bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling Streamflow Enhanced by Precipitation from Atmospheric River Using the NOAA National Water Model: A Case Study of the Russian River Basin for February 2004
Authors: Han Heechan , Kim Jungho , Chandrasekar V. , Choi Jeongho , Lim Sanghun
Published: August 2019

This study aims to address hydrological processes and impacts of an atmospheric river (AR) event that occurred during 15–18 February 2004 in the Russian River basin in California. The National Water Model (NWM), a fully distributed hydrologic model, was used to evaluate the hydrological processes including soil moisture flux, overland flow, and streamflow. Observed streamflow and volumetric soil water content data were used to evaluate the performance of the NWM using various error metrics. The simulation results showed that this AR event (15–18 February 2004) with a long duration of precipitation could cause not only deep soil saturation, but also high direct runoff depth. Taken together, the analysis revealed the complex interaction between precipitation and land surface response to the AR event. The results emphasize the significance of a change of water contents in various soil layers and suggest that soil water content monitoring could aid in improving flood forecasting accuracy caused by the extreme events such as the AR.
Expanding the Theory of Planned Behaviour to Reveal Urban Residents’ Pro-Environment Travel Behaviour
Authors: Chen Weiya , Cao Chao , Fang Xiaoping , Kang Zixuan
Published: August 2019

Exploring the mechanism that influences the choice of urban public travel mode is an important policy research topic that can promote urban residents’ pro-environment travel (PET) behaviour and relieve the pressure on urban traffic and environmental problems. By expanding the theory of planned behaviour by considering the effects of the quality of public transport service and individual behaviour, this paper establishes a mixed PET behaviour model. Grounded theory is used to analyse data obtained from in-depth interviews, with the aim of determining the relationships among different attributes of the quality of public transport service and PET. An empirical examination in the form of a questionnaire was conducted in Changsha, China, to obtain the intensity and mechanism of various factors influencing pro-environment behaviour decision-making. The results reveal three new pieces of information. First, the influence of many psychological variables (except subjective norms) is consistent with the prediction results of the theory of planned behaviour (TPB), and the predictions of the model are accurate. More specifically, intention (0.535) and habit (0.354) are key factors in PET behaviour, while attitude (0.527) has the most significant effect on intention towards PET behaviour. Second, the perceived service quality of public transport has a direct and significant impact on intention towards PET behaviour. Satisfaction with public transport service quality exerts a mediating effect on perceived service quality and PET behaviour. More specifically, operation and management (0.808) and vehicle environment (0.809) have the most important influence on intention towards PET behaviour. Last but not least, the extent of the influence of PET behaviour varies based on travellers’ demographic characteristics. The driving age, income and ownership of private cars show the greatest impact. The perceived service quality of public transport and travellers’ social and economic characteristics all play roles in the psychology of travel decisions, and are associated with PET behaviour on several distinct levels. From the perspectives of passenger psychology, public transport service quality and personal attributes of passengers, this paper provides a scientific basis for decision-making in transportation systems and the formulation of traffic intervention strategies to promote voluntary public reductions in carbon-intensive travel behaviour.
The Collective Contribution of Atmospheric and Oceanic Components to ENSO Asymmetry
Authors: Tang Yanli , Li Lijuan , Wang Bin , Lin Pengfei , Dong Wenjie , Xia Kun
Published: August 2019

Four cross-coupled models were used to investigate the relative contributions of atmospheric and oceanic components to the asymmetry of the El Niño–Southern Oscillation (ENSO). Strong El Niño and La Niña events related to the negative heat flux feedbacks were found to be determined mainly by the atmospheric component, and the stronger sea surface temperature (SST) anomalies in the warm phase did not lead to an increased SST asymmetry. The skewness of the four models could be affected by both atmospheric and oceanic components; the atmospheric component determines the strength of positive and negative SST anomalies, and the oceanic component affects the strength of the negative SST anomalies in the cold phase under the same atmospheric component group. The Bjerknes stability index (BJ index) of warm and cold phases contributed to the El Niño–La Niña SSTA asymmetries in observation, but the BJ index did not necessarily explain the El Niño–La Niña SSTA asymmetries in climate model simulations. The SST asymmetries in these four models were closely associated with convective precipitation and wind stress asymmetries, which are also determined by both the atmospheric and oceanic components.
Multifactorial Modeling Reveals a Dominant Role of Wnt Signaling in Lineage Commitment of Human Pluripotent Stem Cells
Authors: Dias Tiago P. , Fernandes Tiago G. , Diogo Maria Margarida , Cabral Joaquim M. S.
Published: August 2019

The human primed pluripotent state is maintained by a complex balance of several signaling pathways governing pluripotency maintenance and commitment. Here, we explore a multiparameter approach using a full factorial design and a simple well-defined culture system to assess individual and synergistic contributions of Wnt, FGF and TGFβ signaling to pluripotency and lineage specification of human induced pluripotent stem cells (hiPSC). Hierarchical clustering and quadratic models highlighted a dominant effect of Wnt signaling over FGF and TGFβ signaling, drawing hiPSCs towards mesendoderm lineages. In addition, a synergistic effect between Wnt signaling and FGF was observed to have a negative contribution to pluripotency maintenance and a positive contribution to ectoderm and mesoderm commitment. Furthermore, FGF and TGFβ signaling only contributed significantly for negative ectoderm scores, suggesting that the effect of both factors for pluripotency maintenance resides in a balance of inhibitory signals instead of proactive stimulation of hiPSC pluripotency. Overall, our dry-signaling multiparameter modeling approach can contribute to elucidate individual and synergistic inputs, providing an additional degree of comprehension of the complex regulatory mechanisms of human pluripotency and commitment.
Neutrophil Extracellular Trap Formation: Physiology, Pathology, and Pharmacology
Authors: Ravindran Mithunan , Khan Meraj A. , Palaniyar Nades
Published: August 2019

Neutrophil extracellular traps (NETs), a unique DNA framework decorated with antimicrobial peptides, have been in the scientific limelight for their role in a variety of pathologies ranging from cystic fibrosis to cancer. The formation of NETs, as well as relevant regulatory mechanisms, physiological factors, and pharmacological agents have not been systematically discussed in the context of their beneficial and pathological aspects. Novel forms of NET formation including vital NET formation continue to be uncovered, however, there remain fundamental questions around established mechanisms such as NADPH-oxidase (Nox)-dependent and Nox-independent NET formation. Whether NET formation takes place in the tissue versus the bloodstream, internal factors (e.g. reactive oxygen species (ROS) production and transcription factor activation), and external factors (e.g. alkaline pH and hypertonic conditions), have all been demonstrated to influence specific NET pathways. Elements of neutrophil biology such as transcription and mitochondria, which were previously of unknown significance, have been identified as critical mediators of NET formation through facilitating chromatin decondensation and generating ROS, respectively. While promising therapeutics inhibiting ROS, transcription, and gasdermin D are being investigated, neutrophil phagocytosis plays a critical role in host defense and any therapies targeting NET formation must avoid impairing the physiological functions of these cells. This review summarizes what is known in the many domains of NET research, highlights the most relevant challenges in the field, and inspires new questions that can bring us closer to a unified model of NET formation.
Ziziphora taurica subsp. taurica: Analytical Characterization and Biological Activities
Authors: Tomczyk Michał , Ceylan Olcay , Locatelli Marcello , Tartaglia Angela , Ferrone Vincenzo , Sarikurkcu Cengiz
Published: August 2019

The Lamiaceae family comprises many flowering plants classified into about 236 genera. The genus Ziziphora is one of the well-known genera of this family and its species are important in different fields of pharmaceutical, chemical, traditional, and folk medicines. The phytochemicals present in Ziziphora include monoterpenic essential oils, triterpenes, and phenolic substances. The aim of this paper was to study the phytochemical profile of Ziziphora taurica subsp. taurica and compare and evaluate the biological activities of its ethyl acetate (ZTT-EtOAc), methanolic (ZTT-MeOH), and aqueous (ZTT-W) extracts based on their enzyme inhibition and antioxidant capacities. Determination of total phenolic (TPC) and total flavonoid (TFC) contents as well as biological activities were determined using spectrophotometric procedures. Subsequently, the individual phenolic compounds were detected by liquid chromatography–electrospray ionization–tandem mass spectrometry (LC–ESI–MS/MS). In total, twenty-two different phenolic compounds were identified, including apigenin, ferulic acid, and luteolin which were the most common. ZTT-MeOH extract showed the best antioxidant activity, whereas ZTT-EtOAc extract was the most effective against tyrosinase and α-amylase. Ziziphora taurica subsp. taurica represents a potential source of natural compounds with positive effects on human health.
Post-Translational Modifications in NETosis and NETs-Mediated Diseases
Authors: Hamam Hussein J. , Palaniyar Nades
Published: August 2019

Neutrophils undergo a unique form of cell death that generates neutrophil extracellular traps (NETs) that may help to neutralize invading pathogens and restore homeostasis. However, uncontrolled NET formation (NETosis) can result in numerous diseases that adversely affect health. Recent studies further elucidate the mechanistic details of the different forms of NETosis and their common end structure, as NETs were constantly found to contain DNA, modified histones and cytotoxic enzymes. In fact, emerging evidence reveal that the post translational modifications (PTMs) of histones in neutrophils have a critical role in regulating neutrophil death. Histone citrullination is shown to promote a rapid form of NET formation independent of NADPH oxidase (NOX), which relies on calcium influx. Interestingly, few studies suggest an association between histone citrullination and other types of PTMs to control cell survival and death, such as histone methylation. Even more exciting is the finding that histone acetylation has a biphasic effect upon NETosis, where histone deacetylase (HDAC) inhibitors promote baseline, NOX-dependent and -independent NETosis. However, increasing levels of histone acetylation suppresses NETosis, and to switch neutrophil death to apoptosis. Interestingly, in the presence of NETosis-promoting stimuli, high levels of HDACis limit both NETosis and apoptosis, and promote neutrophil survival. Recent studies also reveal the importance of the PTMs of neutrophils in influencing numerous pathologies. Histone modifications in NETs can act as a double-edged sword, as they are capable of altering multiple types of neutrophil death, and influencing numerous NET-mediated diseases, such as acute lung injury (ALI), thrombosis, sepsis, systemic lupus erythematosus, and cancer progression. A clear understanding of the role of different PTMs in neutrophils would be important for an understanding of the molecular mechanisms of NETosis, and to appropriately treat NETs-mediated diseases.
Structural Changes in the Acceptor Site of Photosystem II upon Ca2+/Sr2+ Exchange in the Mn4CaO5 Cluster Site and the Possible Long-Range Interactions
Authors: Koua Faisal Hammad Mekky
Published: August 2019

The Mn4CaO5 cluster site in the oxygen-evolving complex (OEC) of photosystem II (PSII) undergoes structural perturbations, such as those induced by Ca2+/Sr2+ exchanges or Ca/Mn removal. These changes have been known to induce long-range positive shifts (between +30 and +150 mV) in the redox potential of the primary quinone electron acceptor plastoquinone A (QA), which is located 40 Å from the OEC. To further investigate these effects, we reanalyzed the crystal structure of Sr-PSII resolved at 2.1 Å and compared it with the native Ca-PSII resolved at 1.9 Å. Here, we focus on the acceptor site and report the possible long-range interactions between the donor, Mn4Ca(Sr)O5 cluster, and acceptor sites.
Gold Nanoparticle Size-Dependent Enhanced Chemiluminescence for Ultra-Sensitive Haptoglobin Biomarker Detection
Authors: Nirala Narsingh R. , Shtenberg Giorgi
Published: August 2019

Bovine mastitis (BM) is a frequent disease in the dairy industry that causes staggering economical losses due to decreased milk production and increased health care costs. Traditionally, BM detection depends on the efficacy and reliability of analytical techniques that measure somatic cell counts (SCC), detect pathogens, and reveal inflammatory status. Herein, we demonstrate the detection of bovine haptoglobin, a well-documented acute phase protein for evaluating BM clinical status, by utilizing hemoglobin-binding capacity within luminol chemiluminescence (CL) system. The resulting haptoglobin–hemoglobin complex reduces the CL signal proportionally to inherent haptoglobin concentrations. Different sizes of cross-linked gold nanoparticles (GNPs) were examined for enhanced CL (eCL) signal amplification, presenting over 30-fold emitted radiation enhancement for optimized size within real milk samples with respect to nanoparticle-free assay. The eCL values were proportionally related to nanoparticle size and content, influenced by SCC and pathogen type (e.g., Escherichia coli and coagulase-negative staphylococci). The optimized bioassay showed a broad linear response (1 pg mL−1–10 µg mL−1) and minute detection limit of 0.19 pg mL−1, while presenting quantitative performance in agreement with commercial ELISA kit. Finally, the resulting optimized eCL concept offers an efficient label-free detection of haptoglobin biomarker, offering means to diagnose the severity of the associated diseases.
Human FcRn Tissue Expression Profile and Half-Life in PBMCs
Authors: Fan Yao-Yun , Farrokhi Vahid , Caiazzo Teresa , Wang Mengmeng , O’Hara Denise M. , Neubert Hendrik
Published: August 2019

System-wide quantitative characterization of human neonatal Fc receptor (FcRn) properties is critical for understanding and predicting human PK (pharmacokinetics) as well as the distribution of mAbs and Fc-fusion proteins using PBPK (physiologically-based pharmacokinetic) modeling. To this end, tissue-specific FcRn expression and half-life are important model inputs. Herein, human FcRn tissue expression was measured by peptide immunoaffinity chromatography coupled with high-resolution mass spectrometry. FcRn concentrations across 14 human tissues ranged from low to 230 pmol per gram of tissue. Furthermore, the FcRn half-life was determined to be 11.1 h from a human stable isotope labelled leucine pulse labeling experiment. The spatial and temporal quantitative human FcRn data now promise to enable a refined PBPK model with improved accuracy of human PK predictions for Fc-containing biotherapeutics.
Gold Nanostar Colorimetric Detection of Fructosyl Valine as a Potential Future Point of Care Biosensor Candidate for Glycated Haemoglobin Detection
Authors: Mulder Danielle Wingrove , Phiri Masauso Moses , Vorster Barend Christiaan
Published: August 2019

Diabetes Mellitus is a growing global concern. The current methods used to detect glycated haemoglobin are precise, however, utilise expensive equipment, reagents and consumables. These are luxuries which rural communities cannot access. The nanotechnology methods which have been developed for glycated haemoglobin detection are predominantly electrochemically based, have complicated lengthy fabrication processes and utilise toxic chemicals. Here a fructosyl amino acid oxidase gold nanostar biosensor has been developed as a potential future point of care biosensor candidate for glycated haemoglobin detection. The workup done on this biosensor showed that it was able to give a spectrophotometric readout and colorimetric result with naked eye detection in blank serum spiked with fructosyl valine.
Shifting Gear in the Study of the Bilingual Advantage: Language Switching Examined as a Possible Moderator
Authors: Woumans Evy , Van Herck Shauni , Struys Esli
Published: August 2019

The bilingual advantage is a heavily debated topic in research on bilingualism. The current study further investigated one specific aspect of bilingualism proposed to be a determining factor for the bilingual advantage, namely language switching behaviour. We investigated whether a bilingual advantage can be detected in the executive functions of inhibition and shifting by comparing monolingual and bilingual participants on a Simon task and a colour–shape switching task. Furthermore, we examined the relation between these executive functions and language switching proficiency, as measured by a semantic verbal fluency task. In addition, the current study set out to investigate the convergence of self-reported language switching estimates and actual language switching proficiency. Results revealed a bilingual advantage for shifting, but not for inhibition. However, this bilingual advantage for shifting was not related to language switching behaviour. Additionally, we were unable to identify a relation between objective and subjective measures of switching abilities. These findings seem to confirm the existence of a bilingual advantage, but also once again validate its elusiveness, as demonstrated by the absence of bilingual benefits on our measure of inhibition. It furthermore questions the validity of switching measures employed in previous studies.
Mindfulness Meditation and Fantasy Relaxation in a Group Setting Leads to a Diminished Sense of Self and an Increased Present Orientation
Authors: Kohls Niko , Esch Tobias , Gerber Lea , Adrian Lucas , Wittmann Marc
Published: August 2019

(1) Background: Mind-body interventions (MBI), such as meditation or other relaxation techniques, have become the focus of attention in the clinical and health sciences. Differences in the effects of induction techniques are being increasingly investigated. (2) Methods: Here, we compared changes in the individual experience of time, space, and self in 44 students in an integrative health-promotion program. They participated in a study employing mindfulness meditation and a relaxation intervention with one week between sessions, thus employing a within-subjects design. (3) Results: No significant differences were detected when subjective reports were compared directly after each intervention. However, we found significant sequence effects between t1 and t2, independent of the meditation type. The sense of self diminished, the present orientation increased, and the past and future orientations decreased in both interventions. (4) Conclusions: We propose using scales to assess subjective time, self, and space as basic constituents of experience to measure the specificity of intervention methods, as well as longitudinal changes.
An EEG Study on Emotional Intelligence and Advertising Message Effectiveness
Authors: Ciorciari Joseph , Pfeifer Jeffrey , Gountas John
Published: August 2019

Some electroencephalography (EEG) studies have investigated emotional intelligence (EI), but none have examined the relationships between EI and commercial advertising messages and related consumer behaviors. This study combines brain (EEG) techniques with an EI psychometric to explore the brain responses associated with a range of advertisements. A group of 45 participants (23 females, 22 males) had their EEG recorded while watching a series of advertisements selected from various marketing categories such as community interests, celebrities, food/drink, and social issues. Participants were also categorized as high or low in emotional intelligence (n = 34). The EEG data analysis was centered on rating decision-making in order to measure brain responses associated with advertising information processing for both groups. The findings suggest that participants with high and low emotional intelligence (EI) were attentive to different types of advertising messages. The two EI groups demonstrated preferences for “people” or “object,” related advertising information. This suggests that differences in consumer perception and emotions may suggest why certain advertising material or marketing strategies are effective or not.
A Solar Thermal Application for Mongolian Detached Houses: An Energy, Environmental, and Economic Analysis Based on Dynamic Simulations
Authors: Rosato Antonio , Erdenedavaa Purevdalai , Ciervo Antonio , Akisawa Atsushi , Adiyabat Amarbayar , Sibilio Sergio
Published: August 2019

Ulaanbaatar (Mongolia) is the coldest capital city in the world with approximately 98% of its heating demand satisfied by means of coal-burning stoves. This leads to enormous air pollutant emissions, with Ulaanbaatar being one of the top five most polluted cities in the world. In this study, an innovative solar hybrid heating system for the Mongolian scenario was used, which was based on the operation of a solar field composed of four series-connected evacuated tube heat pipe collectors, coupled with a thermal energy storage. The solar hybrid heating system was simulated and analyzed using the software TRNSYS. The simulations were designed to satisfy the heating demand of a typical single-family detached house located in Ulaanbaatar and were carried out with and without considering the soiling effects on the solar system operation. The overall performance of the proposed plant was compared with those associated with different fossil fuel-based Mongolian conventional heating systems, in order to assess the potential energy, environmental and economic benefits. The results highlighted that the proposed plant allowed for the obtainment of significant reductions in terms of primary energy consumption (up to 34.6%), global CO2 equivalent emissions (up to 52.3%), and operating costs (up to 49.6%), even if the expected return on the investment could be unacceptable.
A Holistic Decision Support Tool for Facade Design
Authors: Kültür Sinem , Türkeri Nil , Knaack Ulrich
Published: August 2019

This paper presents a holistic decision support tool developed for use during the early stages of facade design. The tool is based on the interdependent relationships between facade performance, facade parameters, and conditions (environmental and spatial). It assumes that a decision maker has the ability to enhance the performance of a facade by making proper decisions on the design parameters in line with the conditions. However, since facade performance has various aspects (sometimes conflicting) to be considered at once, it is hard to predict the impacts of decisions on the overall performance. A single design decision may increase the performance in one aspect while decreasing it in other aspects. The tool aims to function as a guide to decision makers by indicating the impacts of design decisions on different functional aspects of facade performance from a holistic point of view. Functional requirements included within the tool are safety requirements such as structural stability and fire protection, health-related requirements such as weather protection (protection against water, air, and moisture), and requirements related to the well-being of the users such as thermal, visual, and acoustic comfort. Information provided in the tool is based upon an extensive literature review and structured as an Excel spreadsheet.
Improving Understanding of City Spaces for Tourism Applications
Authors: Al-Kodmany Kheir
Published: August 2019

This paper explores a blend of digital and traditional methods to inform about a city’s popular spaces. Using locational data from social media platforms including Twitter, Facebook, and Instagram, along with using participatory field surveys and direct observations and combining insights from architecture and urban design literature, this study reveals popular socio-spatial clusters in the city of Chicago. The locational data of photographs were visualized by using geographic information systems, and they helped in producing heat maps that showed the spatial distribution of posted photographs. The geo-intensity of photographs illustrated the areas that are the most visited in the city. The study’s results indicate that the city’s most popular places include Millennium Park, Maggie Daley Park, Navy Pier, the Magnificent Mile Gateway, the Inner Loop, the Water Tower Area, the River Confluence, Museum Campus, Urban Giants, Grant Park, and the River City complex. The findings elucidate that social media plays an important role in promoting places and thereby sustaining a greater interest and stream of visitors. Consequently, planners should tap into the public’s digital engagement in city places to improve tourism and the economy.
Embodied Energy and Lifecycle Costs: Questioning (Mis)conceptions about Underground Construction
Authors: Doyle Michael Robert , Thalmann Philippe , Parriaux Aurèle
Published: August 2019

In the construction community, underground construction is perceived as being significantly more costly and more energy-consuming than comparable surface construction. Although the literature is scarce, studies that have attempted to quantify this difference tend to compare built projects in heterogeneous conditions. The objective of this article is to present the results of life cycle cost and energy consumption simulations conducted as part of the Deep City project at the École Polytechnique fédérale de Lausanne in Switzerland. This article begins by examining the preconceptions the construction industry seems to have about underground construction as reported in the press from 2007 to 2017. Then, we present the method and results of two unpublished studies on the differences in costs and energy consumption of a hypothetical commercial building project in two different geological contexts. We find that energy consumption can be 15% higher but also 4% lower. We also find that underground construction in unconsolidated sediment ground is approximately 23% more expensive, while only 10% in bedrock, which is significantly lower than the 200% to 300% differentials reported in previous studies. We attribute this to the level of detail of our studies, the inclusion of ground conditions, and conclude that our results help to dispel certain misconceptions about underground construction, which can contribute positively to urban sustainable development goals.
Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting Affibody–DM1 Drug Conjugates
Authors: Ding Haozhong , Altai Mohamed , Rinne Sara S. , Vorobyeva Anzhelika , Tolmachev Vladimir , Gräslund Torbjörn , Orlova Anna
Published: August 2019

Affibody molecules are small affinity-engineered scaffold proteins which can be engineered to bind to desired targets. The therapeutic potential of using an affibody molecule targeting HER2, fused to an albumin-binding domain (ABD) and conjugated with the cytotoxic maytansine derivate MC-DM1 (AffiDC), has been validated. Biodistribution studies in mice revealed an elevated hepatic uptake of the AffiDC, but histopathological examination of livers showed no major signs of toxicity. However, previous clinical experience with antibody drug conjugates have revealed a moderate- to high-grade hepatotoxicity in treated patients, which merits efforts to also minimize hepatic uptake of the AffiDCs. In this study, the aim was to reduce the hepatic uptake of AffiDCs and optimize their in vivo targeting properties. We have investigated if incorporation of hydrophilic glutamate-based spacers adjacent to MC-DM1 in the AffiDC, (ZHER2:2891)2–ABD–MC-DM1, would counteract the hydrophobic nature of MC-DM1 and, hence, reduce hepatic uptake. Two new AffiDCs including either a triglutamate–spacer–, (ZHER2:2891)2–ABD–E3–MC-DM1, or a hexaglutamate–spacer–, (ZHER2:2891)2–ABD–E6–MC-DM1 next to the site of MC-DM1 conjugation were designed. We radiolabeled the hydrophilized AffiDCs and compared them, both in vitro and in vivo, with the previously investigated (ZHER2:2891)2–ABD–MC-DM1 drug conjugate containing no glutamate spacer. All three AffiDCs demonstrated specific binding to HER2 and comparable in vitro cytotoxicity. A comparative biodistribution study of the three radiolabeled AffiDCs showed that the addition of glutamates reduced drug accumulation in the liver while preserving the tumor uptake. These results confirmed the relation between DM1 hydrophobicity and liver accumulation. We believe that the drug development approach described here may also be useful for other affinity protein-based drug conjugates to further improve their in vivo properties and facilitate their clinical translatability.
The PTEN Tumor Suppressor Gene in Soft Tissue Sarcoma
Authors: Stefano Sioletic , Giovanni Scambia
Published: August 2019

Soft tissue sarcoma (STS) is a rare malignancy of mesenchymal origin classified into more than 50 different subtypes with distinct clinical and pathologic features. Despite the poor prognosis in the majority of patients, only modest improvements in treatment strategies have been achieved, largely due to the rarity and heterogeneity of these tumors. Therefore, the discovery of new prognostic and predictive biomarkers, together with new therapeutic targets, is of enormous interest. Phosphatase and tensin homolog (PTEN) is a well-known tumor suppressor that commonly loses its function via mutation, deletion, transcriptional silencing, or protein instability, and is frequently downregulated in distinct sarcoma subtypes. The loss of PTEN function has consequent alterations in important pathways implicated in cell proliferation, survival, migration, and genomic stability. PTEN can also interact with other tumor suppressors and oncogenic signaling pathways that have important implications for the pathogenesis in certain STSs. The aim of the present review is to summarize the biological significance of PTEN in STS and its potential role in the development of new therapeutic strategies.
Comparative Cytogenetic Abnormalities in Paired Choroidal Melanoma Samples Obtained Before and After Proton Beam Irradiation by Transscleral Fine-Needle Aspiration Biopsy and Endoresection
Authors: Matet Alexandre , Aït Raïs Khadija , Malaise Denis , Angi Martina , Dendale Rémi , Tick Sarah , Lumbroso-Le Rouic Livia , Lévy-Gabriel Christine , Rodrigues Manuel , Pierron Gaëlle , Cassoux Nathalie
Published: August 2019

This study compared the cytogenetic profiles of choroidal melanoma samples retrieved before and after proton beam irradiation. Twenty-four consecutive patients who underwent both fine-needle aspiration biopsy (FNAB) during tantalum clip positioning, and endoresection within three months of irradiation, were retrospectively included. Chromosome alterations were explored by array comparative genomic hybridization. Age at diagnosis was 50 ± 14 years, tumor thickness was 8.6 ± 1.7 mm and tumor diameter was 12.4 ± 2.3 mm. Six FNAB samples were non-contributive (25%), versus one endoresection sample (4%) (p = 0.049). Among 17 cases with paired contributive samples, the profiles of chromosomes 3 and 8 were identical in all cases, except one with partial chromosome 3 loss on the FNAB sample only. Three cases presented additional discordant aberrations on chromosomes other than 3 or 8q. Overall, we identified monosomy 3 in two cases, 8q gain in six cases, and both alterations in three cases. All cases presented GNAQ or GNA11 mutations assessed by a custom next-generation sequencing panel. Among the six cases with non-contributive initial FNAB, three cases presented abnormal 3 or 8q chromosomes detected on the endoresection material. These results demonstrate the higher rentability of endoresection material for cytogenetic analysis compared to FNAB, and provide clinical evidence of tumor heterogeneity in choroidal melanoma.
Adaptive Responses as Mechanisms of Resistance to BRAF Inhibitors in Melanoma
Authors: Saei Azad , Eichhorn Pieter Johan Adam
Published: August 2019

The introduction of v-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors in melanoma patients with BRAF (V600E) mutations has demonstrated significant clinical benefits. However, rarely do tumours regress completely. Frequently, the reason for this is that therapies targeting specific oncogenic mutations induce a number of intrinsic compensatory mechanisms, also known as adaptive responses or feedback loops, that enhance the pro-survival and pro-proliferative capacity of a proportion of the original tumour population, thereby resulting in tumour progression. In this review we will summarize the known adaptive responses that limit BRAF mutant therapy and discuss potential novel combinatorial therapies to overcome resistance.
Electrochemotherapy Causes Caspase-Independent Necrotic-Like Death in Pancreatic Cancer Cells
Authors: Fernandes Philana , O’Donovan Tracey R. , McKenna Sharon L. , Forde Patrick F.
Published: August 2019

Pancreatic cancer represents a major challenge in oncology. Poor permeability of the pancreas and resistance to currently available therapies are impediments to improved patient survival. By transiently increasing cell membrane porosity and increasing drug uptake, Electrochemotherapy (ECT) has the potential to overcome these issues. In this study, we have evaluated the response of human and murine pancreatic cancer cells, in vitro, to electroporation in combination with Bleomycin, Cisplatin, or Oxaliplatin (ECT). The cytotoxic actions of all three drugs are potentiated when combined with electroporation in these cells. The biochemical and morphological changes post ECT are associated with immunogenic cell death that occurs with necroptosis rather than apoptosis. Moreover, ECT-induced cell death is rescued by Nec-1 suggesting that necroptosis may play a role in cell death mediated by cancer therapies.
p21 in Cancer Research
Authors: Shamloo Bahar , Usluer Sinem
Published: August 2019

p21 functions as a cell cycle inhibitor and anti-proliferative effector in normal cells, and is dysregulated in some cancers. Earlier observations on p21 knockout models emphasized the role of this protein in cell cycle arrest under the p53 transcription factor activity. Although tumor-suppressor function of p21 is the most studied aspect of this protein in cancer, the role of p21 in phenotypic plasticity and its oncogenic/anti-apoptotic function, depending on p21 subcellular localization and p53 status, have been under scrutiny recently. Basic science and translational studies use precision gene editing to manipulate p21 itself, and proteins that interact with it; these studies have led to regulatory/functional/drug sensitivity discoveries as well as therapeutic approaches in cancer field. In this review, we will focus on targeting p21 in cancer research and its potential in providing novel therapies.
Third Epidemiological Analysis of Nasopharyngeal Carcinoma in the Central Region of Japan from 2006 to 2015
Authors: Kanno Masafumi , Narita Norihiko , Fujimoto Yasushi , Wakisaka Naohiro , Yoshizaki Tomokazu , Kodaira Takeshi , Makita Chiyoko , Sato Yuichiro , Yamazaki Keisuke , Wakaoka Takanori , Shimode Yuzo , Tsuji Hiroyuki , Kito Ryosuke , Ishinaga Hajime , Hosokawa Seiji , Takakura Hiromasa , Nishimura Kunihiro , Matoba Takuma , Fujieda Shigeharu
Published: August 2019

The present study aimed to clarify the incidence and clinical outcomes of nasopharyngeal carcinoma (NPC) in the Chubu region of Japan from 2006 to 2015, compared with previous reports. A retrospective analysis was conducted based on medical records from 40 hospitals located in the Chubu region in the central Japanese main island, with a population of around 22.66 million individuals. This study was designed in line with to two previous clinical studies into NPC conducted in the same area of Japan. We recruited NPC patients diagnosed in hospitals across this area over a 10-year period (2006–2015) using a questionnaire about sex, age, primary site, clinical symptoms, pathology, Union for International Cancer Control (UICC) staging, serological exam, treatment, and survival. A total of 620 NPC patients were identified. The age-standardized incidence of NPC from 2006 to 2015 was 0.27 per 100,000 individuals per year. There were no significant differences between this study and the previous two studies conducted in the same area of Japan. The five-year overall survival rate for all patients was 75.9%, while those for patients with stages I, II, III, and IVA were 97%, 91%, 79%, and 68%, respectively. The age-standardized annual incidence of NPC in the present study was 0.27 per 100,000 individuals per year, which was relatively low and stable. The five-year overall survival rate for all NPC patients was significantly improved in this decade compared with previous studies. The smoking rates in male and female NPC patients were 64.5% and 18.8%, respectively, thereby suggesting the involvement of smoking in the incidence of NPC.
Unravelling the Diagnostic Dilemma: A MicroRNA Panel of Circulating MiR-16 and MiR-877 as A Diagnostic Classifier for Distal Bile Duct Tumors
Authors: Meijer Laura L. , Puik Jisce R. , Le Large Tessa Y.S. , Heger Michal , Dijk Frederike , Funel Niccola , Wurdinger Thomas , Garajová Ingrid , van Grieken Nicole C.T. , van de Wiel Mark A. , Giovannetti Elisa , Kazemier Geert
Published: August 2019

Accurate diagnosis of pancreatic head lesions remains challenging as no minimally invasive biomarkers are available to discriminate distal cholangiocarcinoma (CCA) from pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to identify specific circulating microRNAs (miRNAs) to diagnose distal CCA. In the discovery phase, PCR profiling of 752 miRNAs was performed on fourteen patients with distal CCA and age- and sex-matched healthy controls. Candidate miRNAs were selected for evaluation and validation by RT-qPCR in an independent cohort of distal CCA (N = 24), healthy controls (N = 32), benign diseases (N = 20), and PDAC (N = 24). The optimal diagnostic combination of miRNAs was determined by multivariate logistic regression analysis and evaluated by ROC curves with AUC values. The discovery phase revealed 19 significantly dysregulated miRNAs, of which six were validated in the evaluation phase. The validation phase confirmed downregulated miR-16 in patients with distal CCA compared to benign disease or PDAC (P = 0.048 and P = 0.012), while miR-877 was significantly upregulated (P = 0.003 and P = 0.006). This two-miRNA panel was validated as a CCA-specific profile, discriminating distal CCA from benign disease (AUC = 0.90) and from PDAC (AUC = 0.88). In conclusion, the present study identified a two-miRNA panel of downregulated miR-16 and upregulated miR-877 with promising capability to diagnose patients with distal CCA.
TIMP-1-Mediated Chemoresistance via Induction of IL-6 in NSCLC
Authors: Xiao Wei , Wang Lan , Howard John , Kolhe Ravindra , Rojiani Amyn M. , Rojiani Mumtaz V.
Published: August 2019

Elevated tissue inhibitor of metalloproteinase-1 (TIMP-1) is a negative prognosticator in non-small cell lung carcinoma NSCLC patients. This study sought to identify mechanisms whereby TIMP-1 impacts anticancer therapy. Using NSCLC cells and their TIMP-1 knockdown clones, we examined the chemoresistance against two chemotherapeutic agents, Gemcitabine and Cisplatin, as identified by increased apoptosis in the knockdown clones. A bead-based cytokine screening assay identified interleukin-6 (IL-6) as a key factor in chemoresistance. Exogenous human recombinant rhTIMP-1 or rhIL-6 resulted in reduced apoptosis. IL-6 expression was closely correlated with TIMP-1 kinetics and was upregulated by the addition of exogenous TIMP-1 while TIMP-1 neutralizing antibodies delayed IL-6 elevation. IL-6 production was regulated by TIMP-1, exerting its effect via activation of downstream signal transducer and activator of transcription 3 (STAT3) signaling. Both molecules and their documented transcription factors were upregulated and activated in chemoresistant NSCLC cells, confirming the roles of TIMP-1 and IL-6 in chemoresistance. To examine the role of these genes in patients, survival data from lung adenocarcinoma (LUAD) patients was curated from the cancer genome atlas (TCGA) database. Kaplan-Meier analysis found that individuals expressing low TIMP-1 and IL-6 have a higher survival rate and that the two-gene signature was more significant than the single-gene status. We define for the first time, a regulatory relationship between TIMP-1 and IL-6 in NSCLCs, suggesting that the TIMP-1/IL6 axis may be a valuable prognostic biomarker. Therapeutic interventions directed at this dual target may improve overall prognosis while negatively affecting the development of chemoresistance in NSCLC.
Targeted Treatment Options of Recurrent Radioactive Iodine Refractory Hürthle Cell Cancer
Authors: Aydemirli Mehtap Derya , Corver Willem , Beuk Ruben , Roepman Paul , Solleveld-Westerink Nienke , van Wezel Tom , Kapiteijn Ellen , Morreau Hans
Published: August 2019

Objective: To evaluate the efficacy and treatment rationale of Hürthle cell carcinoma (HCC) following a patient with progressive and metastatic HCC. HCC was recently shown to harbor a distinct genetic make-up and the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kiase (PI3K)/AKT signaling pathways are potential targets for anti-cancer agents in the management of recurrent HCC. The presence or absence of gene variants can give a rationale for targeted therapies that could be made available in the context of drug repurposing trials. Methods: Treatment included everolimus, sorafenib, nintedanib, lenvatinib, and panitumumab. Whole genome sequencing (WGS) of metastatic tumor material obtained before administration of the last drug, was performed. We subsequently evaluated the rationale and efficacy of panitumumab in thyroid cancer and control cell lines after epidermal growth factor (EGF) stimulation and treatment with panitumumab using immunofluorescent Western blot analysis. EGF receptor (EGFR) quantification was performed using flow cytometry. Results: WGS revealed a near-homozygous genome (NHG) and a somatic homozygous TSC1 variant, that was absent in the primary tumor. In the absence of RAS variants, panitumumab showed no real-life efficacy. This might be explained by high constitutive AKT signaling in the two thyroid cancer cell lines with NHG, with panitumumab only being a potent inhibitor of pEGFR in all cancer cell lines tested. Conclusions: In progressive HCC, several treatment options outside or inside clinical trials are available. WGS of metastatic tumors might direct the timing of therapy. Unlike other cancers, the absence of RAS variants seems to provide insufficient justification of single-agent panitumumab administration in HCC cases harboring a near-homozygous genome.
4-Methylumbelliferone Inhibits Cancer Stem Cell Activation and Overcomes Chemoresistance in Ovarian Cancer
Authors: Lokman Noor A. , Price Zoe K. , Hawkins Emily K. , Macpherson Anne M. , Oehler Martin K. , Ricciardelli Carmela
Published: August 2019

We have recently shown that the extracellular matrix molecule hyaluronan (HA) plays a role in the development of ovarian cancer chemoresistance. This present study determined if HA production is increased in chemotherapy-resistant ovarian cancers and if the HA inhibitor 4-methylubelliferone (4-MU) can overcome chemoresistance to the chemotherapeutic drug carboplatin (CBP) and inhibit spheroid formation and the expression of cancer stem cell (CSC) markers. We additionally assessed whether 4-MU could inhibit in vivo invasion of chemoresistant primary ovarian cancer cells in the chicken embryo chorioallantoic membrane (CAM) assay. The expression of the HA synthases HAS2 and HAS3 was significantly increased in chemoresistant compared to chemosensitive primary ovarian cancer cells isolated from patient ascites. 4-MU significantly inhibited HA production, cell survival, and spheroid formation of chemoresistant serous ovarian cancer cells. In combination with CBP, 4-MU treatment significantly decreased ovarian cancer cell survival and increased apoptosis of chemoresistant primary cells compared to CBP alone. 4-MU significantly reduced spheroid formation, expression of CSC markers ALDH1A1 and ABCG2 in primary cell spheroid cultures, and ALDH1 immunostaining in patient-derived tissue explant assays following treatment with CBP. Furthermore, 4-MU was very effective at inhibiting in vivo invasion of chemoresistant primary cells in CAM assays. Inhibition of HA is therefore a promising new strategy to overcome chemoresistance and to improve ovarian cancer survival.
FDG-PET/CT for Response Monitoring in Metastatic Breast Cancer: Today, Tomorrow, and Beyond
Authors: Hildebrandt Malene , Lauridsen Jeppe , Vogsen Marianne , Holm Jorun , Vilstrup Mie , Braad Poul-Erik , Gerke Oke , Thomassen Mads , Ewertz Marianne , Høilund-Carlsen Poul ,   The Centre for Personalized Response Monitoring in Oncology (PREMIO)
Published: August 2019

While current international guidelines include imaging of the target lesion for response monitoring in metastatic breast cancer, they do not provide specific recommendations for choice of imaging modality or response criteria. This is important as clinical decisions may vary depending on which imaging modality is used for monitoring metastatic breast cancer. FDG-PET/CT has shown high accuracy in diagnosing metastatic breast cancer, and the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) have shown higher predictive values than the CT-based Response Evaluation Criteria in Solid Tumors (RECIST) for prediction of progression-free survival. No studies have yet addressed the clinical impact of using different imaging modalities or response evaluation criteria for longitudinal response monitoring in metastatic breast cancer. We present a case study of a patient with metastatic breast cancer who was monitored first with conventional CT and then with FDG-PET/CT. We retrospectively applied PERCIST to evaluate the longitudinal response to treatment. We used the one-lesion PERCIST model measuring SULpeak in the hottest metastatic lesion on consecutive scans. This model provides a continuous variable that allows graphical illustration of disease fluctuation along with response categories. The one-lesion PERCIST approach seems able to reflect molecular changes and has the potential to support clinical decision-making. Prospective clinical studies addressing the clinical impact of PERCIST in metastatic breast cancer are needed to establish evidence-based recommendations for response monitoring in this disease.