
Published: May 2020

We report estimations of the Mexicali Valley (Mexico) mixing height for three seasons. Surface and upper air meteorological measurements were carried out nearby Cerro Prieto geothermal power plant during July 2010 (summer), January 2012 (winter), and October 2016 (autumn). Four different methods were applied to estimate the convective boundary layer (CBL) height from radiosonde (RS) profiles: the parcel method, the gradients method, the least-squares variational approach based on the slab model of the CBL structure, and a covariance method. For nocturnal conditions, we used diagnostic models based on friction velocity and Monin–Obukhov length. Under unstable conditions, we obtained (on average) mixing heights of 497 m at 06:00 LST, 1242 m at 12:00 LST, 1404 m at 15:00 LST, and 482 at 18:00 LST during summer; 754 m at 12:00 LST during winter; and 1195 m at 12:00 LST and 13:00 m between the 14:00 and 15:00 LST during the autumn. The results allowed adjusting a semiempirical model to evaluate mixing height from turbulent sensible heat flux and friction velocity data. Our results provide practical tools that could facilitate the application of regulatory dispersion models to assess air quality in the region.
Vaidya Collapse with Nonzero Radial Pressure and Charge
Authors: Beesham Aroonkumar
Published: May 2020

The cosmic censorship hypothesis is regarded as one of the most important unsolved problems in classical general relativity; viz., will generic gravitational collapse of a star after it has exhausted its nuclear fuel lead to black holes only, under reasonable physical conditions. We discuss the collapse of a fluid with nonzero radial pressure within the context of the Vaidya spacetime considering a decaying cosmological parameter as well as nonzero charge. Previously, a similar analysis was done, but without considering charge. A decaying cosmological parameter may also be associated with dark energy. We found that both black holes and naked singularities can form, depending upon the initial conditions. Hence, charge does not restore the validity of the hypothesis. This provides another example of the violation of the cosmic censorship hypothesis. We also discuss some radiating rotating solutions, arriving at the same conclusion.
The Generalized Hypergeometric Structure of the Ward Identities of CFT’s in Momentum Space in d > 2
Authors: Corianò Claudio , Maglio Matteo Maria
Published: May 2020

We review the emergence of hypergeometric structures (of F4 Appell functions) from the conformal Ward identities (CWIs) in conformal field theories (CFTs) in dimensions d > 2. We illustrate the case of scalar 3- and 4-point functions. 3-point functions are associated to hypergeometric systems with four independent solutions. For symmetric correlators, they can be expressed in terms of a single 3K integral—functions of quadratic ratios of momenta—which is a parametric integral of three modified Bessel K functions. In the case of scalar 4-point functions, by requiring the correlator to be conformal invariant in coordinate space as well as in some dual variables (i.e., dual conformal invariant), its explicit expression is also given by a 3K integral, or as a linear combination of Appell functions which are now quartic ratios of momenta. Similar expressions have been obtained in the past in the computation of an infinite class of planar ladder (Feynman) diagrams in perturbation theory, which, however, do not share the same (dual conformal/conformal) symmetry of our solutions. We then discuss some hypergeometric functions of 3 variables, which define 8 particular solutions of the CWIs and correspond to Lauricella functions. They can also be combined in terms of 4K integral and appear in an asymptotic description of the scalar 4-point function, in special kinematical limits.
Different Classes of Phytohormones Act Synergistically to Enhance the Growth, Lipid and DHA Biosynthetic Capacity of Aurantiochytrium sp. SW1
Authors: Nazir Yusuf , Halim Hafiy , Prabhakaran Pranesha , Ren Xiaojie , Naz Tahira , Mohamed Hassan , Nosheen Shaista , Mustafa Kiren , Yang Wu , Abdul Hamid Aidil , Song Yuanda
Published: May 2020

In the present study, the impact of eight phytohormones from six different classes on the growth, lipid and docosahexaenoic acid (DHA) biosynthetic capacity of Aurantiochytrium sp. SW1 (SW1) was evaluated. Kinetin (KIN), jasmonic acid (JA) and gibberellic acid (GA) significantly enhanced the growth and DHA production of SW1 by 16%–28% and 66%–84% in comparison to the control, respectively. The synergistic effect of these three phytohormones, evaluated by the response surface methodology (RSM), showed that a combination of 3.6 mg/L GA, 2.0 mg/L KIN and 20.0 mg/L JA further increased the growth and DHA production of SW1 by 16% to 28% and 22% to 36%, respectively, in comparison to the individual supplementation. The synergistic effect of these phytohormones was also shown to be time-dependent, where feeding at 24 h of cultivation led to 15%, 26% and 35% further increments in the biomass, lipid and DHA production in comparison to that of 0 h, respectively. The determination of stress markers, antioxidant enzymes and key enzymes involved in fatty acid biosynthesis aided to elucidate the potential mechanism underlying the improvement of growth and DHA production by SW1 at various times of feeding. Supplementation with the phytohormones at 24 h exhibited the maximum impact on reducing the level of reactive oxygen species (ROS) and malondialdehyde (MDA), as well as augmented the antioxidants (superoxide dismutase and catalase) and key metabolic enzymes involved in lipogenesis (malic, glucose-6-phosphate dehydrogenase and ATP-citrate lyase) in comparison to the control and other time points. This study signifies the potential application of phytohormones for improving the growth, lipid and DHA production in Aurantiochytrium spp.
High Levels of ROS Impair Lysosomal Acidity and Autophagy Flux in Glucose-Deprived Fibroblasts by Activating ATM and Erk Pathways
Authors: Song Seon Beom , Hwang Eun Seong
Published: May 2020

Under glucose deprivation, cells heavily mobilize oxidative phosphorylation to maintain energy homeostasis. This leads to the generation of high levels of ATP, as well as reactive oxygen species (ROS), from mitochondria. In nutrient starvation, autophagy is activated, likely to facilitate resource recycling, but recent studies suggest that autophagy flux is inhibited in cells undergoing glucose deprivation. In this study, we analyzed the status of autophagic flux in glucose-deprived human fibroblasts. Although lysosomes increased in quantity due in part to an increase of biogenesis, a large population of them suffered low acidity in the glucose-deprived cells. Autophagosomes also accumulated due to poor autolysis in these cells. A treatment of antioxidants not only restored lysosomal acidity but also released the flux blockade. The inhibition of ataxia telangiectasia mutated (ATM) serine/threonine kinase, which is activated by ROS, also attenuated the impairment of lysosomal acidity and autophagic flux, suggesting an effect of ROS that might be mediated through ATM activation. In addition, the activity of extracellular signal-regulated kinase (Erk) increased upon glucose deprivation, but this was also compromised by a treatment of antioxidants. Furthermore, the Erk inhibitor treatment also alleviated the failure in lysosomal acidity and autophagic flux. These together indicate that, upon glucose deprivation, cells undergo a failure of autophagy flux through an impairment of lysosomal acidity and that a high-level ROS-induced activation of Erk and ATM is involved in this impairment.
Acute Effects of Butyrate on Induced Hyperpermeability and Tight Junction Protein Expression in Human Colonic Tissues
Authors: Tabat Mathias W. , Marques Tatiana M. , Markgren Malin , Löfvendahl Liza , Brummer Robert J. , Wall Rebecca
Published: May 2020

Intact intestinal barrier function is essential for maintaining intestinal homeostasis. A dysfunctional intestinal barrier can lead to local and systemic inflammation through translocation of luminal antigens and has been associated with a range of health disorders. Butyrate, a short-chain fatty acid derived from microbial fermentation of dietary fibers in the colon, has been described as an intestinal barrier-strengthening agent, although mainly by using in vitro and animal models. This study aimed to investigate butyrate’s ability to prevent intestinal hyperpermeability, induced by the mast cell degranulator Compound 48/80 (C48/80), in human colonic tissues. Colonic biopsies were collected from 16 healthy subjects and intestinal permeability was assessed by Ussing chamber experiments. Furthermore, the expression levels of tight junction-related proteins were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Pre-treatment with 5 mM butyrate or 25 mM butyrate did not protect the colonic tissue against induced paracellular or transcellular hyperpermeability, measured by FITC-dextran and horseradish peroxidase passage, respectively. Biopsies treated with 25 mM butyrate prior to stimulation with C48/80 showed a reduced expression of claudin 1. In conclusion, this translational ex vivo study did not demonstrate an acute protective effect of butyrate against a chemical insult to the intestinal barrier in healthy humans.
Non-Invasive Delivery of Therapeutics into the Brain: The Potential of Aptamers for Targeted Delivery
Authors: Bukari Bakhtiar , Samarasinghe Rasika M. , Noibanchong Jinjutha , Shigdar Sarah L.
Published: May 2020

The blood-brain barrier (BBB) is a highly specialised network of blood vessels that effectively separates the brain environment from the circulatory system. While there are benefits, in terms of keeping pathogens from entering the brain, the BBB also complicates treatments of brain pathologies by preventing efficient delivery of macromolecular drugs to diseased brain tissue. Although current non-invasive strategies of therapeutics delivery into the brain, such as focused ultrasound and nanoparticle-mediated delivery have shown various levels of successes, they still come with risks and limitations. This review discusses the current approaches of therapeutic delivery into the brain, with a specific focus on non-invasive methods. It also discusses the potential for aptamers as alternative delivery systems and several reported aptamers with promising preliminary results.
Flavolignans from Silymarin as Nrf2 Bioactivators and Their Therapeutic Applications
Authors: Vargas-Mendoza Nancy , Morales-González Ángel , Morales-Martínez Mauricio , Soriano-Ursúa Marvin A. , Delgado-Olivares Luis , Sandoval-Gallegos Eli Mireya , Madrigal-Bujaidar Eduardo , Álvarez-González Isela , Madrigal-Santillán Eduardo , Morales-Gonzalez José A.
Published: May 2020

Silymarin (SM) is a mixture of flavolignans extracted from the seeds of species derived from Silybum marianum, commonly known as milk thistle or St. Mary’sthistle. These species have been widely used in the treatment of liver disorders in traditional medicine since ancient times. Several properties had been attributed to the major SM flavolignans components, identified as silybin, isosilybin, silychristin, isosilychristin, and silydianin. Previous research reported antioxidant and protective activities, which are probably related to the activation of the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), known as a master regulator of the cytoprotector response. Nrf2 is a redox-sensitive nuclear transcription factor able to induce the downstream-associated genes. The disruption of Nrf2 signaling has been associated with different pathological conditions. Some identified phytochemicals from SM had shown to participate in the Nrf2 signaling pathway; in particular, they have been suggested as activators that disrupt interactions in the Keap1-Nrf2 system, but also as antioxidants or with additional actions regarding Nrf2 regulation. Thus, the study of these molecules makes them appear attractive as novel targets for the treatment or prevention of several diseases.
Advances in Biomimetic Systems for Molecular Recognition and Biosensing
Authors: Saylan Yeşeren , Erdem Özgecan , Inci Fatih , Denizli Adil
Published: May 2020

Understanding the fundamentals of natural design, structure, and function has pushed the limits of current knowledge and has enabled us to transfer knowledge from the bench to the market as a product. In particular, biomimicry―one of the crucial strategies in this respect―has allowed researchers to tackle major challenges in the disciplines of engineering, biology, physics, materials science, and medicine. It has an enormous impact on these fields with pivotal applications, which are not limited to the applications of biocompatible tooth implants, programmable drug delivery systems, biocompatible tissue scaffolds, organ-on-a-chip systems, wearable platforms, molecularly imprinted polymers (MIPs), and smart biosensors. Among them, MIPs provide a versatile strategy to imitate the procedure of molecular recognition precisely, creating structural fingerprint replicas of molecules for biorecognition studies. Owing to their affordability, easy-to-fabricate/use features, stability, specificity, and multiplexing capabilities, host-guest recognition systems have largely benefitted from the MIP strategy. This review article is structured with four major points: (i) determining the requirement of biomimetic systems and denoting multiple examples in this manner; (ii) introducing the molecular imprinting method and reviewing recent literature to elaborate the power and impact of MIPs on a variety of scientific and industrial fields; (iii) exemplifying the MIP-integrated systems, i.e., chromatographic systems, lab-on-a-chip systems, and sensor systems; and (iv) closing remarks.
Differential Changes in Early Somatosensory Evoked Potentials between the Dominant and Non-Dominant Hand, Following a Novel Motor Tracing Task
Authors: Zabihhosseinian Mahboobeh , Gilley Ryan , Andrew Danielle , Murphy Bernadette , Yielder Paul
Published: May 2020

During training in a novel dynamic environment, the non-dominant upper limb favors feedback control, whereas the dominant limb favors feedforward mechanisms. Early somatosensory evoked potentials (SEPs) offer a means to explore differences in cortical regions involved in sensorimotor integration (SMI). This study sought to compare differences in SMI between the right (Dom) and left (Non-Dom) hand in healthy right-handed participants. SEPs were recorded in response to median nerve stimulation, at baseline and post, a motor skill acquisition-tracing task. One group (n = 12) trained with their Dom hand and the other group (n = 12), with their Non-Dom hand. The Non-Dom hand was significantly more accurate at baseline (p < 0.0001) and both groups improved with time (p < 0.0001), for task accuracy, with no significant interaction effect between groups for both post-acquisition and retention. There were significant group interactions for the N24 (p < 0.001) and the N30 (p < 0.0001) SEP peaks. Post motor acquisition, the Dom hand had a 28.9% decrease in the N24 and a 23.8% increase in the N30, with opposite directional changes for the Non-Dom hand; 22.04% increase in N24 and 24% decrease in the N30. These SEP changes reveal differences in early SMI between Dom and Non-Dom hands in response to motor acquisition, providing objective, temporally sensitive measures of differences in neural mechanisms between the limbs.
Orientations to Happiness between the Dark Triad Traits and Subjective Well-Being
Authors: Limone Pierpaolo , Sinatra Maria , Monacis Lucia
Published: May 2020

Previous research investigated the linkage between the Dark Triad traits and subjective well-being, but the factors explaining individual differences in terms of cognitive strategies for achieving happiness remained poorly understood. This study (N = 460) examined the indirect effects of orientations to happiness in the link between dark personality traits and subjective well-being in terms of life satisfaction and positive emotion. Participants completed a questionnaire comprising the Dark Triad Questionnaire, the Orientations to Happiness scale, the Satisfaction with Life scale, and the PANAS. Descriptive statistics, bivariate and partial correlations, and structural equation model were applied to the data. Zero-order and partial correlations showed no significant associations of Machiavellianism and psychopathy with subjective well-being measures, and positive associations of narcissism with the three orientations to happiness and the two dimensions of subjective well-being. Indirect effects indicated that the bright side of narcissism sought the pursuit of the emotional component of SWB by adopting engaging activities. Further studies should replicate our findings.
Instability of Personality Traits of Teachers in Risk Conditions due to Work-Related Stress
Authors: Andrisano Ruggieri Ruggero , Iervolino Anna , Mossi PierGiorgio , Santoro Emanuela , Boccia Giovanni
Published: May 2020

The following study aims to verify whether psychosocial risk conditions determine a variation in personality traits. The sample consisted of 301 teachers, comprising 84 men (27.1%) and 217 women (72.9%). The Big Five Questionnaire (BFQ) was used to measure personality traits, while the Organizational and Psychosocial Risk Assessment (OPRA) questionnaire was used to measure psychosocial risk. The ANOVA results notice the change of BFQ traits. These are significant (Extraversion = 0.000; Agreeableness = 0.001; Neuroticism = 0.000; Openness = 0.017), with the exception of the Conscientiousness trait (Conscientiousness = 0.213). The research supports the approach of seeing personality as the result of the interaction between the individual and the environment; this position is also recognized by work-related stress literature. Stress conditions can lead to a change in the state of health and possibly determine the onset of work-related stress diseases. In the future, it would be useful to start a series of longitudinal studies to understand in greater detail the variability of personality traits due to changes in the Risk Index.
Deformability of Glued Laminated Beams with Combined Reinforcement
Authors: Sobczak-Piąstka Justyna , Gomon Svyatoslav S. , Polishchuk Mykola , Homon Sviatoslav , Gomon Petro , Karavan Victor
Published: May 2020

Wood is one of the most popular renewable natural materials. Nowadays, raw wood is hardly ever used in the construction industry. It has been substituted by glued laminated wood that is processed with the use of high-tech methods, thus eliminating the principal flaws and defects of the natural material. The deformability of glued laminated beams with combined reinforcement has been studied, under which the steel reinforcement of the periodic profile was placed in the dappings of the upper compressed zone, while ribbon-reinforced composite was glued to the bottom of the stretched zone. The graphical charts for the layer change of the deformations of wood, steel, and composite reinforcement from the beginning of the loading application to the moment of destruction are presented.
Molecular-Biology-Driven Treatment for Metastatic Colorectal Cancer
Authors: Lai Eleonora , Liscia Nicole , Donisi Clelia , Mariani Stefano , Tolu Simona , Pretta Andrea , Persano Mara , Pinna Giovanna , Balconi Francesca , Pireddu Annagrazia , Impera Valentino , Dubois Marco , Migliari Marco , Spanu Dario , Saba Giorgio , Camera Silvia , Musio Francesca , Ziranu Pina , Puzzoni Marco , Demurtas Laura , Pusceddu Valeria , Dettori Manuela , Massa Elena , Atzori Francesco , Dessì Mariele , Astara Giorgio , Madeddu Clelia , Scartozzi Mario
Published: May 2020

Background: Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. Methods: A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. Results: RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-β, which require further research. Conclusion: Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients.
GRK2-Dependent HuR Phosphorylation Regulates HIF1α Activation under Hypoxia or Adrenergic Stress
Authors: Reglero Clara , Lafarga Vanesa , Rivas Verónica , Albitre Ángela , Ramos Paula , Berciano Susana R. , Tapia Olga , Martínez-Chantar María L. , Mayor Jr Federico , Penela Petronila
Published: May 2020

Adaptation to hypoxia is a common feature in solid tumors orchestrated by oxygen-dependent and independent upregulation of the hypoxia-inducible factor-1α (HIF-1α). We unveiled that G protein-coupled receptor kinase (GRK2), known to be overexpressed in certain tumors, fosters this hypoxic pathway via phosphorylation of the mRNA-binding protein HuR, a central HIF-1α modulator. GRK2-mediated HuR phosphorylation increases the total levels and cytoplasmic shuttling of HuR in response to hypoxia, and GRK2-phosphodefective HuR mutants show defective cytosolic accumulation and lower binding to HIF-1α mRNA in hypoxic Hela cells. Interestingly, enhanced GRK2 and HuR expression correlate in luminal breast cancer patients. GRK2 also promotes the HuR/HIF-1α axis and VEGF-C accumulation in normoxic MCF7 breast luminal cancer cells and is required for the induction of HuR/HIF1-α in response to adrenergic stress. Our results point to a relevant role of the GRK2/HuR/HIF-1α module in the adaptation of malignant cells to tumor microenvironment-related stresses.
Immune Cell Subtypes and Cytokines in Lung Tumor Microenvironment: Influence of COPD
Authors: Tang Jun , Ramis-Cabrer Daniel , Curull Víctor , Wang Xuejie , Qin Liyun , Mateu-Jiménez Mercé , Duran Xavier , Pijuan Lara , Rodríguez-Fuster Alberto , Espases Rafael Aguiló , Barreiro Esther
Published: May 2020

Background: The immune microenvironment plays a role in tumorigenesis. Chronic Obstructive Pulmonary Disease (COPD) is an independent risk factor for lung cancer (LC). We hypothesized that immune profile characterized by T regulatory (Treg), natural killer (NK), and plasma cells, as well as interleukin (IL)-10 and interferon-gamma, may differ within tumors of LC patients with/without COPD. Methods: Treg (anti-CD3 and anti-forkhead boxP3 antibodies), NK (anti-NCR1 antibody), IgG (anti-CD138-IgG antibody), IgA (anti-CD138-IgA antibody) using immunohistochemistry, and both IL-10 and interferon-gamma (ELISA) were quantified in tumor and non-tumor specimens (thoracotomy for lung tumor resection) from 33 LC–COPD patients and 20 LC-only patients. Results: Immune profile in tumor versus non-tumor specimens: Treg cell counts significantly increased in tumors of both LC and LC–COPD patients, while in tumors of the latter group, IgG-secreting plasma cells significantly decreased and IL-10 increased. No significant differences were seen in levels of NK cells, IgA-secreting cells, IgA/IgG, or interferon-gamma. Immune profile in tumors of LC–COPD versus LC: No significant differences were observed in tumors between LC–COPD and LC patients for any study marker. Conclusions: Immune cell subtypes and cytokines are differentially expressed in lung tumors, and the presence of COPD elicited a decline in IgG-secreting plasma cell levels but not in other cell types.
Novel Gene Fusions in Glioblastoma Tumor Tissue and Matched Patient Plasma
Authors: Wang Lan , Yekula Anudeep , Muralidharan Koushik , Small Julia L. , Rosh Zachary S. , Kang Keiko M. , Carter Bob S. , Balaj Leonora
Published: May 2020

Sequencing studies have provided novel insights into the heterogeneous molecular landscape of glioblastoma (GBM), unveiling a subset of patients with gene fusions. Tissue biopsy is highly invasive, limited by sampling frequency and incompletely representative of intra-tumor heterogeneity. Extracellular vesicle-based liquid biopsy provides a minimally invasive alternative to diagnose and monitor tumor-specific molecular aberrations in patient biofluids. Here, we used targeted RNA sequencing to screen GBM tissue and the matched plasma of patients (n = 9) for RNA fusion transcripts. We identified two novel fusion transcripts in GBM tissue and five novel fusions in the matched plasma of GBM patients. The fusion transcripts FGFR3-TACC3 and VTI1A-TCF7L2 were detected in both tissue and matched plasma. A longitudinal follow-up of a GBM patient with a FGFR3-TACC3 positive glioma revealed the potential of monitoring RNA fusions in plasma. In summary, we report a sensitive RNA-seq-based liquid biopsy strategy to detect RNA level fusion status in the plasma of GBM patients.
Immune Cytolytic Activity for Comprehensive Understanding of Immune Landscape in Hepatocellular Carcinoma
Authors: Takahashi Hideo , Kawaguchi Tsutomu , Yan Li , Peng Xuan , Qi Qianya , Morris Luc G.T. , Chan Timothy A. , Tsung Allan , Otsuji Eigo , Takabe Kazuaki
Published: May 2020

Cytolytic activity score (CYT), defined by granzyme A and perforin expression, is a useful marker for underlying immunity. We hypothesized that CYT-high hepatocellular carcinomas (HCCs) have stronger immunogenicity and favorable tumor microenvironments, which would result in better clinical outcomes, using the cancer genome atlas (TCGA) cohort with 371 patients with HCC. We found CYT-high HCCs were associated with higher expressions of the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3), well-known mutagenic enzymes. Further, higher numbers of anti-cancer immune cells, such as CD8+ T cells and M1 macrophages, were infiltrated in CYT-high HCCs. Major T cell exhaustion markers were expressed significantly higher in CYT-high HCCs, likely as a negative feedback loop. Additionally, CYT-high HCCs strongly enriched gene sets related with enhanced immune activity. With strong immunity, patients with CYT-high HCCs had significantly longer disease-specific survival (DSS) and overall survival (OS) (p = 0.03 and <0.01). Furthermore, when the OS is stratified by exhaustion marker expressions, the CYT-high/exhaustion-low group had the best and CYT-low/exhaustion-high groups had the worst OS. Lastly, high CYT was an independent protective factor for prognosis. In conclusion, CYT-high HCCs were associated with enhanced immunity and better survival. Our findings suggest that proper identification of tumor-immune microenvironments could stratify the patients for appropriate treatments.
Comparison of Circulating Cell-Free DNA Extraction Methods for Downstream Analysis in Cancer Patients
Authors: van der Leest Paul , Boonstra Pieter A. , ter Elst Arja , van Kempen Léon C. , Tibbesma Marco , Koopmans Jill , Miedema Anneke , Tamminga Menno , Groen Harry J. M. , Reyners Anna K. L. , Schuuring Ed
Published: May 2020

Circulating cell-free DNA (ccfDNA) may contain DNA originating from the tumor in plasma of cancer patients (ctDNA) and enables noninvasive cancer diagnosis, treatment predictive testing, and response monitoring. A recent multicenter evaluation of workflows by the CANCER-ID consortium using artificial spiked-in plasma showed significant differences and consequently the importance of carefully selecting ccfDNA extraction methods. Here, the quantity and integrity of extracted ccfDNA from the plasma of cancer patients were assessed. Twenty-one cancer patient-derived cell-free plasma samples were selected to compare the Qiagen CNA, Maxwell RSC ccfDNA plasma, and Zymo manual quick ccfDNA kit. High-volume citrate plasma samples collected by diagnostic leukapheresis from six cancer patients were used to compare the Qiagen CNA (2 mL) and QIAamp MinElute ccfDNA kit (8 mL). This study revealed similar integrity and similar levels of amplified short-sized fragments and tumor-specific mutants comparing the CNA and RSC kits. However, the CNA kit consistently showed the highest yield of ccfDNA and short-sized fragments, while the RSC and ME kits showed higher variant allelic frequencies (VAFs). Our study pinpoints the importance of standardizing preanalytical conditions as well as consensus on defining the input of ccfDNA to accurately detect ctDNA and be able to compare results in a clinical routine practice, within and between clinical studies.
Merkel Cell Carcinoma Treatment in Finland in 1986–2016—A Real-World Data Study
Authors: Sahi Helka , Their Jenny , Gissler Mika , Koljonen Virve
Published: May 2020

Merkel cell carcinoma (MCC) is a rare cutaneous carcinoma that has gained enormous interest since the discovery of Merkel cell polyoma virus, which is a causative oncogenic agent in the majority of MCC tumours. Increased research has focused on effective treatment options with immuno-oncology. In this study, we reviewed the real-world data on different treatments given to MCC patients in Finland in 1986–2016. We used the Finnish Cancer Registry database to find MCC patients and the Hospital Discharge Register and the Cause-of-Death Register to obtain treatment data. We identified 376 MCC patients and 33 different treatment entities and/or combinations of treatment. An increase was noted in the incidence of MCC since 2005. Therefore, the cohort was divided into two groups: the “early“ group with time of diagnosis between years 1986 and 2004 and the “late” group with time of diagnosis between 2005 and 2016. The multitude of different treatment combinations is a relatively new phenomenon; before the year 2005, only 11 treatments or treatment combinations were used for MCC patients. Our data show that combining radiation therapy with simple excision provided a survival advantage, which was, however, lost after adjustment for stage or age. Our registry study serves as a baseline treatment efficacy comparison as we move into the age of immunotherapy in MCC. Standardizing the treatment of MCC patients in Finland requires more work on awareness and multidisciplinary co-operation.
Erratum: Benelli, R., et al. Aspartate-β-Hydroxylase: A Promising Target to Limit the Local Invasiveness of Colorectal Cancer. Cancers 2020, 12, 971
Authors: Benelli Roberto , Costa Delfina , Mastracci Luca , Grillo Federica , Olsen Mark Jon , Barboro Paola , Poggi Alessandro , Ferrari Nicoletta
Published: May 2020

The authors wish to make the following corrections to this paper [...]
Role of Tumor and Stroma-Derived IGF/IGFBPs in Pancreatic Cancer
Authors: Thomas Divya , Radhakrishnan Prakash
Published: May 2020

Pancreatic cancer (PC) is the utmost stroma-rich cancer, which is accompanied by fibrotic reactions that stimulate interactions between tumor cells and stroma to promote tumor progression. Considerable research evidence denotes that insulin-like growth factor (IGF)/IGF binding proteins (IGFBP) signaling axis facilitate tumor growth, metastasis, drug resistance, and thereby facilitate PC into an advanced stage. The six members of IGFBPs were initially considered as passive carriers of free IGFs; however, current evidence revealed their functions beyond the endocrine role in IGF transport. Though numerous efforts have been made in blocking IGF/IGFBPs, the targeted therapies remain unsuccessful due to the complexity of tumor-stromal interactions in the pancreas. In this review, we explore the emerging evidence of the various roles of the tumor as well as stroma derived IGF/IGFBPs and highlight as a novel therapeutic target against PC progression.
The Effects of Obesity on Anti-Cancer Immunity and Cancer Immunotherapy
Authors: Woodall Matthew J. , Neumann Silke , Campbell Katrin , Pattison Sharon T. , Young Sarah L.
Published: May 2020

Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient’s own immune system, enabling it to destroy cancerous cells. Obesity is a metabolic disorder characterized by significant weight that is an important contributor to many different diseases, including cancers. Obesity impacts the immune system and causes, among other things, a state of chronic low-grade inflammation. This is hypothesized to impact the efficacy of the immunotherapies. This review discusses the effects of obesity on the immune system and cancer immunotherapy, including the current evidence on the effect of obesity on immune checkpoint blockade, something which currently published reviews on this topic have not delved into. Data from several studies show that even though obesity causes a state of chronic low-grade inflammation with reductions in effector immune populations, it has a beneficial effect on patient survival following anti-PD-1/PD-L1 and anti-CTLA-4 treatment. However, research in this field is just emerging and further work is needed to expand our understanding of which cancer patients are likely to benefit from immunotherapy.
Communication in the Cancer Microenvironment as a Target for Therapeutic Interventions
Authors: Dominiak Agnieszka , Chełstowska Beata , Olejarz Wioletta , Nowicka Grażyna
Published: May 2020

The tumor microenvironment (TME) is a complex system composed of multiple cells, such as non-cancerous fibroblasts, adipocytes, immune and vascular cells, as well as signal molecules and mediators. Tumor cells recruit and reprogram other cells to produce factors that maintain tumor growth. Communication between cancerous and surrounding cells is a two-way process and engages a diverse range of mechanisms that, in consequence, can lead to rapid proliferation, metastasis, and drug resistance, or can serve as a tumors-suppressor, e.g., through tumor–immune cell interaction. Cross-talk within the cancer microenvironment can be direct by cell-to-cell contact via adhesion molecules, electrical coupling, and passage through gap junctions, or indirect through classical paracrine signaling by cytokines, growth factors, and extracellular vesicles. Therapeutic approaches for modulation of cell-cell communication may be a promising strategy to combat tumors. In particular, integrative approaches targeting tumor communication in combination with conventional chemotherapy seem reasonable. Currently, special attention is paid to suppressing the formation of open-ended channels as well as blocking exosome production or ablating their cargos. However, many aspects of cell-to-cell communication have yet to be clarified, and, in particular, more work is needed in regard to mechanisms of bidirectional signal transfer. Finally, it seems that some interactions in TEM can be not only cancer-specific, but also patient-specific, and their recognition would help to predict patient response to therapy.
Predictive Value of Early Post-Treatment Diffusion-Weighted MRI for Recurrence or Tumor Progression of Head and Neck Squamous Cell Carcinoma Treated with Chemo-Radiotherapy
Authors: Brenet Esteban , Barbe Coralie , Hoeffel Christine , Dubernard Xavier , Merol Jean-Claude , Fath Léa , Servagi-Vernat Stéphanie , Labrousse Marc
Published: May 2020

Aims: To investigate the predictive capacity of early post-treatment diffusion-weighted magnetic resonance imaging (MRI) for recurrence or tumor progression in patients with no tumor residue after chemo-radiotherapy (CRT) for head and neck squamous cell carcinoma, and, to assess the predictive capacity of pre-treatment diffusion-weighted MRI for persistent tumor residue post-CRT. Materials and Method: A single center cohort study was performed in one French hospital. All patients with squamous cell carcinoma receiving CRT (no surgical indication) were included. Two diffusion-weighted MRI were performed: one within 8 days before CRT and one 3 months after completing CRT with determination of median tumor apparent diffusion coefficient (ADC). Main outcome: The primary endpoint was progression-free survival. Results: 59 patients were included prior to CRT and 46 (78.0%) completed CRT. A post-CRT tumor residue was found in 19/46 (41.3%) patients. In univariate analysis, initial ADC was significantly lower in patients with residue post CRT (0.56 ± 0.11 versus 0.79 ± 0.13; p < 0.001). When initial ADC was dichotomized at the median, initial ADC lower than 0.7 was significantly more frequent in patients with residue post CRT (73.7% versus 11.1%, p < 0.0001). In multivariate analysis, only initial ADC lower than 0.7 was significantly associated with tumor residue (OR = 22.6; IC [4.9–103.6], p < 0.0001). Among 26 patients without tumor residue after CRT and followed up until 12 months, 6 (23.1%) presented recurrence or progression. Only univariate analysis was performed due to a small number of events. The only factor significantly associated with disease progression or early recurrence was the delta ADC (p = 0.0009). When ADC variation was dichotomized at the median, patients with ADC variation greater than 0.7 had time of disease-free survival significantly longer than patients with ADC variation lower than 0.7 (377.5 [286–402] days versus 253 [198–370], p < 0.0001). Conclusion and relevance: Diffusion-weighted MRI could be a technique that enables differentiation of patients with high potential for early recurrence for whom intensive post-CRT monitoring is mandatory. Prospective studies with more inclusions would be necessary to validate our results.
MicroRNA Response and Toxicity of Potential Pathways in Human Colon Cancer Cells Exposed to Titanium Dioxide Nanoparticles
Authors: Li Wen , Jia Ming Xi , Deng Jing , Wang Jian Hui , Zuberi Zavuga , Yang Sheng , Ba Jie , Chen Zhu
Published: May 2020

Titanium dioxide nanoparticles (TiO2-NPs) are widely used for biomedical and food applications, the toxicity of TiO2-NPs in vivo and in vitro has been elucidated, but the underlying cytotoxicity of TiO2-NPs against microRNA remains largely unknown. The purpose of this study was to analyze microRNA profiling induced by TiO2-NPs against NCM460 and HCT116 cell lines. Comparative analysis identified 34 and 24 microRNAs were significantly altered in the TiO2-NPs treated cells at concentrations of 3 μg/mL and 30 μg/mL, respectively. Functional classification demonstrated that a large proportion of genes involved in metabolism, human disease, and environmental information process were significantly upregulated by TiO2-NPs. Bioinformatics analysis suggested that microRNA 378 might be an early indicator of cellular response to exogenous stimuli with apoptotic signals. Furthermore, TiO2-NPs significantly altered the expression of microRNA 378b and 378g in HCT116 and NCM460 cell lines at different concentrations from 3 to 6 μg/mL. These concentrations elicit high-sensitivity of stimuli response in colon cancer cells when exposed to the slight doses of TiO2-NPs. Our study indicated that microRNAs 378b and 378g may play an important role in TiO2-NPs-mediated colonic cytotoxicity, which may provide a valuable insight into the molecular mechanisms of potential risks in colitis and colon cancer.
Biliary Tract Cancer: Current Medical Treatment Strategies
Authors: Oneda Ester , Abu Hilal Mohammed , Zaniboni Alberto
Published: May 2020

Background: Biliary tract cancers (BTCs) include cholangiocarcinomas and gallbladder cancers usually present at an advanced stage, which are considered resectable in less than 20% of cases and characterised by poor prognosis. Methods: In this review, we discussed the most recent therapeutic options on the basis of the most updated and complete reviews and recent prospective studies in selected BTC patients. Results: Due to the high recurrence rate of BTCs, we suggest the new recommendations that have been made on adjuvant chemotherapy and radiotherapy treatment after surgery. New chemotherapy combinations in advanced-stage patients allow a better survival benefit than the standard treatment. Furthermore, the revelation of complex molecular events and their interactions and relationships with some risk factors allowed the development of targeted/toxic agents alone or combination with chemotherapy that is really promising. In unresectable patients, hepatic arterial infusion of high-dose chemotherapy or selective internal radiotherapy could offer a primary mass volume reduction or its resection with the maintenance of liver function. Conclusions: The therapeutic landscape for BTCs is blooming again, the knowledge of their biology is still growing, but the available data on chemotherapy, radiotherapy, locoregional treatments, and target therapies have added hopes to improve patient survival.