bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Nonlinear Kerr Effect on the Focusing Performance of Optical Lens with High-Intensity Laser Incidence
Authors: Yu Bosong , Lin Zhili , Chen Xudong , Qiu Weibin , Pu Jixiong
Published: March 2020

The rapid development of high-energy and high-power laser technology provides an important experimental means for the research of extreme physical state in the laboratory and for the design of large laser facilities for realizing inertial confinement fusion. However, when the incident laser field is very strong, the Kerr effect of materials affects the nominal performance of optical elements. In this work, the impact of Kerr effect on the focusing performance of an optical lens is studied by calculating and comparing the filed patterns of focal spots for three different incident laser beams together with three different levels of light intensities. The traditional transfer function of an optical lens is firstly modified according to the theory of nonlinear Kerr effect. We use the two-dimensional fast Fourier transform algorithm and angular spectrum algorithm to numerically calculate the field distributions of focal spots in the nominal focal plane of lens and its adjacent planes based on the Fresnel diffraction integral formula. The obtained results show that the Kerr effect affects the focusing characteristics of lens, especially for the incidence of high-order Gaussian beams, such as Hermite-Gaussian beams and Laguerre-Gaussian beams. At the same time, the focal length and refractive index of lens also change the field patterns of focal spots. The presented methodology is of great value in engineering applications where the practical problem with beam size up to 100 mm can be calculated using a common laptop computer. The work provides an efficient numerical technique for high-intensity incident laser beams focused by lens that takes Kerr effect into consideration, which has potential applications in high energy density physics and large laser facilities for inertial confinement fusion.
Assessing Water Infiltration and Soil Water Repellency in Brazilian Atlantic Forest Soils
Authors: Lozano-Baez Sergio Esteban , Cooper Miguel , de Barros Ferraz Silvio Frosini , Ribeiro Rodrigues Ricardo , Lassabatere Laurent , Castellini Mirko , Di Prima Simone
Published: March 2020

This study presents the results of the soil hydraulic characterization performed under three land covers, namely pasture, 9-year-old restored forest, and remnant forest, in the Brazilian Atlantic Forest. Two types of infiltration tests were performed, namely tension (Mini-Disk Infiltrometer, MDI) and ponding (Beerkan) tests. MDI and Beerkan tests provided complementary information, highlighting a clear increase of the hydraulic conductivity, especially at the remnant forest plots, when moving from near-saturated to saturated conditions. In addition, measuring the unsaturated soil hydraulic conductivity with different water pressure heads allowed the estimation of the macroscopic capillary length in the field. This approach, in conjunction with Beerkan measurements, allowed the design better estimates of the saturated soil hydraulic conductivity under challenging field conditions, such as soil water repellency (SWR). This research also reports, for the first time, evidence of SWR in the Atlantic Forest, which affected the early stage of the infiltration process with more frequency in the remnant forest.
Optimization of a Method for the Detection of Biomass-Burning Relevant VOCs in Urban Areas Using Thermal Desorption Gas Chromatography Mass Spectrometry
Authors: Chandra Boggarapu Praphulla , McClure Crystal D. , Mulligan JoAnne , Jaffe Daniel A.
Published: March 2020

Forest fire smoke influence in urban areas is relatively easy to detect at high concentrations but more challenging to detect at low concentrations. In this study, we present a simplified method that can reliably quantify smoke tracers in an urban environment at relatively low cost and complexity. For this purpose, we used dual-bed thermal desorption tubes with an auto-sampler to collect continuous samples of volatile organic compounds (VOCs). We present the validation and evaluation of this approach using thermal desorption gas chromatography mass spectrometry (TD-GC-MS) to detect VOCs at ppt to ppb concentrations. To evaluate the method, we tested stability during storage, interferences (e.g., water and O3), and reproducibility for reactive and short-lived VOCs such as acetonitrile (a specific chemical tracer for biomass burning), acetone, n-pentane, isopentane, benzene, toluene, furan, acrolein, 2-butanone, 2,3-butanedione, methacrolein, 2,5- dimethylfuran, and furfural. The results demonstrate that these VOCs can be quantified reproducibly with a total uncertainty of ≤30% between the collection and analysis, and with storage times of up to 15 days. Calibration experiments performed over a dynamic range of 10–150 ng loaded on to each thermal desorption tube at different relative humidity showed excellent linearity (r2 ≥ 0.90). We utilized this method during the summer 2019 National Oceanic and Atmospheric Administration (NOAA) Fire Influence on Regional to Global Environments Experiment–Air Quality (FIREX-AQ) intensive experiment at the Boise ground site. The results of this field study demonstrate the method’s applicability for ambient VOC speciation to identify forest fire smoke in urban areas.
An Overview of the Integrated Meteorological Observations in Complex Terrain Region at Dali National Climate Observatory, China
Authors: Xu Anlun , Li Jian
Published: March 2020

Systematically observing components of the climate system as well as their processes and interactions are crucial to understand the weather, climate, climate change, etc. In order to launch long-term, continuous, stereoscopic, and integrated meteorological observations for key regions of the climate system in southwestern China where it is sensitive to interactions among multiple layers and exchanges of mass and energy, the Dali National Climate Observatory (DNCO) was established in May 2006. To date, the DNCO has gradually performed an integrated meteorological observation network in a complex terrain region over the southeastern Tibetan Plateau including the conventional observations of weather and climate, and the special observations of radiation, lightning, soil moisture, wind profile, water vapor, water quality, water level, water temperature profile, turbulent fluxes of momentum, sensible heat, latent heat, carbon dioxide, and methane, etc. Furthermore, the DNCO mainly focuses on the field observation experiments and scientific research activities for mountain meteorology. This paper presents an overview of the DNCO including its location, climatology, scientific objectives, research tasks, and existing observation projects. The progresses in observation and associated research including data quality controls and assessments, recent observation results, and regional numerical model tests are summarized. Future works are also discussed.
Batteries and Supercapacitors Aging
Authors: Venet Pascal , Redondo-Iglesias Eduardo
Published: March 2020

Electrochemical energy storage is a key element of systems in a wide range of sectors, such as electro-mobility, portable devices, or renewable energy [...]
Mechanics and Microstructure of the Atrioventricular Heart Valve Chordae Tendineae: A Review
Authors: Ross Colton J. , Zheng Junnan , Ma Liang , Wu Yi , Lee Chung-Hao
Published: March 2020

The atrioventricular heart valves (AHVs) are responsible for directing unidirectional blood flow through the heart by properly opening and closing the valve leaflets, which are supported in their function by the chordae tendineae and the papillary muscles. Specifically, the chordae tendineae are critical to distributing forces during systolic closure from the leaflets to the papillary muscles, preventing leaflet prolapse and consequent regurgitation. Current therapies for chordae failure have issues of disease recurrence or suboptimal treatment outcomes. To improve those therapies, researchers have sought to better understand the mechanics and microstructure of the chordae tendineae of the AHVs. The intricate structures of the chordae tendineae have become of increasing interest in recent literature, and there are several key findings that have not been comprehensively summarized in one review. Therefore, in this review paper, we will provide a summary of the current state of biomechanical and microstructural characterizations of the chordae tendineae, and also discuss perspectives for future studies that will aid in a better understanding of the tissue mechanics–microstructure linking of the AHVs’ chordae tendineae, and thereby improve the therapeutics for heart valve diseases caused by chordae failures.
Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)
Authors: de Castro Alexandre A. , Assis Letícia C. , Soares Flávia V. , Kuca Kamil , Polisel Daniel A. , da Cunha Elaine F. F. , Ramalho Teodorico C.
Published: March 2020

Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.
Unusual Secondary Metabolites of the Aerial Parts of Dionysia diapensifolia Bioss. (Primulaceae) and Their Anti-Inflammatory Activity
Authors: Alilou Mostafa , Marzocco Stefania , Batooli Hossein , Troppmair Jakob , Schwaiger Stefan , Stuppner Hermann
Published: March 2020

The genus Dionysia, belonging to the Primulaceae family, encompasses more than 50 species worldwide with a center of diversity located in the arid Irano-Turanian mountains. In this study, a phytochemical investigation of the aerial parts of D. diapensifolia Bioss. led to the isolation of 24 phenolic compounds 1–7 and 9–25, and one sesquiterpenoid 8. Compound 1 was identified as new natural product, while isolation of 2 and 3, already known as synthetic products, from a natural source is reported for the first time in the present study. Isolation of compound 8 from a Dionysia species and indeed the whole Primulaceae family is reported for the first time too. Structure elucidation was performed by extensive spectroscopic analyses (1D-, 2D-NMR, and MS), and by comparison with reported literature data. Furthermore, DP4+ chemical shift probability calculations were performed to establish the relative configuration of compound 1. Additionally, subfractions obtained by liquid-liquid extraction of the methanolic extract of the plant, and subsequently the isolated new and selected known compounds 1–4, 6, 8–11 obtained from the diethyl ether subfraction were investigated for their inhibitory effect on NO release and iNOS and COX-2 expression in J774A.1 murine macrophages. The results showed a potential anti-inflammatory activity of the obtained subfractions, of which the diethyl ether subfraction was the most active one in inhibiting NO release and COX-2 expression (p < 0.001). Among the investigated isolated compounds, compound 4 significantly (p < 0.001) inhibited NO release and iNOS and COX-2 expression in a comparable manner like the used positive controls (L-NAME and indomethacin, respectively). Moreover, other isolated substances displayed moderate to high inhibitory activities, illustrating the potential anti-inflammatory activity of Dionysia diapensifolia.
Sarcomeric Gene Variants and Their Role with Left Ventricular Dysfunction in Background of Coronary Artery Disease
Authors: Kumar Surendra , Kumar Vijay , Kim Jong-Joo
Published: March 2020

Cardiovascular diseases are one of the leading causes of death in developing countries, generally originating as coronary artery disease (CAD) or hypertension. In later stages, many CAD patients develop left ventricle dysfunction (LVD). Left ventricular ejection fraction (LVEF) is the most prevalent prognostic factor in CAD patients. LVD is a complex multifactorial condition in which the left ventricle of the heart becomes functionally impaired. Various genetic studies have correlated LVD with dilated cardiomyopathy (DCM). In recent years, enormous progress has been made in identifying the genetic causes of cardiac diseases, which has further led to a greater understanding of molecular mechanisms underlying each disease. This progress has increased the probability of establishing a specific genetic diagnosis, and thus providing new opportunities for practitioners, patients, and families to utilize this genetic information. A large number of mutations in sarcomeric genes have been discovered in cardiomyopathies. In this review, we will explore the role of the sarcomeric genes in LVD in CAD patients, which is a major cause of cardiac failure and results in heart failure.
Joint Neuropsychological Assessment through Coma/Near Coma and Level of Cognitive Functioning Assessment Scales Reduces Negative Findings in Pediatric Disorders of Consciousness
Authors: Molteni Erika , Colombo Katia , Pastore Valentina , Galbiati Susanna , Recla Monica , Locatelli Federica , Galbiati Sara , Fedeli Claudia , Strazzer Sandra
Published: March 2020

The present study aimed to: (a) characterize the emergence to a conscious state (CS) in a sample of children and adolescents with severe brain injury during the post-acute rehabilitation and through two different neuropsychological assessment tools: the Rappaport Coma/Near Coma Scale (CNCS) and Level of Cognitive Functioning Assessment Scale (LOCFAS); (b) compare the evolution in patients with brain lesions due to traumatic and non-traumatic etiologies; and (c) describe the relationship between the emergence to a CS and some relevant clinical variables. In this observational prospective longitudinal study, 92 consecutive patients were recruited. Inclusion criteria were severe disorders of consciousness (DOC), Glasgow Coma Scale (GCS) score ≤8 at insult, age 0 to 18 years, and direct admission to inpatient rehabilitation from acute care. The main outcome measures were CNCS and LOCFAS, both administered three and six months after injury. The cohort globally shifted towards milder DOC over time, moving from overall ‘moderate/near coma’ at three months to ‘near/no coma’ at six months post-injury. The shift was captured by both CNCS and LOCFAS. CNCS differentiated levels of coma at best, while LOCFAS was superior in characterizing the emergence from coma. Agreement between scales was fair, and reduced negative findings at less than 10%. Patients with traumatic brain injury (TBI) vs. non-traumatic brain injury (NTBI) were older and had neurosurgical intervention more frequently. No relation between age and the level of consciousness was found overall. Concurrent administration of CNCS and LOCFAS reduced the rate of false negatives and better detected signs of arousal and awareness. This provides indication to administer both tools to increase measurement precision.
A Fractal Model of Cracking of Cement Matrix Composites
Authors: Konkol Janusz
Published: March 2020

The modern methods of materials (including cement matrix materials) design and testing impose the application of an approach appropriate to materials engineering. A quantitative description of the association between the properties of these materials and their structure is a necessity. What remains the scientific aim, however, is the clarification and description of the occurring phenomena by means of models mapping their actual behavior in the closest way possible. The article presents a cracking fractal model based on tests on the morphology of concrete fracture surfaces. The recorded fractal nature of the cracking of cement matrix materials enabled fractal geometry in the model development to be applied. Owing to the application of statistical analysis, together with an extensive base of data on the profile lines separated out of the real fracture surfaces of concrete, it was possible to develop a cracking fractal model. Not only does this model satisfy the condition of the equality of the fractal dimension of the real and model profile lines, it also offers the possibility of introducing an order to the apparently chaotic phenomena, such as the cracking process. An advantage and novelty of the model is that unlike the other authors’ proposals, there is a possibility of reaching an infinitely large number of solutions for model profile lines, which approximates the model to the real-life scenario. The results of fractal tests were supplemented with strength measurements, identifying concrete’s compressive and fracture toughness (determining the critical stress intensity factor KIcS). A connection between the fractal dimension and the investigated properties of concrete was demonstrated. A higher fractal dimension was observed in the profile lines separated out of the fracture surfaces of concretes of higher water–cement ratio. The advantages of the model include the simplicity and applicability in model studies on other materials of the cement matrix.
Durability and Climate Change—Implications for Service Life Prediction and the Maintainability of Buildings
Authors: Lacasse Michael A. , Gaur Abhishek , Moore Travis V.
Published: March 2020

Sustainable building practices are rooted in the need for reliable information on the long-term performance of building materials; specifically, the expected service-life of building materials, components, and assemblies. This need is ever more evident given the anticipated effects of climate change on the built environment and the many governmental initiatives world-wide focused on ensuring that structures are not only resilient at their inception but also, can maintain their resilience over the long-term. The Government of Canada has funded an initiative now being completed at the National Research Council of Canada’s (NRC) Construction Research Centre on “Climate Resilience of Buildings and Core Public infrastructure”. The outcomes from this work will help permit integrating climate resilience of buildings into guides and codes for practitioners of building and infrastructure design. In this paper, the impacts of climate change on buildings are discussed and a review of studies on the durability of building envelope materials and elements is provided in consideration of the expected effects of climate change on the longevity and resilience of such products over time. Projected changes in key climate variables affecting the durability of building materials is presented such that specifications for the selection of products given climate change effects can be offered. Implications in regard to the maintainability of buildings when considering the potential effects of climate change on the durability of buildings and its components is also discussed.
Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma
Authors: Poirier Jonathan , Gagnon Nadia , Terzolo Massimo , Puglisi Soraya , Ghorayeb Nada El , Calabrese Anna , Lacroix André , Bourdeau Isabelle
Published: March 2020

Mitotane is a steroidogenesis inhibitor and adrenolytic drug used for treatment of adrenocortical cancer (ACC). Mitotane therapy causes adrenal insufficiency requiring glucocorticoid replacement in all patients. However, it is unclear whether chronic therapy with mitotane induces complete destruction of zona fasciculata and whether hypothalamic-pituitary-adrenal (HPA) axis can recover after treatment cessation. Our objective was to assess the HPA axis recovery in a cohort of patients after cessation of adjuvant mitotane therapy for ACC. We retrospectively reviewed patient files with stage I-II-III ACC in two referral centers in Canada and Italy. Data on demographics, tumor characteristics, hormonal profile, and HPA axis were collected. Data from 23 patients with pathologically proven ACC treated with adjuvant mitotane for a minimum of two years were analyzed. Eight patients were males and 15 were females and the median age was 41 years old (range 18 to 73). After mitotane cessation, 18/23 (78.3%) patients achieved a complete HPA axis recovery while 3/23 (13.0%) were unable to tolerate glucocorticoid withdrawal despite having normal hormonal test values and 2/23 (8.7%) never achieved recovery. The mean time interval between mitotane cessation and HPA axis recovery was 2.7 years. A high proportion of patients achieved HPA axis recovery following cessation of mitotane adjuvant therapy. However, complete recovery was often delayed up to 2.5 years and regular assessment of the hormonal profile is required.
Proton Pump Inhibitors Reduce Pancreatic Adenocarcinoma Progression by Selectively Targeting H+, K+-ATPases in Pancreatic Cancer and Stellate Cells
Authors: Tozzi Marco , Sørensen Christiane E. , Magni Lara , Christensen Nynne M. , Bouazzi Rayhana , Buch Caroline M. , Stefanini Matteo , Duranti Claudia , Arcangeli Annarosa , Novak Ivana
Published: March 2020

Pancreatic duct cells are equipped with acid/base transporters important for exocrine secretion. Pancreatic ductal adenocarcinoma (PDAC) cells may utilize such transporters to acidify extracellular tumor microenvironment, creating a niche favoring cell proliferation, fibrosis and resistance to chemotherapy—all contributing to the notoriously bad prognosis of this disease. Here, we report that gastric and non-gastric H+, K+-ATPases (coded by ATP4A and ATP12A) are overexpressed in human and murine pancreatic cancer and that we can target them specifically with proton pump inhibitors (PPIs) and potassium-competitive acid blockers (P-CABs) in in vitro models of PDAC. Focusing on pantoprazole, we show that it significantly reduced human cancer cell proliferation by inhibiting cellular H+ extrusion, increasing K+ conductance and promoting cyclin D1-dependent cell cycle arrest and preventing STAT3 activation. Pantoprazole also decreased collagen secretion from pancreatic stellate cells. Importantly, in vivo studies show that pantoprazole treatment of tumor-bearing mice reduced tumor size, fibrosis and expression of angiogenic markers. This work provides the first evidence that H+, K+-ATPases contribute to PDAC progression and that these can be targeted by inhibitors of these pumps, thus proving a promising therapeutic strategy.
Inflammatory Mechanisms of HCC Development
Authors: Refolo Maria Grazia , Messa Caterina , Guerra Vito , Carr Brian Irving , D’Alessandro Rosalba
Published: March 2020

HCC (hepatocellular carcinoma) is the second leading cause of cancer deaths worldwide, with several etiologic causes, mostly inflammation-associated. Different inflammatory responses in the liver can be triggered by different etiological agents. The inflammatory process can be resolved or be persistent, depending on the etiology and multiple other factors. Chronic inflammation, tissue remodeling, genetic alterations, and modifications in cellular signaling are considered to be key processes promoting immunosuppression. The progressive immunosuppression leads to the inactivation of anti-tumor immunity involved in HCC carcinogenesis and progression. Tumor cellular processes including DNA damage, necrosis, and ER (endoplasmic reticulum) stress can affect both immune-surveillance and cancer-promoting inflammation, supporting a mutual interdependence. Here, we review the current understanding of how chronic liver injury and inflammation is triggered and sustained, and how inflammation is linked to HCC. The identification of many hepatic microenvironmental inflammatory processes and their effector molecules, has resulted in extensive translational work and promising clinical trials of new immunomodulatory agents.
Precision Medicine Management of Chronic Lymphocytic Leukemia
Authors: Moia Riccardo , Patriarca Andrea , Schipani Mattia , Ferri Valentina , Favini Chiara , Sagiraju Sruthi , Al Essa Wael , Gaidano Gianluca
Published: March 2020

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in western countries, with an incidence of approximately 5.1/100,000 new cases per year. Some patients may never require treatment, whereas others relapse early after front line therapeutic approaches. Recent whole genome and whole exome sequencing studies have allowed a better understanding of CLL pathogenesis and the identification of genetic lesions with potential clinical relevance. Consistently, precision medicine plays a pivotal role in the treatment algorithm of CLL, since the integration of molecular biomarkers with the clinical features of the disease may guide treatment choices. Most CLL patients present at the time of diagnosis with an early stage disease and are managed with a watch and wait strategy. For CLL patients requiring therapy, the CLL treatment armamentarium includes both chemoimmunotherapy strategies and biological drugs. The efficacy of these treatment strategies relies upon specific molecular features of the disease. TP53 disruption (including both TP53 mutation and 17p deletion) is the strongest predictor of chemo-refractoriness, and the assessment of TP53 status is the first and most important decisional node in the first line treatment algorithm. The presence of TP53 disruption mandates treatment with biological drugs that inhibit the B cell receptor or, alternatively, the B-cell lymphoma 2 (BCL2) pathway and can, at least in part, circumvent the chemorefractoriness of TP53-disrupted patients. Beside TP53 disruption, the mutational status of immunoglobulin heavy variable (IGHV) genes also helps clinicians to improve treatment tailoring. In fact, patients carrying mutated IGHV genes in the absence of TP53 disruption experience a long-lasting and durable response to chemoimmunotherapy after fludarabine, cyclophosphamide, and rituximab (FCR) treatment with a survival superimposable to that of a matched general population. In contrast, patients with unmutated IGHV genes respond poorly to chemoimmunotherapy and deserve treatment with B cell receptor inhibitors. Minimal residual disease is also emerging as a relevant biomarker with potential clinical implications. Overall, precision medicine is now a mainstay in the management and treatment stratification of CLL. The identification of novel predictive biomarkers will allow further improvements in the treatment tailoring of this leukemia.
Molecular Heterogeneity and Cellular Diversity: Implications for Precision Treatment in Medulloblastoma
Authors: Zou Han , Poore Brad , Broniscer Alberto , Pollack Ian F. , Hu Baoli
Published: March 2020

Medulloblastoma, the most common pediatric malignant brain tumor, continues to have a high rate of morbidity and mortality in childhood. Recent advances in cancer genomics, single-cell sequencing, and sophisticated tumor models have revolutionized the characterization and stratification of medulloblastoma. In this review, we discuss heterogeneity associated with four major subgroups of medulloblastoma (WNT, SHH, Group 3, and Group 4) on the molecular and cellular levels, including histological features, genetic and epigenetic alterations, proteomic landscape, cell-of-origin, tumor microenvironment, and therapeutic approaches. The intratumoral molecular heterogeneity and intertumoral cellular diversity clearly underlie the divergent biology and clinical behavior of these lesions and highlight the future role of precision treatment in this devastating brain tumor in children.
High Specificity of BCL11B and GLG1 for EWSR1-FLI1 and EWSR1-ERG Positive Ewing Sarcoma
Authors: Orth Martin F. , Hölting Tilman L.B. , Dallmayer Marlene , Wehweck Fabienne S. , Paul Tanja , Musa Julian , Baldauf Michaela C. , Surdez Didier , Delattre Olivier , Knott Maximilian M. L. , Romero-Pérez Laura , Kasan Merve , Cidre-Aranaz Florencia , Gerke Julia S. , Ohmura Shunya , Li Jing , Marchetto Aruna , Henssen Anton G. , Özen Özlem , Sugita Shintaro , Hasegawa Tadashi , Kanaseki Takayuki , Bertram Stefanie , Dirksen Uta , Hartmann Wolfgang , Kirchner Thomas , Grünewald Thomas G.P.
Published: March 2020

Ewing sarcoma (EwS) is an aggressive cancer displaying an undifferentiated small-round-cell histomorphology that can be easily confused with a broad spectrum of differential diagnoses. Using comparative transcriptomics and immunohistochemistry (IHC), we previously identified BCL11B and GLG1 as potential specific auxiliary IHC markers for EWSR1-FLI1-positive EwS. Herein, we aimed at validating the specificity of both markers in a far larger and independent cohort of EwS (including EWSR1-ERG-positive cases) and differential diagnoses. Furthermore, we evaluated their intra-tumoral expression heterogeneity. Thus, we stained tissue microarrays from 133 molecularly confirmed EwS cases and 320 samples from morphological mimics, as well as a series of patient-derived xenograft (PDX) models for BCL11B, GLG1, and CD99, and systematically assessed the immunoreactivity and optimal cut-offs for each marker. These analyses demonstrated that high BCL11B and/or GLG1 immunoreactivity in CD99-positive cases had a specificity of 97.5% and an accuracy of 87.4% for diagnosing EwS solely by IHC, and that the markers were expressed by EWSR1-ERG-positive EwS. Only little intra-tumoral heterogeneity in immunoreactivity was observed for differential diagnoses. These results indicate that BCL11B and GLG1 may help as specific auxiliary IHC markers in diagnosing EwS in conjunction with CD99, especially if confirmatory molecular diagnostics are not available.
Hippo/YAP Signaling Pathway: A Promising Therapeutic Target in Bone Paediatric Cancers?
Authors: Morice Sarah , Danieau Geoffroy , Rédini Françoise , Brounais-Le-Royer Bénédicte , Verrecchia Franck
Published: March 2020

Osteosarcoma and Ewing sarcoma are the most prevalent bone pediatric tumors. Despite intensive basic and medical research studies to discover new therapeutics and to improve current treatments, almost 40% of osteosarcoma and Ewing sarcoma patients succumb to the disease. Patients with poor prognosis are related to either the presence of metastases at diagnosis or resistance to chemotherapy. Over the past ten years, considerable interest for the Hippo/YAP signaling pathway has taken place within the cancer research community. This signaling pathway operates at different steps of tumor progression: Primary tumor growth, angiogenesis, epithelial to mesenchymal transition, and metastatic dissemination. This review discusses the current knowledge about the involvement of the Hippo signaling pathway in cancer and specifically in paediatric bone sarcoma progression.
Latest Insights into Marek’s Disease Virus Pathogenesis and Tumorigenesis
Authors: Bertzbach Luca , Conradie Andelé , You Yu , Kaufer Benedikt
Published: March 2020

Marek’s disease virus (MDV) infects chickens and causes one of the most frequent cancers in animals. Over 100 years of research on this oncogenic alphaherpesvirus has led to a profound understanding of virus-induced tumor development. Live-attenuated vaccines against MDV were the first that prevented cancer and minimized the losses in the poultry industry. Even though the current gold standard vaccine efficiently protects against clinical disease, the virus continuously evolves towards higher virulence. Emerging field strains were able to overcome the protection provided by the previous two vaccine generations. Research over the last few years revealed important insights into the virus life cycle, cellular tropism, and tumor development that are summarized in this review. In addition, we discuss recent data on the MDV transcriptome, the constant evolution of this highly oncogenic virus towards higher virulence, and future perspectives in MDV research.
Mechanistic and Functional Shades of Mucins and Associated Glycans in Colon Cancer
Authors: Pothuraju Ramesh , Krishn Shiv Ram , Gautam Shailendra K. , Pai Priya , Ganguly Koelina , Chaudhary Sanjib , Rachagani Satyanarayana , Kaur Sukhwinder , Batra Surinder K.
Published: March 2020

Mucus serves as the chief protective barrier against pathogenic and mechanical insults in respiratory, gastrointestinal, and urogenital tracts. Altered mucin expression, the major component of mucus, in conjunction with differential glycosylation has been strongly associated with both benign and malignant pathologies of colon. Mucins and their associated glycans arbitrate their impact sterically as well as mechanically by altering molecular and microbial spectrum during pathogenesis. Mucin expression in normal and pathological conditions is regulated by nonspecific (dietary factors and gut microbiota) and specific (epigenetic and transcriptional) modulators. Further, recent studies highlight the impact of altering mucin glycome (cancer-associated carbohydrate antigens including Tn, Sialyl-Tn, Sialyl-Lew A, and Sialyl-Lewis X) on host immunomodulation, antitumor immunity, as well as gut microbiota. In light of emerging literature, the present review article digs into the impact of structural organization and of expressional and glycosylation alteration of mucin family members on benign and malignant pathologies of colorectal cancer.
Mitochondrial Respiration Correlates with Prognostic Markers in Chronic Lymphocytic Leukemia and Is Normalized by Ibrutinib Treatment
Authors: Roy Chowdhury Subir , Bouchard Eric D. J. , Saleh Ryan , Nugent Zoann , Peltier Cheryl , Mejia Edgard , Hou Sen , McFall Carly , Squires Mandy , Hewitt Donna , Davidson Linda , Shen Garry X. , Johnston James B. , Doucette Christine , Hatch Grant M. , Fernyhough Paul , Marshall Aaron , Gibson Spencer B. , Dawe David E. , Banerji Versha
Published: March 2020

Mitochondrial bioenergetics profiling, a measure of oxygen consumption rates, correlates with prognostic markers and can be used to assess response to therapy in chronic lymphocytic leukemia (CLL) cells. In this study, we measured mitochondrial respiration rates in primary CLL cells using respirometry to evaluate mitochondrial function. We found significant increases in mitochondrial respiration rates in CLL versus control B lymphocytes. We also observed amongst CLL patients that advanced age, female sex, zeta-chain-associated protein of 70 kD (ZAP-70+), cluster of differentiation 38 (CD38+), and elevated β2-microglobulin (β2-M) predicted increased maximal respiration rates. ZAP-70+ CLL cells exhibited significantly higher bioenergetics than B lymphocytes or ZAP-70− CLL cells and were more sensitive to the uncoupler, carbonyl cyanide-p-trifluoro-methoxyphenylhydrazone (FCCP). Univariable and multivariable linear regression analysis demonstrated that ZAP-70+ predicted increased maximal respiration. ZAP-70+ is a surrogate for B cell receptor (BCR) activation and can be targeted by ibrutinib, which is a clinically approved Bruton’s tyrosine kinase (BTK) inhibitor. Therefore, we evaluated the oxygen consumption rates (OCR) of CLL cells and plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4) levels from ibrutinib-treated patients and demonstrated decreased OCR similar to control B lymphocytes, suggesting that ibrutinib treatment resets the mitochondrial bioenergetics, while diminished CCL3/CCL4 levels indicate the down regulation of the BCR signaling pathway in CLL. Our data support evaluation of mitochondrial respiration as a preclinical tool for the response assessment of CLL cells.
Molecular-Clinical Correlation in Pediatric Medulloblastoma: A Cohort Series Study of 52 Cases in Taiwan
Authors: Wu Kuo-Sheng , Ho Donald Ming-Tak , Jou Shiann-Tarng , Yu Alice L. , Tran Huy Minh , Liang Muh-Lii , Chen Hsin-Hung , Lee Yi-Yen , Chen Yi-Wei , Lin Shih-Chieh , Chang Feng-Chi , Tsai Min-Lan , Liu Yen-Lin , Lee Hsin-Lun , Hsieh Kevin Li-Chun , Huang Wen-Chang , Sung Shian-Ying , Chang Che-Chang , Changou Chun Austin , Liang Kung-Hao , Hsieh Tsung-Han , Liu Yun-Ru , Chao Meng-En , Chen Wan , Chu Shing-Shung , Cho Er-Chieh , Wong Tai-Tong
Published: March 2020

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). In this study, we aimed to identify a molecular-clinical correlation and somatic mutation for exploring risk-adapted treatment, drug targets, and potential genetic predisposition. In total, 52 frozen tumor tissues of childhood MBs were collected. RNA sequencing (RNA-Seq) and DNA methylation array data were generated. Molecular subgrouping and clinical correlation analysis were performed. An adjusted Heidelberg risk stratification scheme was defined for updated clinical risk stratification. We selected 51 genes for somatic variant calling using RNA-Seq data. Relevant clinical findings were defined. Potential drug targets and genetic predispositions were explored. Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Genetic backgrounds of metastasis at diagnosis and extent of tumor resection were observed. The adjusted Heidelberg scheme showed its applicability. Potential drug targets were detected in the pathways of DNA damage response. Among the 10 patients with SHH MBs analyzed using whole exome sequencing studies, five patients exhibited potential genetic predispositions and four patients had relevant germline mutations. The findings of this study provide valuable information for updated risk adapted treatment and personalized care of childhood MBs in our cohort series and in Taiwan.
MK2 Inhibition Induces p53-Dependent Senescence in Glioblastoma Cells
Authors: Phoa Athena F. , Recasens Ariadna , Gurgis Fadi M. S. , Betts Tara A. , Menezes Sharleen V. , Chau Diep , Nordfors Kristiina , Haapasalo Joonas , Haapasalo Hannu , Johns Terrance G. , Stringer Brett W. , Day Bryan W. , Buckland Michael E. , Lalaoui Najoua , Munoz Lenka
Published: March 2020

MAPK-activated protein kinase 2 (MK2) has diverse roles in cancer. In response to chemotherapy, MK2 inhibition is synthetically lethal to p53-deficiency. While TP53 deletion is rare in glioblastomas, these tumors often carry TP53 mutations. Here, we show that MK2 inhibition strongly attenuated glioblastoma cell proliferation through p53wt stabilization and senescence. The senescence-inducing efficacy of MK2 inhibition was particularly strong when cells were co-treated with the standard-of-care temozolomide. However, MK2 inhibition also increased the stability of p53 mutants and enhanced the proliferation of p53-mutant stem cells. These observations reveal that in response to DNA damaging chemotherapy, targeting MK2 in p53-mutated cells produces a phenotype that is distinct from the p53-deficient phenotype. Thus, MK2 represents a novel drug target in 70% glioblastomas harboring intact TP53 gene. However, targeting MK2 in tumors with TP53 mutations may accelerate disease progression. These findings are highly relevant since TP53 mutations occur in over 50% of all cancers.
Modelling Curved Contact Flexible Microstrip Applicators for Patient-Specific Superficial Hyperthermia Treatment Planning
Authors: Kok H. Petra , Groen Jort , Bakker Akke , Crezee Johannes
Published: March 2020

This paper describes a method to reconstruct bendable superficial hyperthermia applicators for routine clinical patient-specific treatment planning. The reconstruction uses a CT scan with a flexible silicone dummy applicator positioned on the patient. The curvature was approximated by two second-degree polynomial functions. A realistic treatment series was mimicked using a standard Alderson radiation therapy phantom and a treatment planning model was reconstructed from a CT scan. The variation among treatment curvatures was compared to the modelled curvature. The mathematical approximation of the applicator curvature was validated for this phantom experiment, as well as for clinical treatments. The average maximum variation among the successive mimicked sessions was 3.67 ± 0.69 mm (range 2.98–4.60 mm). The maximum deviation between the treatment curvature and the modelled curvature was 4.35 mm. Comparing the treatment and approximated curvature yielded a maximum deviation between 2.98 mm and 4.12 mm. For clinical treatments the maximum deviation of the treatment and approximated curvature varied between 0.48 mm and 1.98 mm. These results allow adequate reconstruction of bendable hyperthermia applicators for treatment planning, which can further improve treatment quality, for example by optimizing the water bolus temperature for patient-specific tumor depths. Predictive parameters for hyperthermia treatment outcome can easily be evaluated and compared for various input parameters.
Aurora Kinase A-YBX1 Synergy Fuels Aggressive Oncogenic Phenotypes and Chemoresistance in Castration-Resistant Prostate Cancer
Authors: Nikhil Kumar , Raza Asif , Haymour Hanan S. , Flueckiger Benjamin V. , Chu Jiachong , Shah Kavita
Published: March 2020

Multifunctional protein YBX1 upregulation promotes castration-resistant prostate cancer (CRPC). However, YBX1 protein abundance, but not its DNA status or mRNA levels, predicts CRPC recurrence, although the mechanism remains unknown. Similarly, the mechanism by which YBX1 regulates androgen receptor (AR) signaling remains unclear. We uncovered the first molecular mechanism of YBX1 upregulation at a post-translational level. YBX1 was identified as an Aurora Kinase-A (AURKA) substrate using a chemical screen. AURKA phosphorylates YBX1 at two key residues, which stabilizes it and promotes its nuclear translocation. YBX1 reciprocates and stabilizes AURKA, thereby initiating a synergistic loop. Notably, phospho-resistant YBX1 is dominant-negative and fully inhibits epithelial to mesenchymal transition, chemoresistance, drug-resistance and tumorigenesis in vivo. Unexpectedly, we further observed that YBX1 upregulates AR post-translationally by preventing its ubiquitylation, but not by increasing its transcription as reported before. Uncovering YBX1-mediated AR stabilization is highly significant due to AR’s critical role in both androgen-sensitive prostate cancer and CRPC. As YBX1 inhibitors are unknown, AURKA inhibitors provide a potent tool to degrade both YBX1 and AR simultaneously. Finally, this is the first study to show a reciprocal loop between YBX1 and its kinase, indicating that their concomitant inhibition will be act synergistically for CRPC therapy.
Recent Developments in Synthesis and Photocatalytic Applications of Carbon Dots
Authors: Sakdaronnarong Chularat , Sangjan Amornrat , Boonsith Suthida , Kim Dong Chung , Shin Hyeon Suk
Published: March 2020

The tunable photoluminescent and photocatalytic properties of carbon dots (CDs) via chemical surface modification have drawn increased attention to this emerging class of carbon nanomaterials. Herein, we summarize the advances in CD synthesis and modification, with a focus on surface functionalization, element doping, passivation, and nanocomposite formation with metal oxides, transition metal chalcogenides, or graphitic carbon nitrides. The effects of CD size and functionalization on photocatalytic properties are discussed, along with the photocatalytic applications of CDs in energy conversion, water splitting, hydrogen evolution, water treatment, and chemical degradation. In particular, the enzyme-mimetic and photodynamic applications of CDs for bio-related uses are thoroughly reviewed.
Conducting Polymer Mediated Electrical Stimulation Induces Multilineage Differentiation with Robust Neuronal Fate Determination of Human Induced Pluripotent Stem Cells
Authors: Tomaskovic-Crook Eva , Gu Qi , Rahim Siti N Abdul , Wallace Gordon G , Crook Jeremy M
Published: March 2020

Electrical stimulation is increasingly being used to modulate human cell behaviour for biotechnological research and therapeutics. Electrically conductive polymers (CPs) such as polypyrrole (PPy) are amenable to in vitro and in vivo cell stimulation, being easy to synthesise with different counter ions (dopants) to augment biocompatibility and cell-effects. Extending our earlier work, which showed that CP-mediated electrical stimulation promotes human neural stem cell differentiation, here we report using electroactive PPy containing the anionic dopant dodecylbenzenesulfonate (DBS) to modulate the fate determination of human induced pluripotent stem cells (iPSCs). Remarkably, the stimulation without conventional chemical inducers resulted in the iPSCs differentiating to cells of the three germ lineages—endoderm, ectoderm, and mesoderm. The unstimulated iPSC controls remained undifferentiated. Phenotypic characterisation further showed a robust induction to neuronal fate with electrical stimulation, again without customary chemical inducers. Our findings add to the growing body of evidence supporting the use of electrical stimulation to augment stem cell differentiation, more specifically, pluripotent stem cell differentiation, and especially neuronal induction. Moreover, we have shown the versatility of electroactive PPy as a cell-compatible platform for advanced stem cell research and translation, including identifying novel mechanisms of fate regulation, tissue development, electroceuticals, and regenerative medicine.
“Circulating Tumor Cells: Finding Rare Events for a Huge Knowledge of Cancer Dissemination”
Authors: Alix-Panabières Catherine
Published: March 2020

Circulating tumor cells (CTCs) as real-time liquid biopsy [...]
Diversity of RNA-Binding Proteins Modulating Post-Transcriptional Regulation of Protein Expression in the Maturing Mammalian Oocyte
Authors: Christou-Kent Marie , Dhellemmes Magali , Lambert Emeline , Ray Pierre F. , Arnoult Christophe
Published: March 2020

The oocyte faces a particular challenge in terms of gene regulation. When oocytes resume meiosis at the end of the growth phase and prior to ovulation, the condensed chromatin state prevents the transcription of genes as they are required. Transcription is effectively silenced from the late germinal vesicle (GV) stage until embryonic genome activation (EGA) following fertilisation. Therefore, during its growth, the oocyte must produce the mRNA transcripts needed to fulfil its protein requirements during the active period of meiotic completion, fertilisation, and the maternal-to zygote-transition (MZT). After meiotic resumption, gene expression control can be said to be transferred from the nucleus to the cytoplasm, from transcriptional regulation to translational regulation. Maternal RNA-binding proteins (RBPs) are the mediators of translational regulation and their role in oocyte maturation and early embryo development is vital. Understanding these mechanisms will provide invaluable insight into the oocyte’s requirements for developmental competence, with important implications for the diagnosis and treatment of certain types of infertility. Here, we give an overview of post-transcriptional regulation in the oocyte, emphasising the current knowledge of mammalian RBP mechanisms, and develop the roles of these mechanisms in the timely activation and elimination of maternal transcripts.