bluuebunny/crossref_metadata_2025 huggingface dataset:
Generation of Multiple Pseudo Bessel Beams with Accurately Controllable Propagation Directions and High Efficiency Using a Reflective Metasurface
Authors: Liu Haixia , Xue Hao , Liu Yongjie , Li Long
Published: October 2020

In this paper, a generation method procedure based on a reflective metasurface is proposed to generate multiple pseudo Bessel beams with accurately controllable propagation directions and high efficiency. Firstly, by adjusting the miniaturized unit cell of the reflective metasurface to modulate the electromagnetic waves using the proposed method, some off-axis pseudo Bessel beams with different propagation directions are generated. Then, by achieving the large-angle deflection and comparing the results with previous existing methods, the superiority of the proposed method is demonstrated. Based on the generated single off-axis pseudo Bessel beam and the superposition principle of the electromagnetic wave, a reflective metasurface with 47 × 47 elements is designed and fabricated at 10 GHz to generate dual pseudo Bessel beams. Full-wave simulation and experimental measurement results validate that the dual pseudo Bessel beams were generated successfully. The propagation directions of the dual pseudo Bessel beams can be controlled accurately by the reflective metasurface, and the efficiency of the beams is 59.2% at a propagation distance of 400 mm. The energy of the beams keeps concentrating along the propagation axes, which provides a new choice for wireless power transfer and wireless communication with one source to multiple receiving targets.
A Resilient Large-Scale Trajectory Index for Cloud-Based Moving Object Applications
Authors: Alqahtani Omar , Altman Tom
Published: October 2020

The availability of location-aware devices generates tremendous volumes of moving object trajectories. The processing of these large-scale trajectories requires innovative techniques that are capable of adapting to changes in cloud systems to satisfy a wide range of applications and non-programmer end users. We introduce a Resilient Moving Object Index that is capable of balancing both spatial and object localities to maximize the overall performance in numerous environments. It is equipped with compulsory, discrete, and impact factor prediction models. The compulsory and discrete models are used to predict a locality pivot based on three fundamental aspects: computation resources, nature of the trajectories, and query types. The impact factor model is used to predict the influence of contrasting queries. Moreover, we provide a framework to extract efficient training sets and features without adding overhead to the index construction. We conduct an extensive experimental study to evaluate our approach. The evaluation includes two testbeds and covers spatial, temporal, spatio-temporal, continuous, aggregation, and retrieval queries. In most cases, the experiments show a significant performance improvement compared to various indexing schemes on a compact trajectory dataset as well as a sparse dataset. Most important, they demonstrate how our proposed index adapts to change in various environments.
Design of a Monopulse System Using a Single Patch Radiator with a Simple Multi-Mode Substrate Integrated Waveguide Feeding Network
Authors: Youn Sangwoon , Lim Tae Heung , Jang Byung-jun , Choo Hosung
Published: October 2020

This paper proposes the design of a single radiator monopulse antenna with a substrate integrated waveguide (SIW) multi-mode feeding system to reduce the aperture size and simplify the feeding structure. The proposed antenna can effectively reduce the overall system size by using a single patch radiator, compared to conventional systems that require multiple radiators. In addition, to simplify the structure of the pattern comparator we use a SIW multi-mode feeding system with TE10 and TE20 modes. To verify the feasibility, the patch antenna with the SIW multi-mode feed is fabricated, and its antenna characteristics of reflection coefficients, mutual coupling, and radiation patterns are measured in a full anechoic chamber. The accuracy of the direction of arrival (DOA) estimation is further improved by applying the derived calibration factor to the resulting sum and difference ratio. The results demonstrate that the proposed antenna is suitable for compact and lightweight monopulse systems with the single radiator and the simple multi-mode feeding network.
Skills Needs of the Civil Engineering Sector in the European Union Countries: Current Situation and Future Trends
Authors: Akyazi Tugce , Alvarez Irantzu , Alberdi Elisabete , Oyarbide-Zubillaga Aitor , Goti Aitor , Bayon Felix
Published: October 2020

The construction sector has always occupied a strategic place in the European economy. The European construction industry suffered during the 2007–2008 global financial crisis, and today the sector is undergoing a recovery process. Among all the construction subsectors, civil engineering has the highest growth rate. Currently, the sector has to face profound industrial changes emerging with digital transformations (Industry 4.0), sustainability, climate change and energy efficiency. To promote the growth of the civil engineering sector and accelerate the recovery, we need to create a highly qualified and competent workforce that can handle the challenges coming up with the technological progress and global competitiveness. The main condition to achieve this capable workforce is to define the expected evolution of skills requirements. For that purpose, our work focuses on identifying current and near-future key skills required by the civil engineering occupations. To achieve this, we developed an automated sectoral database for the current and near-future skills requirements of the selected professional profiles. It is our belief that this sectoral database is a fundamental framework that will guide the sector through the future changes. We also believe that our research can be used as a key tool for construction companies, policy-makers, academics and training centers to develop well-designed and efficient training programs for upskilling and reskilling the workforce.
Premature Adult Mortality and Years of Life Lost Attributed to Long-Term Exposure to Ambient Particulate Matter Pollution and Potential for Mitigating Adverse Health Effects in Tuzla and Lukavac, Bosnia and Herzegovina
Authors: Matkovic Vlatka , Mulić Maida , Azabagić Selma , Jevtić Marija
Published: October 2020

Ambient air pollution is one of eight global risk factors for deaths and accounts for 38.44 all causes death rates attributable to ambient PM pollution, while in Bosnia and Herzegovina, it is 58.37. We have estimated health endpoints and possible gains if two policy scenarios were implemented and air pollution reduction achieved. Real-world health and recorded PM pollution data for 2018 were used for assessing the health impacts and possible gains. Calculations were performed with WHO AirQ+ software against two scenarios with cut-off levels at country-legal values and WHO air quality recommendations. Ambient PM2.5 pollution is responsible for 16.20% and 22.77% of all-cause mortality among adults in Tuzla and Lukavac, respectively. Our data show that life expectancy could increase by 2.1 and 2.4 years for those cities. In the pollution hotspots, in reality, there is a wide gap in what is observed and the implementation of the legally binding air quality limit values and, thus, adverse health effects. Considerable health gains and life expectancy are possible if legal or health scenarios in polluted cities were achieved. This estimate might be useful in providing additional health burden evidence as a key component for a clean air policy and action plans.
Modified Viscosity Subgradient Extragradient-Like Algorithms for Solving Monotone Variational Inequalities Problems
Authors: Wairojjana Nopparat , Younis Mudasir , Rehman Habib ur , Pakkaranang Nuttapol , Pholasa Nattawut
Published: October 2020

Variational inequality theory is an effective tool for engineering, economics, transport and mathematical optimization. Some of the approaches used to resolve variational inequalities usually involve iterative techniques. In this article, we introduce a new modified viscosity-type extragradient method to solve monotone variational inequalities problems in real Hilbert space. The result of the strong convergence of the method is well established without the information of the operator’s Lipschitz constant. There are proper mathematical studies relating our newly designed method to the currently state of the art on several practical test problems.
In Vitro and In Vivo Antioxidant Activity of Agave sisalana Agro-Industrial Residue
Authors: Barreto Stella Maria Andrade Gomes , Cadavid Cesar Orlando Muñoz , Moura Rafael Amir de Oliveira , Silva Giovanna Melo Martins , Araújo Samara Vitória Ferreira de , Silva Filho Jean Antônio Aderaldo da , Rocha Hugo Alexandre Oliveira , Oliveira Riva de Paula , Giordani Raquel Brandt , Ferrari Márcio
Published: October 2020

Agave sisalana agro-industrial residue has considerable potential against damage associated with oxidative stress and skin aging. This study aims to demonstrate, in vitro and in vivo, the potential of Agave sisalana agro-industrial residue as a safe and effective alternative for the prevention of damage caused by oxidative stress and aging. The antioxidant activity was evaluated in vitro (total antioxidant capacity, reducing power, DPPH radical scavenging, metal chelating (Fe2+ and Cu2+), and hydroxyl radical scavenging) and in vivo using the Caenorhabditis elegans organism model. The extract showed in vitro antioxidant activity in all tests performed. Tests with C. elegans showed that the extract was able to reduce the intracellular levels of reactive oxygen species (ROS) and increase the survival rate of worms. A downregulation of gst-4::GFP expression suggests a direct action against free radicals. Agave sisalana agro-industrial residue extract (AsRE) can therefore be considered as a source of antioxidant biomolecules, and the use of this agro-industrial residue in a new production process can lead to sustainability and socioeconomic development.
TRPA1 Expression in Synovial Sarcoma May Support Neural Origin
Authors: De Logu Francesco , Ugolini Filippo , Caporalini Chiara , Palomba Annarita , Simi Sara , Portelli Francesca , Campanacci Domenico Andrea , Beltrami Giovanni , Massi Daniela , Nassini Romina
Published: October 2020

Synovial sarcoma (SS) is a malignant mesenchymal soft tissue neoplasm. Despite its name, the cells of origin are not synovial cells, but rather neural, myogenic, or multipotent mesenchymal stem cells have been proposed as possible cells originators. Unlike other sarcomas, an unusual presentation of long-term pain at the tumor site has been documented, but the exact mechanisms have not been fully clarified yet. The transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel mainly expressed in primary sensory neurons, where it functions as a pain sensor. TRPA1 have also been described in multiple non-excitable cells, including those derived from neural crest stem cells such as glial cells and, in particular, Schwann cell oligodendrocytes and astrocytes. We evaluated TRPA1 expression in SS. We selected a cohort of 41 SSs, and by immunohistochemistry, we studied TRPA1 expression. TRPA1 was found in 92.6% of cases. Triple TRPA1/pS100/SOX10 and TRPA1/SLUG/SNAIL staining strongly supports a neural origin of SS. TRPA1 positivity was also observed in a subset of cases negative with pS100, SOX10 and/or SLUG/SNAIL, and these divergent phenotypes may reflect a process of tumor plasticity and dedifferentiation of neural-derived SSs. Given the functional diversity of TRPA1 and its expression in neuronal and non-neuronal multipotent neural crest stem cells, it remains to be determined whether TRPA1 expression in SSs neoplastic cells plays a role in the molecular mechanism associated with premonitory pain symptoms and tumor progression.
Current Topics in Esophageal Squamous Cell Carcinoma
Authors: Kurumi Hiroki , Isomoto Hajime
Published: October 2020

Esophageal squamous cell carcinoma (ESCC) is one of the most deadly cancers due to its extremely aggressive nature and poor survival rate. Central to East Asia is one of regions with the highest incidence of ESCC. In these five papers, the international leaders of ESCC in Asia have taken various approaches to ESCC. Lin et al. compared intensity-modulated radiation therapy with three-dimensional stereoscopic radiation therapy with respect to treatment of ESCC. Song et al. demonstrated that (S)-10-Hydroxycamptothecin is useful in the ESCC cell lines as well as in vivo using a patients-derived xenograft tumor model in mice. Chen et al. showed Stromal cell-derived factor-1α expression is an independent prognostic predictor of ESCC. Lin et al. showed that the SUVLN/SUVTumor ratio of PET-CT was associated with ESCC prognosis. Yoon et al. investigated the association between sarcopenia and prognosis in the ESCC patients. All reports are an essential approach to overcoming ESCC.
Liver Function Changes in Patients with Hepatocellular Carcinoma Treated with Lenvatinib: Predictive Factors of Progression to Child-Pugh Class B, the Formation of Ascites and the Candidates for the Post-Progression Treatment
Authors: Hatanaka Takeshi , Kakizaki Satoru , Nagashima Tamon , Namikawa Masashi , Ueno Takashi , Tojima Hiroki , Takizawa Daichi , Naganuma Atsushi , Arai Hirotaka , Sato Ken , Harimoto Norifumi , Shirabe Ken , Uraoka Toshio
Published: October 2020

The aim of this multicenter retrospective study was to assess the change in liver function in patients with hepatocellular carcinoma treated with lenvatinib. Among 139 consecutive patients receiving lenvatinib treatment between March 2018 and July 2019, 28 patients with Child-Pugh class B and one patient with inadequate patient information were excluded. Remaining 110 patients with Child-Pugh class A were analyzed. The median age of 110 patients was 73 years (IQR 66.7–80) and 88 patients (80.0%) were men. Child-Pugh score was 5 (CP5A) and 6 (CP6A) in 58 (52.7%) and 52 patients (47.3%), and ALBI grade was 1 and 2 in 38 (34.5%) and 72 patients (65.5%), respectively. The deterioration to Child-Pugh class B was found in 43 patients (39.1%) during the lenvatinib treatment. The favorable factors related to preserving liver function were significantly shown to be male, ALBI grade 1, CP5A and BCLC early or intermediate stage in the multivariate analysis. The formation of ascites was found in 32 patients (28.6%). The significant unfavorable factors associated with the formation of ascites were found to be low platelet count and CP6A. Among the 79 patients, there were 36 (45.6%) and 11 patients (13.9%) who fulfilled the criteria for candidate for the post-progression treatment and ramucirumab treatment, respectively. The predictive factors of the post-progression treatment were shown to be ALBI grade 1 and CP5A in multivariate analysis. In conclusion, male, ALBI grade 1, CP5A and BCLC early or intermediate stage were favorable factors related to sustaining liver function and the patients with ALBI grade 1 and CP5A were eligible for the post-progression treatment. Careful screening for ascites was needed in patients with low platelet count and CP6A.
Circulating Tumor DNA Testing Opens New Perspectives in Melanoma Management
Authors: Sacco Alessandra , Forgione Laura , Carotenuto Marianeve , De Luca Antonella , Ascierto Paolo A. , Botti Gerardo , Normanno Nicola
Published: October 2020

Malignant melanoma accounts for about 1% of all skin cancers, but it causes most of the skin cancer-related deaths. Circulating tumor DNA (ctDNA) testing is emerging as a relevant tool for the diagnosis and monitoring of cancer. The availability of highly sensitive techniques, including next generation sequencing (NGS)-based panels, has increased the fields of application of ctDNA testing. While ctDNA-based tests for the early detection of melanoma are not available yet, perioperative ctDNA analysis in patients with surgically resectable melanoma offers relevant prognostic information: i) the detection of ctDNA before surgery correlates with the extent and the aggressiveness of the disease; ii) ctDNA testing after surgery/adjuvant therapy identifies minimal residual disease; iii) testing ctDNA during the follow-up can detect a tumor recurrence, anticipating clinical/radiological progression. In patients with advanced melanoma, several studies have demonstrated that the analysis of ctDNA can better depict tumor heterogeneity and provides relevant prognostic information. In addition, ctDNA testing during treatment allows assessing the response to systemic therapy and identifying resistance mechanisms. Although validation in prospective clinical trials is needed for most of these approaches, ctDNA testing opens up new scenarios in the management of melanoma patients that could lead to improvements in the diagnosis and therapy of this disease.
Regulatory Mechanisms of Epigenetic miRNA Relationships in Human Cancer and Potential as Therapeutic Targets
Authors: Arif K. M. Taufiqul , Elliott Esther K. , Haupt Larisa M. , Griffiths Lyn R.
Published: October 2020

Initiation and progression of cancer are under both genetic and epigenetic regulation. Epigenetic modifications including alterations in DNA methylation, RNA and histone modifications can lead to microRNA (miRNA) gene dysregulation and malignant cellular transformation and are hereditary and reversible. miRNAs are small non-coding RNAs which regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. miRNAs can target epigenetic modifier enzymes involved in epigenetic modulation, establishing a trilateral regulatory “epi–miR–epi” feedback circuit. The intricate association between miRNAs and the epigenetic architecture is an important feature through which to monitor gene expression profiles in cancer. This review summarises the involvement of epigenetically regulated miRNAs and miRNA-mediated epigenetic modulations in various cancers. In addition, the application of bioinformatics tools to study these networks and the use of therapeutic miRNAs for the treatment of cancer are also reviewed. A comprehensive interpretation of these mechanisms and the interwoven bond between miRNAs and epigenetics is crucial for understanding how the human epigenome is maintained, how aberrant miRNA expression can contribute to tumorigenesis and how knowledge of these factors can be translated into diagnostic and therapeutic tool development.
Uveal Melanoma-Derived Extracellular Vesicles Display Transforming Potential and Carry Protein Cargo Involved in Metastatic Niche Preparation
Authors: Tsering Thupten , Laskaris Alexander , Abdouh Mohamed , Bustamante Prisca , Parent Sabrina , Jin Eva , Ferrier Sarah Tadhg , Arena Goffredo , Burnier Julia V.
Published: October 2020

Extracellular vesicles (EVs) carry molecules derived from donor cells and are able to alter the properties of recipient cells. They are important players during the genesis and progression of tumors. Uveal melanoma (UM) is the most common primary intraocular tumor in adults and is associated with a high rate of metastasis, primarily to the liver. However, the mechanisms underlying this process are poorly understood. In the present study, we analyzed the oncogenic potential of UM-derived EVs and their protein signature. We isolated and characterized EVs from five UM cell lines and from normal choroidal melanocytes (NCMs). BRCA1-deficient fibroblasts (Fibro-BKO) were exposed to the EVs and analyzed for their growth in vitro and their reprograming potential in vivo following inoculation into NOD-SCID mice. Mass spectrometry of proteins from UM-EVs and NCM-EVs was performed to determine a protein signature that could elucidate potential key players in UM progression. In-depth analyses showed the presence of exosomal markers, and proteins involved in cell-cell and focal adhesion, endocytosis, and PI3K-Akt signaling pathway. Notably, we observed high expression levels of HSP90, HSP70 and integrin V in UM-EVs. Our data bring new evidence on the involvement of UM-EVs in cancer progression and metastasis.
External Validation of the SERC Trial Population: Comparison with the Multicenter French Cohort, the Swedish and SENOMIC Trial Populations for Breast Cancer Patients with Sentinel Node Micro-Metastasis
Authors: Houvenaeghel Gilles , El Hajj Houssein , Barrou Julien , Cohen Monique , Raro Pédro , De Troyer Jérémy , Gimbergues Pierre , Tunon de Lara Christine , Ceccato Vivien , Vaini-Cowen Véronique , Faure-Virelizier Christelle , Marchal Frédéric , Gauthier Tristan , Jouve Eva , Theret Pierrick , Regis Claudia , Desmons François , Tallet Agnès , Boher Jean-Marie ,   the SERC Trial Group
Published: October 2020

Many trials confirmed the safety of omitting axillary dissection in the selected patients treated for early breast cancer. The external validity of these trials is questionable. Our study aimed to evaluate the accuracy of the French population representativity in the SERC trial and the differences between these two populations as well as comparing the French and the Swedish populations (the SENOMIC trial population and the Swedish National Breast Cancer Registry (NKBC) cohort) of patients with sentinel node (SN) micro-metastasis. A higher rate of smaller tumors and grade 1 tumors was observed in the French cohort when compared to the SERC population. Our findings conclude that both French populations show similar characteristics. Positive non-sentinel node (NSN) rates at completion axillary lymph node dissection (ALND) were 10.28 % and 11.3 % in the SERC trial and French cohort, respectively (p = 0.5). The rate of grade 1 tumors was lower in the SENOMIC trial (16.2%) and in the NKBC cohort (17.4%) compared to the SERC trial population (27.3%) and the French cohort (34.4%). Our findings in addition to the previously demonstrated concordance between the SENOMIC trial and the NKBC populations imply that the results of both the SERC and the SENOMIC trials can be applied to both French and Swedish real populations.
Drug Resistance and Novel Therapies in Cancers
Authors: Wang Zhixiang
Published: October 2020

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Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia
Authors: Mouchel Pierre-Luc , Serhan Nizar , Betous Rémy , Farge Thomas , Saland Estelle , De Medina Philippe , Hoffmann Jean-Sébastien , Sarry Jean-Emmanuel , Poirot Marc , Silvente-Poirot Sandrine , Récher Christian
Published: October 2020

Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients.
The In Vitro and In Vivo Anticancer Properties of Chalcone Flavokawain B through Induction of ROS-Mediated Apoptotic and Autophagic Cell Death in Human Melanoma Cells
Authors: Hseu You-Cheng , Chiang Yu-Chi , Vudhya Gowrisankar Yugandhar , Lin Kai-Yuan , Huang Sheng-Teng , Shrestha Sirjana , Chang Geng-Ruei , Yang Hsin-Ling
Published: October 2020

Melanoma is the most prevalent type of skin cancer with high mortality rates. This study demonstrates the in vitro and in vivo anticancer properties of chalcone flavokawain B (FKB) induced ROS-mediated apoptosis and autophagy in human melanoma (human epithelial melanoma cell line A375 and/or human skin lymph node derived melanoma cell line A2058) cells. Cell viability was calculated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the expression patterns of various apoptosis, autophagy-associated proteins were determined by Western blot methods. Annexin V was detected by flow cytometry, whereas acidic vesicular organelles (AVOs) and intracellular ROS levels were measured by fluorescence microscopy. The in vivo anticancer properties of FKB were evaluated by xenografting the A375 cells into nude mice. The results convey that FKB inhibited cell viability, B-Raf proto-oncogene, serine/threonine kinase (BRAF)/extracellular signal-regulated kinase (ERK) expression in human melanoma cells. Caspase-3 activation, poly (ADP-ribose) polymerase (PARP) cleavage pathway, and Bcl2 associated X (Bax)/B-cell lymphoma 2 (Bcl-2) dysregulation were involved in the execution of apoptosis. Moreover, FKB-induced autophagy was observed through increased microtubule-associated protein 1A/1B-light chain 3B (LC3-II) accumulation and AVOs formation, which was also associated with an increase in sequestosome 1 (SQSTM1/p62), decreased protein kinase B (AKT)/mammalian target of rapamycin (mTOR) expressions, and dysregulated Beclin-1/Bcl-2 levels. Autophagy inhibitors [3-methyladenine (3-MA)/chloroquine (CQ)] and LC3 silencing suppressed FKB-induced apoptosis by decreasing caspase-3 in melanoma cells. The antioxidant N-acetylcysteine (NAC) diminished FKB-induced apoptotic and autophagic cell death. However, the inhibition of apoptosis decreased FKB-induced autophagy (LC3-I/II). The in vivo study confirmed that FKB inhibited melanoma growth in A375-xenografted nude mice. This study concluded that FKB is critically associated with the execution and generation of ROS-modulated apoptotic and autophagic cell death of melanoma cells. FKB also repressed tumor growth in xenografted nude mice. Therefore, flavokawain B might be a potential anti-tumor agent in human melanoma treatment.
Predictive Markers for Malignant Urothelial Transformation in Balkan Endemic Nephropathy: A Case–Control Study
Authors: Kocic Gordana , Hadzi-Djokic Jovan , Cukuranovic-Kokoris Jovana , Gajic Mihajlo , Veljkovic Andrej , Cukuranović Rade , Basic Dragoslav , Jovanovic Ivan , Smelcerovic Andrija
Published: October 2020

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease frequently accompanied by urothelial carcinoma (UC). In light of the increased UC incidence and the markers observed in BEN patients with developed UC, the aim of the current case–control study is to assess survivin, p53 protein, growth factors and receptors (VEGF, VEGFR1, IGF I, IGF-1R and IGFBP5), tumor marker (TF)/CD142, circulating soluble Fas receptor and neopterin, as potentially predictive markers for UC in patients with BEN (52 patients), compared to healthy, age-matched subjects (40). A threefold increase was registered in both circulating and urinary survivin level in BEN patients. Especially noticeable was the ratio of U survivin/U Cr level five times the ratio of BEN patients associated with standard renal markers in multivariate regression models. The concentrations of VEGF, VEGFR1, (TF)/CD142, (sFas) were not significantly different in BEN patients, while urinary/plasma level demonstrated a significant decrease for VEGF. The levels of IGF I, IGFBP5 and IGF-1R were significantly reduced in the urine of BEN patients. Plasma concentration of neopterin was significantly higher, while urinary neopterin value was significantly lower in BEN patients compared to healthy controls, which reflected a significantly lower urine/plasma ratio and low local predictive value. As BEN is a slow-progressing chronic kidney disease, early detection of survivin may be proposed as potential predictor for malignant alteration and screening tool in BEN patients without the diagnosis of UC.
Regenerative Wound Dressings for Skin Cancer
Authors: Pavel Teodor Iulian , Chircov Cristina , Rădulescu Marius , Grumezescu Alexandru Mihai
Published: October 2020

Skin cancer is considered the most prevalent cancer type globally, with a continuously increasing prevalence and mortality growth rate. Additionally, the high risk of recurrence makes skin cancer treatment among the most expensive of all cancers, with average costs estimated to double within 5 years. Although tumor excision is the most effective approach among the available strategies, surgical interventions could be disfiguring, requiring additional skin grafts for covering the defects. In this context, post-surgery management should involve the application of wound dressings for promoting skin regeneration and preventing tumor recurrence and microbial infections, which still represents a considerable clinical challenge. Therefore, this paper aims to provide an up-to-date overview regarding the current status of regenerative wound dressings for skin cancer therapy. Specifically, the recent discoveries in natural biocompounds as anti-cancer agents for skin cancer treatment and the most intensively studied biomaterials for bioactive wound dressing development will be described.
De Novo A-to-I RNA Editing Discovery in lncRNA
Authors: Silvestris Domenico Alessandro , Scopa Chiara , Hanchi Sara , Locatelli Franco , Gallo Angela
Published: October 2020

Background: Adenosine to inosine (A-to-I) RNA editing is the most frequent editing event in humans. It converts adenosine to inosine in double-stranded RNA regions (in coding and non-coding RNAs) through the action of the adenosine deaminase acting on RNA (ADAR) enzymes. Long non-coding RNAs, particularly abundant in the brain, account for a large fraction of the human transcriptome, and their important regulatory role is becoming progressively evident in both normal and transformed cells. Results: Herein, we present a bioinformatic analysis to generate a comprehensive inosinome picture in long non-coding RNAs (lncRNAs), using an ad hoc index and searching for de novo editing events in the normal brain cortex as well as in glioblastoma, a highly aggressive human brain cancer. We discovered >10,000 new sites and 335 novel lncRNAs that undergo editing, never reported before. We found a generalized downregulation of editing at multiple lncRNA sites in glioblastoma samples when compared to the normal brain cortex. Conclusion: Overall, our study discloses a novel layer of complexity that controls lncRNAs in the brain and brain cancer.
Immunohistochemically Characterized Intratumoral Heterogeneity Is a Prognostic Marker in Human Glioblastoma
Authors: Liesche-Starnecker Friederike , Mayer Karoline , Kofler Florian , Baur Sandra , Schmidt-Graf Friederike , Kempter Johanna , Prokop Georg , Pfarr Nicole , Wei Wu , Gempt Jens , Combs Stephanie E. , Zimmer Claus , Meyer Bernhard , Wiestler Benedikt , Schlegel Jürgen
Published: October 2020

Tumor heterogeneity is considered to be a hallmark of glioblastoma (GBM). Only more recently, it has become apparent that GBM is not only heterogeneous between patients (intertumoral heterogeneity) but more importantly, also within individual patients (intratumoral heterogeneity). In this study, we focused on assessing intratumoral heterogeneity. For this purpose, the heterogeneity of 38 treatment-naïve GBM was characterized by immunohistochemistry. Perceptible areas were rated for ALDH1A3, EGFR, GFAP, Iba1, Olig2, p53, and Mib1. By clustering methods, two distinct groups similar to subtypes described in literature were detected. The classical subtype featured a strong EGFR and Olig2 positivity, whereas the mesenchymal subtype displayed a strong ALDH1A3 expression and a high fraction of Iba1-positive microglia. 18 tumors exhibited both subtypes and were classified as “subtype-heterogeneous”, whereas the areas of the other tumors were all assigned to the same cluster and named “subtype-dominant”. Results of epigenomic analyses corroborated these findings. Strikingly, the subtype-heterogeneous tumors showed a clearly shorter overall survival compared to subtype-dominant tumors. Furthermore, 21 corresponding pairs of primary and recurrent GBM were compared, showing a dominance of the mesenchymal subtype in the recurrent tumors. Our study confirms the prognostic impact of intratumoral heterogeneity in GBM, and more importantly, makes this hallmark assessable by routine diagnostics.
Understanding the Biological Activities of Vitamin D in Type 1 Neurofibromatosis: New Insights into Disease Pathogenesis and Therapeutic Design
Authors: Riccardi Claudia , Perrone Lorena , Napolitano Filomena , Sampaolo Simone , Melone Mariarosa Anna Beatrice
Published: October 2020

Vitamin D is a fat-soluble steroid hormone playing a pivotal role in calcium and phosphate homeostasis as well as in bone health. Vitamin D levels are not exclusively dependent on food intake. Indeed, the endogenous production—occurring in the skin and dependent on sun exposure—contributes to the majority amount of vitamin D present in the body. Since vitamin D receptors (VDRs) are ubiquitous and drive the expression of hundreds of genes, the interest in vitamin D has tremendously grown and its role in different diseases has been extensively studied. Several investigations indicated that vitamin D action extends far beyond bone health and calcium metabolism, showing broad effects on a variety of critical illnesses, including cancer, infections, cardiovascular and autoimmune diseases. Epidemiological studies indicated that low circulating vitamin D levels inversely correlate with cutaneous manifestations and bone abnormalities, clinical hallmarks of neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant tumour predisposition syndrome causing significant pain and morbidity, for which limited treatment options are available. In this context, vitamin D or its analogues have been used to treat both skin and bone lesions in NF1 patients, alone or combined with other therapeutic agents. Here we provide an overview of vitamin D, its characteristic nutritional properties relevant for health benefits and its role in NF1 disorder. We focus on preclinical and clinical studies that demonstrated the clinical correlation between vitamin D status and NF1 disease, thus providing important insights into disease pathogenesis and new opportunities for targeted therapy.
Cancer-Associated Fibroblasts: Accomplices in the Tumor Immune Evasion
Authors: Hilmi Marc , Nicolle Rémy , Bousquet Corinne , Neuzillet Cindy
Published: October 2020

Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment, by communicating with other cells within the tumor and by secreting the extracellular matrix components. The discovery of the immunogenic role of CAFs has made their study particularly attractive due to the potential applications in the field of cancer immunotherapy. Indeed, CAFs are highly involved in tumor immune evasion by physically impeding the immune system and interacting with both myeloid and lymphoid cells. However, CAFs do not represent a single cell entity but are divided into several subtypes with different functions that may be antagonistic. Considering that CAFs are orchestrators of the tumor microenvironment and modulate immune cells, targeting their functions may be a promising strategy. In this review, we provide an overview of (i) the mechanisms involved in immune regulation by CAFs and (ii) the therapeutic applications of CAFs modulation to improve the antitumor immune response and the efficacy of immunotherapy.
Stage-Specific Value of Carbohydrate Antigen 19-9 and Carcinoembryonic Antigen Serum Levels on Survival and Recurrence in Pancreatic Cancer: A Single Center Study and Meta-Analysis
Authors: van Manen Labrinus , Groen Jesse V. , Putter Hein , Pichler Martin , Vahrmeijer Alexander L. , Bonsing Bert A. , Mieog J. Sven D.
Published: October 2020

This study aimed to determine the stage-specific prognostic value of carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) serum levels at diagnosis on overall survival (OS) and time to local recurrence or distant metastases in patients with pancreatic ductal adenocarcinoma (PDAC). Consecutive PDAC patients, discussed at multidisciplinary team meetings from 2013 through 2017, were reviewed. Prognostic factors were stage-specific (resection vs. advanced PDAC) evaluated in Cox proportional hazard models. Additionally, a systematic literature search and meta-analysis was performed, as current literature is lacking a complete overview of used cut-off values and the added value of CEA as prognostic marker. In the retrospective cohort, elevated CA19-9 (>305 kU/L) level was independently associated with poor OS (Hazard ratio (HR): 1.72(1.31–2.26)) and early recurrence (HR: 1.74(1.06–2.86)), whereas CEA was not significantly associated. The meta-analysis showed that both elevated CA19-9 and CEA serum levels were predictors for poor OS (pooled HR: 1.29(1.17–1.42) and HR: 1.51(1.33–1.73), respectively). In the resected cohort, elevated CA19-9 level was significantly associated with early recurrence (pooled HR: 2.41(1.77–3.29)), whereas CEA was not. Elevated CA19-9 serum level appear to be an independent prognostic factor for poor OS and early recurrence in PDAC patients, whereas the prognostic value of CEA is disputable.
FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer
Authors: Sasaki Norihiko , Gomi Fujiya , Yoshimura Hisashi , Yamamoto Masami , Matsuda Yoko , Michishita Masaki , Hatakeyama Hitoshi , Kawano Yoichi , Toyoda Masashi , Korc Murray , Ishiwata Toshiyuki
Published: October 2020

Fibroblast growth factor receptor 4 (FGFR4), one of four tyrosine kinase receptors for FGFs, is involved in diverse cellular processes. Activation of FGF19/FGFR4 signaling is closely associated with cancer development and progression. In this study, we examined the expression and roles of FGF19/FGFR4 signaling in human pancreatic ductal adenocarcinoma (PDAC). In human PDAC cases, FGFR4 expression positively correlated with larger primary tumors and more advanced stages. Among eight PDAC cell lines, FGFR4 was expressed at the highest levels in PK-1 cells, in which single-nucleotide polymorphism G388R in FGFR4 was detected. For inhibition of autocrine/paracrine FGF19/FGFR4 signaling, we used BLU9931, a highly selective FGFR4 inhibitor. Inhibition of signal transduction through ERK, AKT, and STAT3 pathways by BLU9931 reduced proliferation in FGF19/FGFR4 signaling-activated PDAC cells. By contrast, BLU9931 did not alter stemness features, including stemness marker expression, anticancer drug resistance, and sphere-forming ability. However, BLU9931 inhibited cell invasion, in part, by downregulating membrane-type matrix metalloproteinase-1 in FGF19/FGFR4 signaling-activated PDAC cells. Furthermore, downregulation of SIRT1 and SIRT6 by BLU9931 contributed to senescence induction, priming these cells for quercetin-induced death, a process termed senolysis. Thus, we propose that BLU9931 is a promising therapeutic agent in FGFR4-positive PDAC, especially when combined with senolysis (195/200).
VRK1 Phosphorylates Tip60/KAT5 and Is Required for H4K16 Acetylation in Response to DNA Damage
Authors: García-González Raúl , Morejón-García Patricia , Campillo-Marcos Ignacio , Salzano Marcella , Lazo Pedro A.
Published: October 2020

Dynamic remodeling of chromatin requires acetylation and methylation of histones, frequently affecting the same lysine residue. These alternative epigenetic modifications require the coordination of enzymes, writers and erasers, mediating them such as acetylases and deacetylases. In cells in G0/G1, DNA damage induced by doxorubicin causes an increase in histone H4K16ac, a marker of chromatin relaxation. In this context, we studied the role that VRK1, a chromatin kinase activated by DNA damage, plays in this early step. VRK1 depletion or MG149, a Tip60/KAT5 inhibitor, cause a loss of H4K16ac. DNA damage induces the phosphorylation of Tip60 mediated by VRK1 in the chromatin fraction. VRK1 directly interacts with and phosphorylates Tip60. Furthermore, the phosphorylation of Tip60 induced by doxorubicin is lost by depletion of VRK1 in both ATM +/+ and ATM−/− cells. Kinase-active VRK1, but not kinase-dead VRK1, rescues Tip60 phosphorylation induced by DNA damage independently of ATM. The Tip60 phosphorylation by VRK1 is necessary for the activating acetylation of ATM, and subsequent ATM autophosphorylation, and both are lost by VRK1 depletion. These results support that the VRK1 chromatin kinase is an upstream regulator of the initial acetylation of histones, and an early step in DNA damage responses (DDR).
Racial/Ethnic Disparities and Survival Characteristics in Non-Pancreatic Gastrointestinal Tract Neuroendocrine Tumors
Authors: Goksu Suleyman Yasin , Ozer Muhammet , Beg Muhammad S. , Sanford Nina Niu , Ahn Chul , Fangman Benjamin D. , Goksu Busra B. , Verma Udit , Sanjeevaiah Aravind , Hsiehchen David , Jones Amy L. , Kainthla Radhika , Kazmi Syed M.
Published: October 2020

Background: We studied the effect of race and ethnicity on disease characteristics and survival in gastrointestinal neuroendocrine tumors. Methods: The Surveillance, Epidemiology, and End Results database was used to select patients with non-pancreatic gastrointestinal neuroendocrine tumors diagnosed between 2004 and 2015. Trends in survival were evaluated among three groups: Hispanic, non-Hispanic White, and non-Hispanic Black. Kaplan–Meier and Cox regression methods were performed to calculate overall survival and cause-specific survival after adjusting for patient and tumor characteristics. Results: A total of 26,399 patients were included in the study: 65.1% were non-Hispanic White, 19.9% were non-Hispanic Black, and 15% were Hispanic. Non-Hispanic White patients were more likely to be male (50.0%, p < 0.001), older than 60 years (48.0%, p < 0.001), and present with metastatic disease (17.7%, p < 0.001). Non-Hispanic White patients had small intestine neuroendocrine tumors, while Hispanic and non-Hispanic Black patients had rectum neuroendocrine tumors as the most common primary site. Hispanic patients had better overall survival, while non-Hispanic Black patients had better cause-specific survival versus non-Hispanic White patients. This finding was confirmed on multivariable analysis where Hispanic patients had improved overall survival compared to non-Hispanic White patients (Hazard ratio (HR): 0.89 (0.81–0.97)), whereas non-Hispanic Black patients had better cause-specific survival compared to non-Hispanic White patients (HR: 0.89 (0.80–0.98)). Conclusions: Race/ethnicity is an independent prognostic factor in patients with gastrointestinal neuroendocrine tumors.
KIR+ CD8+ T Lymphocytes in Cancer Immunosurveillance and Patient Survival: Gene Expression Profiling
Authors: Gimeno Lourdes , Serrano-López Emilio M. , Campillo José A. , Cánovas-Zapata María A. , Acuña Omar S. , García-Cózar Francisco , Martínez-Sánchez María V. , Martínez-Hernández María D. , Soto-Ramírez María F. , López-Cubillana Pedro , Martínez-Escribano Jorge , Martínez-García Jerónimo , Corbalan-García Senena , Álvarez-López María R. , Minguela Alfredo
Published: October 2020

Killer-cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) and effector T cells. Although KIR+ T cells accumulate in oncologic patients, their role in cancer immune response remains elusive. This study explored the role of KIR+CD8+ T cells in cancer immunosurveillance by analyzing their frequency at diagnosis in the blood of 249 patients (80 melanomas, 80 bladder cancers, and 89 ovarian cancers), their relationship with overall survival (OS) of patients, and their gene expression profiles. KIR2DL1+ CD8+ T cells expanded in the presence of HLA-C2-ligands in patients who survived, but it did not in patients who died. In contrast, presence of HLA-C1-ligands was associated with dose-dependent expansions of KIR2DL2/S2+ CD8+ T cells and with shorter OS. KIR interactions with their specific ligands profoundly impacted CD8+ T cell expression profiles, involving multiple signaling pathways, effector functions, the secretome, and consequently, the cellular microenvironment, which could impact their cancer immunosurveillance capacities. KIR2DL1/S1+ CD8+ T cells showed a gene expression signature related to efficient tumor immunosurveillance, whereas KIR2DL2/L3/S2+CD8+ T cells showed transcriptomic profiles related to suppressive anti-tumor responses. These results could be the basis for the discovery of new therapeutic targets so that the outcome of patients with cancer can be improved.
FGF2-Derived PeptibodyF2-MMAE Conjugate for Targeted Delivery of Cytotoxic Drugs into Cancer Cells Overexpressing FGFR1
Authors: Jendryczko Karolina , Chudzian Julia , Skinder Natalia , Opaliński Łukasz , Rzeszótko Jakub , Wiedlocha Antoni , Otlewski Jacek , Szlachcic Anna
Published: October 2020

Fibroblast growth factor receptors (FGFRs) are emerging targets for directed cancer therapy. Presented here is a new FGFR1-targeting conjugate, the peptibodyF2, which employs peptibody, a fusion of peptide and the Fc fragment of human IgG as a selective targeting agent and drug carrier. Short peptide based on FGF2 sequence was used to construct a FGFR1-targeting peptibody. We have shown that this peptide ensures specific delivery of peptibodyF2 into FGFR1-expressing cells. In order to use peptibodyF2 as a delivery vehicle for cytotoxic drugs, we have conjugated it with MMAE, a drug widely used in antibody–drug conjugates for targeted therapy. Resulting conjugate shows high and specific cytotoxicity towards FGFR1-positive cells, i.e., squamous cell lung carcinoma NCI-H520, while remaining non-toxic for FGFR1-negative cells. Such peptibody–drug conjugate can serve as a basis for development of therapy for tumors with overexpressed or malfunctioning FGFRs.