bluuebunny/crossref_metadata_2025 huggingface dataset:
Induction of p53-Dependent Apoptosis by Prostaglandin A2
Authors: Lee Su-Been , Lee Sangsun , Park Ji-Young , Lee Sun-Young , Kim Ho-Shik
Published: March 2020

Prostaglandin (PG) A2, one of cyclopentenone PGs, is known to induce activation of apoptosis in various cancer cells. Although PGA2 has been reported to cause activation of apoptosis by altering the expression of apoptosis-related genes, the role of p53, one of the most critical pro-apoptotic genes, on PGA2-induced apoptosis has not been clarified yet. To address this issue, we compared the apoptosis in HCT116 p53 null cells (HCT116 p53-/-) to that in HCT116 cells containing the wild type p53 gene. Cell death induced by PGA2 was associated with phosphorylation of histone H2A variant H2AX (H2AX), activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase 1 in HCT116 cells. Induction of apoptosis in PGA2-treated cells was almost completely prevented by pretreatment with a pan-caspase inhibitor, z-VAD-Fmk, or an inhibitor of protein synthesis, cycloheximide. While PGA2 induced apoptosis in HCT116 cells, phosphorylation of p53 and transcriptional induction of p53-target genes such as p21WAF1, PUMA, BAX, NOXA, and DR5 occurred. Besides, pretreatment of pifithrin-α (PFT-α), a chemical inhibitor of p53’s transcriptional activity, interfered with the induction of apoptosis in PGA2-treated HCT116 cells. Pretreatment of NU7441, a small molecule inhibitor of DNA-activated protein kinase (DNA-PK) suppressed PGA2-induced phosphorylation of p53 and apoptosis as well. Moreover, among target genes of p53, knockdown of DR5 expression by RNA interference, suppressed PGA2-induced apoptosis. In the meanwhile, in HCT116 p53-/- cells, PGA2 induced apoptosis in delayed time points and with less potency. Delayed apoptosis by PGA2 in HCT116 p53-/- cells was also associated with phosphorylation of H2AX but was not inhibited by either PFT-α or NU7441. Collectively, these results suggest the following. PGA2 may induce p53-dependent apoptosis in which DNA-PK activates p53, and DR5, a transcriptional target of p53, plays a pivotal role in HCT116 cells. In contrast to apoptosis in HCT116 cells, PGA2 may induce apoptosis in a fashion of less potency, which is independent of p53 and DNA-PK in HCT116 p53-/- cells
Transcriptomic and Genomic Testing to Guide Individualized Treatment in Chemoresistant Gastric Cancer Case
Authors: Moisseev Alexey , Albert Eugene , Lubarsky Dan , Schroeder David , Clark Jeffrey
Published: March 2020

Gastric cancer is globally the fifth leading cause of cancer death. We present a case report describing the unique genomic characteristics of an Epstein–Barr virus-negative gastric cancer with esophageal invasion and regional lymph node metastasis. Genomic tests were performed first with the stomach biopsy using platforms FoundationOne, OncoDNA, and Oncopanel at Dana Farber Institute. Following neoadjuvant chemotherapy, residual tumor was resected and the stomach and esophageal residual tumor samples were compared with the initial biopsy by whole exome sequencing and molecular pathway analysis platform Oncobox. Copy number variation profiling perfectly matched the whole exome sequencing results. A moderate agreement was seen between the diagnostic platforms in finding mutations in the initial biopsy. Final data indicate somatic activating mutation Q546K in PIK3CA gene, somatic frameshifts in PIH1D1 and FBXW7 genes, stop-gain in TP53BP1, and a few somatic mutations of unknown significance. RNA sequencing analysis revealed upregulated expressions of MMP7, MMP9, BIRC5, and PD-L1 genes and strongly differential regulation of several molecular pathways linked with the mutations identified. According to test results, the patient received immunotherapy with anti-PD1 therapy and is now free of disease for 2 years. Our data suggest that matched tumor and normal tissue analyses have a considerable advantage over tumor biopsy-only genomic tests in stomach cancer.
Effects of Repetitive Transcranial Magnetic Stimulation (rTMS) Combined with Aerobic Exercise on the Recovery of Motor Function in Ischemic Stroke Rat Model
Authors: Cui Juanxiu , Kim Cuk-Seong , Kim Yeongwook , Sohn Min Kyun , Jee Sungju
Published: March 2020

The therapeutic benefits of repetitive transcranial magnetic stimulation (rTMS) combined with rehabilitation therapy on recovery after stroke have not been fully elucidated. This study aimed to explore the therapeutic effects of rTMS followed by aerobic exercise on neuroplasticity and recovery of motor function in a rat model of permanent middle cerebral artery occlusion (MCAO). Rats were randomized into sham operation (N = 10, sham op), MCAO (N = 10, control group), rTMS (N = 10, MCAO and rTMS therapy), and combination groups (N = 10, MCAO and combination therapy). High-frequency rTMS (10 Hz) was applied on the ipsilesional forepaw motor cortex, and aerobic exercise training on the rotarod was performed for two weeks. The rotarod and Garcia tests were conducted to evaluate changes in behavioral function. Motor evoked potentials (MEPs) were used to evaluate electrophysiological changes. Stroke severity was assessed using infarction volume measurement. Neuronal recovery was explored with western blot for brain-derived neurotrophic factor (BDNF) pathway proteins. Compared with control therapy, combination therapy was significantly more effective than rTMS therapy for improving function on the rotarod test (p = 0.08), Garcia test (p = 0.001), and MEP amplitude (p = 0.001) In conclusion, combination therapy may be a potential treatment to promote recovery of motor function and neuroplasticity in stroke patients.
A Simple Pattern of Movement Is Not Able to Inhibit Experimental Pain in FM Patients and Controls: An sLORETA Study
Authors: Gentile Eleonora , Ricci Katia , Vecchio Eleonora , Libro Giuseppe , Delussi Marianna , Casas-Barragàn Antonio , de Tommaso Marina
Published: March 2020

Motor cortex activation seems to induce an analgesic effect on pain that would be different between patients with fibromyalgia (FM) and control subjects. This study was conducted to analyze the changes of the laser-evoked potentials (LEPs) induced during a finger tapping task in the FM patients and the controls employing a multi-dipolar analysis according to Standardized low resolution brain electromagnetic tomography (sLORETA) method. The LEPs from 38 FM patients and 21 controls were analyzed. The LEPs were recorded while subjects performed a slow and a fast finger tapping task. We confirmed that the difference between N1, N2 and P2 wave amplitudes between conditions and groups was not significant. In control subjects, the fast finger tapping task induced a modification of cortical source activation in the main areas processing laser stimulation from the moving hand independently from the movement speed. In summary, a simple and repetitive movement is not able to induce consistent inhibition of experimental pain evoked by the moving and the not moving hand in each group. It could interfere with LEP sources within the limbic area at least in control subjects, without inhibit cortical responses or explain the different pattern of motor and pain interaction in FM patients.
Mitotane Concentrations Influence Outcome in Patients with Advanced Adrenocortical Carcinoma
Authors: Puglisi Soraya , Calabrese Anna , Basile Vittoria , Ceccato Filippo , Scaroni Carla , Altieri Barbara , Della Casa Silvia , Loli Paola , Pivonello Rosario , De Martino Maria Cristina , Canu Letizia , Russo Marco , Badalamenti Giuseppe , Torlontano Massimo , Stigliano Antonio , Ferraù Francesco , Arnaldi Giorgio , Saba Laura , Quirino Alessandra , Perotti Paola , Berchialla Paola , Terzolo Massimo
Published: March 2020

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online® database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.
The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response
Authors: Cabrita Rita , Mitra Shamik , Sanna Adriana , Ekedahl Henrik , Lövgren Kristina , Olsson Håkan , Ingvar Christian , Isaksson Karolin , Lauss Martin , Carneiro Ana , Jönsson Göran
Published: March 2020

Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The PTEN gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor (MITF) gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of MITF expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.
LRRC15 Targeting in Soft-Tissue Sarcomas: Biological and Clinical Implications
Authors: Ben-Ami Eytan , Perret Raul , Huang Ying , Courgeon Félicie , Gokhale Prafulla C. , Laroche-Clary Audrey , Eschle Benjamin K. , Velasco Valérie , Le Loarer François , Algeo Marie-Paule , Purcell James , Demetri George D. , Italiano Antoine
Published: March 2020

Background: LRRC15 is a member of the LRR (leucine-rich repeat) superfamily present on tumor-associated fibroblasts (CAFs) and stromal cells. The expression of LRRC15 is upregulated by the pro-inflammatory cytokine TGFβ. ABBV-085 is a monomethyl auristatin E (MMAE)-containing antibody-drug conjugate (ADC) designed to target LRRC15, and which has shown significant anti-tumor activity in several tumor models. This is the first focused examination of LRRC15 expression and ABBV-085 activity in soft-tissue sarcomas (STS). Methods: We analyzed the LRRC15 expression profile by immunohistochemistry in 711 STS cases, covering a broad spectrum of STS histologies and sub-classifications. In vivo experiments were carried out by using LRRC15-positive and LRRC15-negative patient-derived xenograft (PDX) models of STS. Results: In contrast to patterns observed in epithelial tumors, LRRC15 was expressed not only by stromal cells but also by cancer cells in multiple subsets of STS with significant variations noted between histological subtypes. Overexpression of LRRC15 is positively correlated with grade and independently associated with adverse outcome. ABBV-085 has robust preclinical efficacy against LRRC15 positive STS patient-derived xenograft (PDX) models. Conclusion: We provide the first preclinical evidence that LRRC15 targeting with an antibody-drug conjugate is a promising strategy in LRRC15-positive STS. ABBV-085 is being evaluated in an ongoing clinical trial in STS and other malignancies.
MeCP2 Promotes Colorectal Cancer Metastasis by Modulating ZEB1 Transcription
Authors: Luo Dan , Ge Wei
Published: March 2020

Background: Recurrence and distant organ metastasis is a major cause of death in colorectal cancer (CRC); however, the underlying molecular mechanisms regulating this phenomenon are poorly understood. MeCP2 is a key epigenetic regulator and is amplified in many types of cancer. Its role in CRC and the molecular mechanisms underlying its action remain unknown. Methods: We used western blot and immunohistochemistry to detect MeCP2 expression in CRC tissues, and then investigated its biological functions in vitro and in vivo. Chromatin immunoprecipitation, co-immunoprecipitation, and electrophoretic mobility shift assays were used to detect the associations among MeCP2 (Methyl-CpG binding protein 2), SPI1 (Spi-1 Proto-Oncogene), and ZEB1 (Zinc Finger E-Box Binding Homeobox 1). Results: Using the Cancer Genome Atlas and Oncomine databases, we found MeCP2 expression was upregulated in CRC tissues and this upregulation was related to poor prognosis. Meanwhile, MeCP2 depletion (KO/KD) in CRC cells significantly inhibited stem cell frequency, and invasion and migration ability in vitro, and suppressed CRC metastasis in vivo. Mechanistically, we show MeCP2 binds to the transcription factor SPI1, and aids its recruitment to the ZEB1 promoter. SPI1 then facilitates ZEB1 expression at the transcription level. In turn, ZEB1 induces the expression of MMP14, CD133, and SOX2, thereby maintaining CRC stemness and metastasis. Conclusions: MeCP2 is a novel regulator of CRC metastasis. MeCP2 suppression may be a promising therapeutic strategy in CRC.
Protein Expression in Metastatic Melanoma and the Link to Disease Presentation in a Range of Tumor Phenotypes
Authors: Kim Yonghyo , Gil Jeovanis , Pla Indira , Sanchez Aniel , Betancourt Lazaro Hiram , Lee Boram , Appelqvist Roger , Ingvar Christian , Lundgren Lotta , Olsson Håkan , Baldetorp Bo , Kwon Ho Jeong , Oskolás Henriett , Rezeli Melinda , Doma Viktoria , Kárpáti Sarolta , Szasz A. Marcell , Németh István Balázs , Malm Johan , Marko-Varga György
Published: March 2020

Malignant melanoma is among the most aggressive skin cancers and it has among the highest metastatic potentials. Although surgery to remove the primary tumor is the gold standard treatment, once melanoma progresses and metastasizes to the lymph nodes and distal organs, i.e., metastatic melanoma (MM), the usual outcome is decreased survival. To improve survival rates and life span, advanced treatments have focused on the success of targeted therapies in the MAPK pathway that are based on BRAF (BRAF V600E) and MEK. The majority of patients with tumors that have higher expression of BRAF V600E show poorer prognosis than patients with a lower level of the mutated protein. Based on the molecular basis of melanoma, these findings are supported by distinct tumor phenotypes determined from differences in tumor heterogeneity and protein expression profiles. With these aspects in mind, continued challenges are to: (1) deconvolute the complexity and heterogeneity of MM; (2) identify the signaling pathways involved; and (3) determine protein expression to develop targeted therapies. Here, we provide an overview of the results from protein expression in MM and the link to disease presentation in a variety of tumor phenotypes and how these will overcome the challenges of clinical problems and suggest new promising approaches in metastatic melanoma and cancer therapy.
30 Years of Experience in the Management of Stage III and IV Epithelial Ovarian Cancer: Impact of Surgical Strategies on Survival
Authors: Delga Berenice , Classe Jean-Marc , Houvenaeghel Gilles , Blache Guillaume , Sabiani Laura , El Hajj Houssein , Andrieux Nicole , Lambaudie Eric
Published: March 2020

Objective: to analyze the evolution of surgical techniques and strategies, and to determine their influence on the survival of patients with stage III or IV epithelial ovarian cancer (EOC). Methods: a retrospective data analysis was performed in two French tertiary cancer institutes. The analysis included clinical information, cytoreductive outcome (complete, optimal and suboptimal), definitive pathology, Overall Survival (OS), and Progression-Free Survival (PFS). Three surgical strategies were compared: Primary Cytoreductive Surgery (PCS), Interval Cytoreductive Surgery (ICS) after three cycles of Neo-Adjuvant Chemotherapy (NAC), and Final Cytoreductive Surgery (FCS) after at least six cycles of NAC. We analyzed four distinct time intervals: prior to 2000, between 2000 and 2004, between 2005 and 2009, and after 2009. Results: data from 1474 patients managed for International Federation of Gynecology and Obstetrics (FIGO) stages III (80%) or IV (20%) EOC were analyzed. Throughout the four time intervals, the rate of patients who were treated only medically increased significantly (10.1% vs. 22.6% p < 0.001). NAC treatment increased from 20.1% to 52.2% (p < 0.001). Complete resection rate increased from 37% to 66.2% (p < 0.001). Of our study population, 1260 patients (85.5%) underwent surgery. OS was longer in cases of complete cytoreduction (Hazard Ratio (HR) = 2.123 CI 95% [1.816–2.481] p < 0.001) but the surgical strategy itself did not affect median OS. OS was 44.9 months, 50.3 months, and 42 months for PCS, ICS, and FCS, respectively (p = 0.410). After adjusting for surgical strategies (PCS, ICS, and FCS), all patients with complete cytoreduction presented similar OS with no significant difference. However, PFS was three months shorter when FCS was compared to PCS (p < 0.001). Conclusion: In our 30 years’ experience of EOC management, complete resection rate was the only independent factor that significantly improved OS and PFS, regardless of the surgical strategy.
Accessing a New Dimension in TP53 Biology: Multiplex Long Amplicon Digital PCR to Specifically Detect and Quantitate Individual TP53 Transcripts
Authors: Lasham Annette , Tsai Peter , Fitzgerald Sandra J. , Mehta Sunali Y. , Knowlton Nicholas S. , Braithwaite Antony W. , Print Cristin G.
Published: March 2020

TP53, the most commonly-mutated gene in cancer, undergoes complex alternative splicing. Different TP53 transcripts play different biological roles, both in normal function and in the progression of diseases such as cancer. The study of TP53’s alternative RNA splice forms and their use as clinical biomarkers has been hampered by limited specificity and quantitative accuracy of current methods. TP53 RNA splice variants differ at both 5’ and 3’ ends, but because they have a common central region of 618 bp, the individual TP53 transcripts are impossible to specifically detect and precisely quantitate using standard PCR-based methods or short-read RNA sequencing. Therefore, we devised multiplex probe-based long amplicon droplet digital PCR (ddPCR) assays, which for the first time allow precise end-to-end quantitation of the seven major TP53 transcripts, with amplicons ranging from 0.85 to 1.85 kb. Multiple modifications to standard ddPCR assay procedures were required to enable specific co-amplification of these long transcripts and to overcome issues with secondary structure. Using these assays, we show that several TP53 transcripts are co-expressed in breast cancers, and illustrate the potential for this method to identify novel TP53 transcripts in tumour cells. This capability will facilitate a new level of biological and clinical understanding of the alternatively-spliced TP53 isoforms.
Promoting Li/MgO Catalyst with Molybdenum Oxide for Oxidative Conversion of n-Hexane
Authors: Boyadjian Cassia , Lefferts Leon
Published: March 2020

In this work, molybdena-promoted Li/MgO is studied as a catalyst for the oxidative conversion of n-hexane. The structure of the catalysts is investigated with X-ray Diffraction (XRD) and Raman spectroscopy. The MoO3/Li/MgO catalyst contains three types of molybdena-containing species, the presence of which depend on molybdena loading. At low Mo/Li ratios (i) isolated dispersed [MoO4]2− anionic species are observed. At high Mo/Li ratios, the formation of crystalline lithium molybdate phases such as (ii) monomeric Li2MoO4 and tentatively (iii) polymeric Li2Mo4O13 are concluded. The presence of these lithium molybdates diminishes the formation of Li2CO3 in the catalyst. Subsequently, the catalyst maintains high surface area and stability with time-on-stream during oxidative conversion. Molybdena loading as low as 0.5 wt % is sufficient to induce these improvements, maintaining the non-redox characteristics of the catalyst, whereas higher loadings enhance deep oxidation and oxidative dehydrogenation reactions. Promoting a Li/MgO catalyst with 0.5 wt % MoO3 is thus efficient for selective conversion of n-hexane to alkenes, giving alkene yield up to 24% as well as good stability.
NK cells and CD38: Implication for (Immuno)Therapy in Plasma Cell Dyscrasias
Authors: Zambello Renato , Barilà Gregorio , Manni Sabrina , Piazza Francesco , Semenzato Gianpietro
Published: March 2020

Immunotherapy represents a promising new avenue for the treatment of multiple myeloma (MM) patients, particularly with the availability of Monoclonal Antibodies (mAbs) as anti-CD38 Daratumumab and Isatuximab and anti-SLAM-F7 Elotuzumab. Although a clear NK activation has been demonstrated for Elotuzumab, the effect of anti-CD38 mAbs on NK system is controversial. As a matter of fact, an initial reduction of NK cells number characterizes Daratumumab therapy, limiting the potential role of this subset on myeloma immunotherapy. In this paper we discuss the role of NK cells along with anti-CD38 therapy and their implication in plasma cell dyscrasias, showing that mechanisms triggered by anti-CD38 mAbs ultimately lead to the activation of the immune system against myeloma cell growth.
Functional Phenotypes of Human Vγ9Vδ2 T Cells in Lymphoid Stress Surveillance
Authors: Nussbaumer Oliver , Thurnher Martin
Published: March 2020

Butyrophilin and butyrophilin-like proteins select γδ T cells and direct the migration of γδ T cell subsets to distinct anatomical sites. γδ T cells expressing Vδ2 paired with Vγ9 (Vγ9Vδ2 T cells) are the predominant γδ T cell type in human peripheral blood. Vγ9Vδ2 T cells, which cannot be studied easily in vivo because they do not exist in rodents, are often referred to as innate-like T cells. The genetically recombined γδ T cell receptor (TCR) that responds to isoprenoid-derived pyrophosphates (phosphoantigens) produced by infected and malignant cells in a butyrophilin-dependent manner qualifies them as therapeutically relevant components of the adaptive immune system. On the other hand, cell-surface proteins such as the C-type lectin CD161 mark a functional phenotype of Vγ9Vδ2 T cells that mediates TCR-independent innate-like responses. Moreover, CD56 (neural cell adhesion molecule, NCAM) and the G protein-coupled receptor GPR56 define Vγ9Vδ2 T cells with increased cytolytic potential and, like CD161, may also be expressed by dendritic cells, principally facilitating the generation of an innate-like immunological synapse. In this review, we summarise current knowledge of Vγ9Vδ2 T cell functional phenotypes that are critical to lymphoid stress surveillance.
Transcriptomic Insights into Mechanisms of Early Seed Maturation in the Garden Pea (Pisum sativum L.)
Authors: Malovichko Yury V. , Shtark Oksana Y. , Vasileva Ekaterina N. , Nizhnikov Anton A. , Antonets Kirill S.
Published: March 2020

The garden pea (Pisum sativum L.) is a legume crop of immense economic value. Extensive breeding has led to the emergence of numerous pea varieties, of which some are distinguished by accelerated development in various stages of ontogenesis. One such trait is rapid seed maturation, which, despite novel insights into the genetic control of seed development in legumes, remains poorly studied. This article presents an attempt to dissect mechanisms of early maturation in the pea line Sprint-2 by means of whole transcriptome RNA sequencing in two developmental stages. By using a de novo assembly approach, we have obtained a reference transcriptome of 25,756 non-redundant entries expressed in pea seeds at either 10 or 20 days after pollination. Differential expression in Sprint-2 seeds has affected 13,056 transcripts. A comparison of the two pea lines with a common maturation rate demonstrates that while at 10 days after pollination, Sprint-2 seeds show development retardation linked to intensive photosynthesis, morphogenesis, and cell division, and those at 20 days show a rapid onset of desiccation marked by the cessation of translation and cell anabolism and accumulation of dehydration-protective and -storage moieties. Further inspection of certain transcript functional categories, including the chromatin constituent, transcription regulation, protein turnover, and hormonal regulation, has revealed transcriptomic trends unique to specific stages and cultivars. Among other remarkable features, Sprint-2 demonstrated an enhanced expression of transposable element-associated open reading frames and an altered expression of major maturation regulators and DNA methyltransferase genes. To the best of our knowledge, this is the first comparative transcriptomic study in which the issue of the seed maturation rate is addressed.
A Wnt-BMP4 Signaling Axis Induces MSX and NOTCH Proteins and Promotes Growth Suppression and Differentiation in Neuroblastoma
Authors: Szemes Marianna , Melegh Zsombor , Bellamy Jacob , Greenhough Alexander , Kollareddy Madhu , Catchpoole Daniel , Malik Karim
Published: March 2020

The Wnt and bone morphogenetic protein (BMP) signaling pathways are known to be crucial in the development of neural crest lineages, including the sympathetic nervous system. Surprisingly, their role in paediatric neuroblastoma, the prototypic tumor arising from this lineage, remains relatively uncharacterised. We previously demonstrated that Wnt/β-catenin signaling can have cell-type-specific effects on neuroblastoma phenotypes, including growth inhibition and differentiation, and that BMP4 mRNA and protein were induced by Wnt3a/Rspo2. In this study, we characterised the phenotypic effects of BMP4 on neuroblastoma cells, demonstrating convergent induction of MSX homeobox transcription factors by Wnt and BMP4 signaling and BMP4-induced growth suppression and differentiation. An immunohistochemical analysis of BMP4 expression in primary neuroblastomas confirms a striking absence of BMP4 in poorly differentiated tumors, in contrast to a high expression in ganglion cells. These results are consistent with a tumor suppressive role for BMP4 in neuroblastoma. RNA sequencing following BMP4 treatment revealed induction of Notch signaling, verified by increases of Notch3 and Hes1 proteins. Together, our data demonstrate, for the first time, Wnt-BMP-Notch signaling crosstalk associated with growth suppression of neuroblastoma.
Farmers’ Willingness to Pay for Index-Based Livestock Insurance in the North West of South Africa
Authors: Oduniyi Oluwaseun Samuel , Antwi Michael Akwasi , Tekana Sibongile Sylvia
Published: March 2020

Rural livelihoods in most developing countries are threatened by climate-related risks such as drought, flood, heat waves, storms, and so on. Although farmers have adopted several adaptation strategies, they have proven less effective than hoped. Hence, index-based livestock insurance, an innovation that significantly assists farmers to acclimatise to climate-related risks, has been proposed; and its adaptability has attracted a notable increase in other African countries. However, the success of its adoption is dependent on the inclination of the farmers to pay for the service. Accordingly, this study investigates their willingness to pay for index-based livestock insurance and its determinants, and the factors influencing the total livestock units to be insured in the North West province of South Africa. Cross-sectional data were obtained from 277 cattle farmers, drawn randomly from the study area. The contingent valuation method was applied to determine the farmers’ willingness to pay; and only 10.8% were willing to pay. Simultaneously, the Heckit sample selection model was used to analyse the data to identify the factors responsible for farmers’ willingness to pay and total livestock units to insure. The findings revealed that farmer’s experience, age, education, marital status, awareness of insurance and household dependents were statistically significant, and influenced the maximum price R600 ($42, max willingness to pay, WTP) of those who accepted index-based livestock insurance. However, by implication, the study concluded that to adopt index-based livestock insurance in the study area among the livestock farmers, there should be policies to cater for the aforementioned factors.
Correction: Wen et al. Fabrication of Dense Gadolinia-Doped Ceria Coatings via Very-Low-Pressure Plasma Spray and Plasma Spray–Physical Vapor Deposition Process. Coatings 2019, 9, 717
Authors: Wen Jing , Song Chen , Liu Taikai , Deng Ziqian , Niu Shaopeng , Zhang Yapeng , Liu Libin , Liu Min
Published: March 2020

The author wishes to make the following correction to this paper [...]
Phytochemical Compounds as Cleaning Agents on Granite Colonized by Phototrophic Subaerial Biofilms
Authors: Genova Chiara , Fuentes Elsa , Sanmartín Patricia , Favero Gabriele , Prieto Beatriz
Published: March 2020

The society has become increasingly interested in using natural products over chemicals for cleaning activities. In this study, the cleaning potential of formulations embedded in a hydrogel matrix and composed respectively of essential oils (EOs) of Origanum vulgare, Thymus vulgaris, and Calamintha nepeta, and their respective main active components (EO-ACs), viz., Carvacrol, Thymol, and Pulegone, on a phototropic biofilm growing on granite was investigated. In addition, and for comparative purposes, analysis with the combination of the three EOs, the combination of the three EO-ACs, and Preventol RI-80® (one of the most effective commercial cleaning agents based on quaternary ammonium salts) in all three cases embedded in a hydrogel matrix, as well as only the hydrogel matrix, distilled water, and Preventol RI-80®, in both latter cases applied with brush, were also studied. The cleaning effect of the treatments was assessed immediately after the treatment and after one and two weeks by color spectrophotometry, a reliable tool to evaluate the presence and vitality of the phototrophs and the cleaning effectiveness in granite. C. nepeta and its active component Pulegone proved to be the most effective and yielded similar results, comparable to those of uncolonized granite, and better than those obtained with Preventol RI-80® applied with brush (most common way), especially at the end of the experiment. These promising first results support the suitable use of the phytochemical compounds used on phototrophs field where there are still few published studies and encourage further investigation toward the evaluation of their exhibited biocidal activity.
Metallurgical Soldering of Duplex CrN Coating in Contact with Aluminum Alloy
Authors: Terek Pal , Kovačević Lazar , Miletić Aleksandar , Škorić Branko , Kovač Janez , Drnovšek Aljaž
Published: March 2020

Coatings deposited by physical vapor deposition (PVD) significantly reduce the wear of high pressure die casting tools; however, cast alloy soldering still has a strong negative effect on production efficiency. Although a lot of research has been already done in this field, the fundamental understanding of aluminum alloy soldering toward PVD coatings is still scarce. Therefore, in this work the performance of CrN duplex coatings with different roughness is evaluated by a modified ejection test performed with delayed (DS) and conventional casting solidification (CS). After the ejection tests, sample surfaces and layers were subjected to comprehensive characterizations of their morphological and chemical characteristics. Considerably lower values of the ejection force were recorded in DS experiments than in CS experiments. Surface roughness played an important role in the CS experiments, while samples with different surface topographies in the DS experiments performed in a similar fashion. The decrease in the ejection force, observed in DS tests, is attributed to the formation of a thick Cr–O layer on CrN coating which reduced soldering and sliding friction against thick Al–O casting scale. The Cr–O layer formed in DS experiments suffered from diffusion wear by cast alloy. The observed oxidation phenomena of nitride coatings may be utilized in a design of non-sticking coatings.
Raman Spectra of Diphenylalanine Microtubes: Polarisation and Temperature Effects
Authors: Krylov Alexander , Krylova Svetlana , Kopyl Svitlana , Krylov Aleksandr , Salehli Ferid , Zelenovskiy Pavel , Vtyurin Alexander , Kholkin Andrei
Published: March 2020

Diphenylalanine microtubes have remarkable physical properties that allow one to use them in electronics. In this work, we measured polarised temperature-dependent Raman spectra in self-assembled diphenylalanine microtubes grown from the solution. We observed the anomalous temperature behaviour of the Raman lines. Their temperature changes were minimal, which required a significant improvement in the resolution and stability of Raman measurements. The anomalies in the behaviour of the spectra at about 178 K, 235 K, 255 K, 278 K, 296 K, 398 K and 412 K were observed. The structural phase transition at 398 K is irreversible. This transition is associated with the release of water molecules from nanochannels. The irreversible phase transition has a temperature range of about 10 K.
First Principles Study on the Thermodynamic and Elastic Mechanical Stability of Mg2X (X = Si,Ge) Intermetallics with (anti) Vacancy Point Defects
Authors: Zhao Yuhong , Tian Jinzhong , Bai Guoning , Zhang Leting , Hou Hua
Published: March 2020

In this paper, based on the density functional theory, through thermodynamic and mechanical stability criteria, the crystal cell model of intermetallic compounds with vacancy and anti-site point defects is constructed and the lattice constant, formation heat, binding energy, elastic constant, and elastic modulus of Mg2X (X = Si, Ge) intermetallics with or without point defects are calculated. The results show that the difference in the atomic radius leads to the instability and distortion of crystal cells with point defects; Mg2X are easier to form vacancy defects than anti-site defects on the X (X = Si, Ge) lattice site, and form anti-site defects on the Mg lattice site. Generally, the point defect is more likely to appear at the Mg position than at the Si or Ge position. Among the four kinds of point defects, the anti-site defect x M g is the easiest to form. The structure of intermetallics without defects is more stable than that with defects, and the structure of the intermetallics with point defects at the Mg position is more stable than that at the Si/Ge position. The anti-site and vacancy defects will reduce the material’s resistance to volume deformation shear strain, and positive elastic deformation, and increase the mechanical instability of the elastic deformation of the material. Compared with the anti-site point defect, the void point defect can lead to the mechanical instability of the transverse deformation of the material and improve the plasticity of the material. The research in this paper is helpful for the analysis of the mechanical stability of the elastic deformation of Mg2X (X = Si, Ge) intermetallics under the service condition that it is easy to produce vacancy and anti-site defects.
Extension of the Recorded Host Range of Caribbean Christmas Tree Worms (Spirobranchus spp.) with Two Scleractinians, a Zoantharian, and an Ascidian
Authors: Hoeksema Bert W. , García-Hernández Jaaziel E. , van Moorsel Godfried W.N.M. , Olthof Gabriël , ten Hove Harry A.
Published: March 2020

Caribbean Christmas tree worms (Annelida: Polychaeta: Serpulidae: Spirobranchus) are considered host generalists in their associations with anthozoan (Scleractinia) and hydrozoan (Millepora) stony corals [...]
Predictive Analyses of Prognostic-Related Immune Genes and Immune Infiltrates for Glioblastoma
Authors: Liang Ping , Chai Yi , Zhao He , Wang Guihuai
Published: March 2020

Glioblastoma (GBM), the most common and aggressive brain tumor, has a very poor outcome and high tumor recurrence rate. The immune system has positive interactions with the central nervous system. Despite many studies investigating immune prognostic factors, there is no effective model to identify predictive biomarkers for GBM. Genomic data and clinical characteristic information of patients with GBM were evaluated by Kaplan–Meier analysis and proportional hazard modeling. Deseq2 software was used for differential expression analysis. Immune-related genes from ImmPort Shared Data and the Cistrome Project were evaluated. The model performance was determined based on the area under the receiver operating characteristic (ROC) curve. CIBERSORT was used to assess the infiltration of immune cells. The results of differential expression analyses showed a significant difference in the expression levels of 2942 genes, comprising 1338 upregulated genes and 1604 downregulated genes (p < 0.05). A population of 24 immune-related genes that predicted GBM patient survival was identified. A risk score model established on the basis of the expressions of the 24 immune-related genes was used to evaluate a favorable outcome of GBM. Further validation using the ROC curve confirmed the model was an independent predictor of GBM (AUC = 0.869). In the GBM microenvironment, eosinophils, macrophages, activated NK cells, and follicular helper T cells were associated with prognostic risk. Our study confirmed the importance of immune-related genes and immune infiltrates in predicting GBM patient prognosis.
Dealing with Academic Difficulty in Medical School: A Pilot Study
Authors: Malau-Aduli Bunmi S , Ray Robin A , O’Connor Teresa , van der Kruk Yolanda , Alele Faith O , Bellingan Michelle
Published: March 2020

Some students struggle through medical school and do not have the confidence to seek help. This pilot study sought to explore the challenges and needs of medical students experiencing academic difficulty. Semi-structured interviews and online surveys were used to collect data from an academic advisor and thirteen medical students who had experienced academic difficulty. Unexpected academic failure and the loss of self-efficacy contributed to students hiding their academic difficulty and avoiding available support systems. Despite the sampling limitations, the findings of this pilot study have value in giving direction to future research. Programs that will change the current attitudes to academic difficulty, normalising access to support and encouraging early intervention, are needed to build the capacity for excellence among these students.
An Anonymous Device to Device Authentication Protocol Using ECC and Self Certified Public Keys Usable in Internet of Things Based Autonomous Devices
Authors: Alzahrani Bander A. , Chaudhry Shehzad Ashraf , Barnawi Ahmed , Al-Barakati Abdullah , Shon Taeshik
Published: March 2020

Two party authentication schemes can be good candidates for deployment in Internet of Things (IoT)-based systems, especially in systems involving fast moving vehicles. Internet of Vehicles (IoV) requires fast and secure device-to-device communication without interference of any third party during communication, and this task can be carried out after registration of vehicles with a trusted certificate issuing party. Recently, several authentication protocols were proposed to enable key agreement in two party settings. In this study, we analyze two recent protocols and show that both protocols are insecure against key compromise impersonation attack (KCIA) as well as both lack of user anonymity. Therefore, this paper proposes an improved protocol that does not only resist KCIA and related attacks, but also offers comparable computation and communication. The security of proposed protocol is tested under formal model as well as using well known Burrows–Abadi–Needham (BAN) logic along with a discussion on security features. While resisting the KCIA and related attacks, proposed protocol also provides comparable trade-of between security features and efficiency and completes a round of key agreement in just 13.42 ms, which makes it a promising candidate to be deployed in IoT environments.
Effect of Mg Doping on the Electrical Performance of a Sol-Gel-Processed SnO2 Thin-Film Transistor
Authors: Lee Won-Yong , Lee Hyunjae , Ha Seunghyun , Lee Changmin , Bae Jin-Hyuk , Kang In-Man , Kim Kwangeun , Jang Jaewon
Published: March 2020

Sol-gel-processed Mg-doped SnO2 thin-film transistors (TFTs) were successfully fabricated. The effect of Mg concentration on the structural, chemical, and optical properties of thin films and the corresponding TFT devices was investigated. The results indicated that an optimal Mg concentration yielded an improved negative bias stability and increased optical band gap, resulting in transparent devices. Furthermore, the optimal device performance was obtained with 0.5 wt% Mg. The fabricated 0.5 wt% Mg-doped SnO2 TFT was characterized by a field effect mobility, a subthreshold swing, and Ion/Ioff ratio of 4.23 cm2/Vs, 1.37 V/decade, and ~1 × 107, respectively. The added Mg suppressed oxygen-vacancy formation, thereby improving the bias stability. This work may pave the way for the development of alkaline-earth-metal-doped SnO2-based thin-film devices.
A Two-Level Flow-Based Anomalous Activity Detection System for IoT Networks
Authors: Ullah Imtiaz , Mahmoud Qusay H.
Published: March 2020

The significant increase of the Internet of Things (IoT) devices in smart homes and other smart infrastructure, and the recent attacks on these IoT devices, are motivating factors to secure and protect IoT networks. The primary security challenge to develop a methodology to identify a malicious activity correctly and mitigate the impact of such activity promptly. In this paper, we propose a two-level anomalous activity detection model for intrusion detection system in IoT networks. The level-1 model categorizes the network flow as normal flow or abnormal flow, while the level-2 model classifies the category or subcategory of detected malicious activity. When the network flow classified as an anomaly by the level-1 model, then the level-1 model forwards the stream to the level-2 model for further investigation to find the category or subcategory of the detected anomaly. Our proposed model constructed on flow-based features of the IoT network. Flow-based detection methodologies only inspect packet headers to classify the network traffic. Flow-based features extracted from the IoT Botnet dataset and various machine learning algorithms were investigated and tested via different cross-fold validation tests to select the best algorithm. The decision tree classifier yielded the highest predictive results for level-1, and the random forest classifier produced the highest predictive results for level-2. Our proposed model Accuracy, Precision, Recall, and F score for level-1 were measured as 99.99% and 99.90% for level-2. A two-level anomalous activity detection system for IoT networks we proposed will provide a robust framework for the development of malicious activity detection system for IoT networks. It would be of interest to researchers in academia and industry.
LoRaWAN Network for Fire Monitoring in Rural Environments
Authors: Sendra Sandra , García Laura , Lloret Jaime , Bosch Ignacio , Vega-Rodríguez Roberto
Published: March 2020

The number of forest fires that occurred in recent years in different parts of the world is causing increased concern in the population, as the consequences of these fires expand beyond the destruction of the ecosystem. However, with the proliferation of the Internet of Things (IoT) industry, solutions for early fire detection should be developed. The assessment of the fire risk of an area and the communication of this fact to the population could reduce the number of fires originated by accident or due to the carelessness of the users. This paper presents a low-cost network based on Long Range (LoRa) technology to autonomously evaluate the level of fire risk and the presence of a forest fire in rural areas. The system is comprised of several LoRa nodes with sensors to measure the temperature, relative humidity, wind speed and CO2 of the environment. The data from the nodes is stored and processed in a The Things Network (TTN) server that sends the data to a website for the graphic visualization of the collected data. The system is tested in a real environment and, the results show that it is possible to cover a circular area of a radius of 4 km with a single gateway.
On the Introduction of Canny Operator in an Advanced Imaging Algorithm for Real-Time Detection of Hyperbolas in Ground-Penetrating Radar Data
Authors: Bugarinović Željko , Pajewski Lara , Ristić Aleksandar , Vrtunski Milan , Govedarica Miro , Borisov Mirko
Published: March 2020

This paper focuses on the use of the Canny edge detector as the first step of an advanced imaging algorithm for automated detection of hyperbolic reflections in ground-penetrating radar (GPR) data. Since the imaging algorithm aims to work in real time; particular attention is paid to its computational efficiency. Various alternative criteria are designed and examined, to fasten the procedure by eliminating unnecessary edge pixels from Canny-processed data, before such data go through the subsequent steps of the detection algorithm. The effectiveness and reliability of the proposed methodology are tested on a wide set of synthetic and experimental radargrams with promising results. The finite-difference time-domain simulator gprMax is used to generate synthetic radargrams for the tests, while the real radargrams come from GPR surveys carried out by the authors in urban areas. The imaging algorithm is implemented in MATLAB.
Evaluation of Using Gas Turbine to Increase Efficiency of the Organic Rankine Cycle (ORC)
Authors: Matuszewska Dominika , Olczak Piotr
Published: March 2020

Power conversion systems based on the Organic Rankine Cycle (ORC) have been identified as a potential technology especially in converting low-grade renewable sources or waste heat. However, it is necessary to improve efficiency of ORC systems. This paper focuses on use of low geothermal resources (for temperature range of 80–128 °C and mass flow 100 kg/s) by using modified ORC. A modification of conventional binary power plant is conducted by combining gas turbines to increase quality of steam from a geothermal well. An analysis has been conducted for three different working fluids: R245fa, R1233zd(E) and R600. The paper discusses the impact of parameter changes not only on system efficiency but on other performance indicators. The results were compared with a conventional geothermal Organic Rankine Cycle (ORC). Increasing of geothermal steam quality by supplying exhaust gas from a gas turbine to the installation has a positive effect on the system efficiency and power. The highest efficiency of the modified ORC system has been obtained for R1233zd(E) as a working fluid and it reaches values from 12.21% to 19.20% (depending on the temperature of the geothermal brine). In comparison, an ORC system without gas turbine support reaches values from 9.43% to 17.54%.