bluuebunny/crossref_metadata_2025 huggingface dataset:
Dendropanax morbifera Leaf Extracts Improved Alcohol Liver Injury in Association with Changes in the Gut Microbiota of Rats
Authors: Eom Taekil , Ko Gwangpyo , Kim Kyeoung Cheol , Kim Ju-Sung , Unno Tatsuya
Published: September 2020

This study evaluated the protective effects of Dendropanax morbifera leaf (DML) extracts in the liver due to excessive ethanol consumption. Our results showed that the ethanol extract had better antioxidant activity than the water extract, likely due to the higher levels of total flavonoid and phenolic compounds in the former. We found that the main phenolic acid was chlorogenic acid and the major flavonoid was rutin. Results from the animal model experiment showed concentration-dependent liver protection with the distilled water extract showing better liver protection than the ethanol extract. Gut microbiota dysbiosis induced by alcohol consumption was significantly shifted by DML extracts through increasing mainly Bacteroides and Allobaculum. Moreover, predicted metabolic activities of biosynthesis of beneficial monounsaturated fatty acids such as oleate and palmitoleate were enhanced. Our results suggest that these hepatoprotective effects are likely due to the increased activities of antioxidant enzymes and partially promoted by intestinal microbiota shifts.
Cloud Computing Based on Computational Characteristics for Disaster Monitoring
Authors: Zou Quan , Li Guoqing , Yu Wenyang
Published: September 2020

Resources related to remote-sensing data, computing, and models are scattered globally. The use of remote-sensing images for disaster-monitoring applications is data-intensive and involves complex algorithms. These characteristics make the timely and rapid processing of disaster-monitoring applications challenging and inefficient. Cloud computing provides a dynamically scalable resource over the Internet. The rapid development of cloud computing has led to an increase in the computational performance of data-intensive computing, providing powerful throughput by distributing computation across many distributed computers. However, the use of current cloud computing models in scientific applications using remote-sensing image data has been limited to a single image-processing algorithm rather than a well-established model and method. This poses problems for the development of complex disaster-monitoring applications on cloud platform architectures. For example, distributed computing strategies and remote-sensing image-processing algorithms are highly coupled and not reusable. The aims of this paper are to identify computational characteristics of various disaster-monitoring algorithms and classify them according to different computational characteristics; explore a reusable processing model based on the MapReduce programming model for disaster-monitoring applications; and then establish a programming model for each type of algorithm. This approach provides a simpler programming method for programmers to implement disaster-monitoring applications. Finally, some examples are given to explain the proposed method and test its performance.
Development and Assist-As-Needed Control of an End-Effector Upper Limb Rehabilitation Robot
Authors: Zhang Leigang , Guo Shuai , Sun Qing
Published: September 2020

Robot-assisted rehabilitation therapy has been proven to effectively improve upper limb motor function and daily behavior of patients with motor dysfunction, and the demand has increased at every stage of the rehabilitation recovery. According to the motor relearning program theory, upper limb motor dysfunction can be restored by a certain amount of repetitive training. Robotics devices can be an approach to accelerate the rehabilitation process by maximizing the patients’ training intensity. This paper develops a new end-effector upper limb rehabilitation robot (EULRR) first and then presents a controller that is suitable for the assist-as-needed (AAN) training of the patients when performing the rehabilitation training. The AAN controller is a strategy that helps the patient’s arm to stay close to the given trajectory while allowing for spatial freedom. This controller enables the patient’s arm to have spatial freedom by constructing a virtual channel around the predetermined training trajectory. Patients could move their arm freely in the allowed virtual channel during rehabilitation training while the robot provides assistance when deviating from the virtual channel. The AAN controller is preliminarily tested with a healthy male subject in different conditions based on the EULRR. The experimental results demonstrate that the proposed AAN controller could provide assistance when moving out of the virtual channel and provide no assistance when moving along the trajectory within the virtual channel. In the close future, the controller is planned to be used in elderly volunteers and help to increase the intensity of the rehabilitation therapy by assisting the arm movement and by provoking active participation.
Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes
Authors: Kahoul Yasmina , Oger Frédérik , Montaigne Jessica , Froguel Philippe , Breton Christophe , Annicotte Jean-Sébastien
Published: September 2020

Besides its role as a cell cycle and proliferation regulator, the INK4a/ARF (CDKN2A) locus and its associated pathways are thought to play additional functions in the control of energy homeostasis. Genome-wide association studies in humans and rodents have revealed that single nucleotide polymorphisms in this locus are risk factors for obesity and related metabolic diseases including cardiovascular complications and type-2 diabetes (T2D). Recent studies showed that both p16INK4a-CDK4-E2F1/pRB and p19ARF-P53 (p14ARF in humans) related pathways regulate adipose tissue (AT) physiology and adipocyte functions such as lipid storage, inflammation, oxidative activity, and cellular plasticity (browning). Targeting these metabolic pathways in AT emerged as a new putative therapy to alleviate the effects of obesity and prevent T2D. This review aims to provide an overview of the literature linking the INK4a/ARF locus with AT functions, focusing on its mechanisms of action in the regulation of energy homeostasis.
A Great Catch for Investigating Inborn Errors of Metabolism—Insights Obtained from Zebrafish
Authors: Breuer Maximilian , Patten Shunmoogum A.
Published: September 2020

Inborn errors of metabolism cause abnormal synthesis, recycling, or breakdown of amino acids, neurotransmitters, and other various metabolites. This aberrant homeostasis commonly causes the accumulation of toxic compounds or depletion of vital metabolites, which has detrimental consequences for the patients. Efficient and rapid intervention is often key to survival. Therefore, it requires useful animal models to understand the pathomechanisms and identify promising therapeutic drug targets. Zebrafish are an effective tool to investigate developmental mechanisms and understanding the pathophysiology of disorders. In the past decades, zebrafish have proven their efficiency for studying genetic disorders owing to the high degree of conservation between human and zebrafish genes. Subsequently, several rare inherited metabolic disorders have been successfully investigated in zebrafish revealing underlying mechanisms and identifying novel therapeutic targets, including methylmalonic acidemia, Gaucher’s disease, maple urine disorder, hyperammonemia, TRAPPC11-CDGs, and others. This review summarizes the recent impact zebrafish have made in the field of inborn errors of metabolism.
Syndecan-1 Promotes Hepatocyte-Like Differentiation of Hepatoma Cells Targeting Ets-1 and AP-1
Authors: Hollósi Péter , Váncza Lóránd , Karászi Katalin , Dobos Katalin , Péterfia Bálint , Tátrai Enikő , Tátrai Péter , Szarvas Tibor , Paku Sándor , Szilák László , Kovalszky Ilona
Published: September 2020

Syndecan-1 is a transmembrane heparan sulfate proteoglycan which is indispensable in the structural and functional integrity of epithelia. Normal hepatocytes display strong cell surface expression of syndecan-1; however, upon malignant transformation, they may lose it from their cell surfaces. In this study, we demonstrate that re-expression of full-length or ectodomain-deleted syndecan-1 in hepatocellular carcinoma cells downregulates phosphorylation of ERK1/2 and p38, with the truncated form exerting an even stronger effect than the full-length protein. Furthermore, overexpression of syndecan-1 in hepatoma cells is associated with a shift of heparan sulfate structure toward a highly sulfated type specific for normal liver. As a result, cell proliferation and proteolytic shedding of syndecan-1 from the cell surface are restrained, which facilitates redifferentiation of hepatoma cells to a more hepatocyte-like phenotype. Our results highlight the importance of syndecan-1 in the formation and maintenance of differentiated epithelial characteristics in hepatocytes partly via the HGF/ERK/Ets-1 signal transduction pathway. Downregulation of Ets-1 expression alone, however, was not sufficient to replicate the phenotype of syndecan-1 overexpressing cells, indicating the need for additional molecular mechanisms. Accordingly, a reporter gene assay revealed the inhibition of Ets-1 as well as AP-1 transcription factor-induced promoter activation, presumably an effect of the heparan sulfate switch.
Sphingolipid Metabolism in Glioblastoma and Metastatic Brain Tumors: A Review of Sphingomyelinases and Sphingosine-1-Phosphate
Authors: Hawkins Cyntanna C. , Ali Tomader , Ramanadham Sasanka , Hjelmeland Anita B.
Published: September 2020

Glioblastoma (GBM) is a primary malignant brain tumor with a dismal prognosis, partially due to our inability to completely remove and kill all GBM cells. Rapid tumor recurrence contributes to a median survival of only 15 months with the current standard of care which includes maximal surgical resection, radiation, and temozolomide (TMZ), a blood–brain barrier (BBB) penetrant chemotherapy. Radiation and TMZ cause sphingomyelinases (SMase) to hydrolyze sphingomyelins to generate ceramides, which induce apoptosis. However, cells can evade apoptosis by converting ceramides to sphingosine-1-phosphate (S1P). S1P has been implicated in a wide range of cancers including GBM. Upregulation of S1P has been linked to the proliferation and invasion of GBM and other cancers that display a propensity for brain metastasis. To mediate their biological effects, SMases and S1P modulate signaling via phospholipase C (PLC) and phospholipase D (PLD). In addition, both SMase and S1P may alter the integrity of the BBB leading to infiltration of tumor-promoting immune populations. SMase activity has been associated with tumor evasion of the immune system, while S1P creates a gradient for trafficking of innate and adaptive immune cells. This review will explore the role of sphingolipid metabolism and pharmacological interventions in GBM and metastatic brain tumors with a focus on SMase and S1P.
IL-17A as a Potential Therapeutic Target for Patients on Peritoneal Dialysis
Authors: Marchant Vanessa , Tejera-Muñoz Antonio , Marquez-Expósito Laura , Rayego-Mateos Sandra , Rodrigues-Diez Raul R. , Tejedor Lucia , Santos-Sanchez Laura , Egido Jesús , Ortiz Alberto , Valdivielso Jose M. , Fraser Donald J. , López-Cabrera Manuel , Selgas Rafael , Ruiz-Ortega Marta
Published: September 2020

Chronic kidney disease (CKD) is a health problem reaching epidemic proportions. There is no cure for CKD, and patients may progress to end-stage renal disease (ESRD). Peritoneal dialysis (PD) is a current replacement therapy option for ESRD patients until renal transplantation can be achieved. One important problem in long-term PD patients is peritoneal membrane failure. The mechanisms involved in peritoneal damage include activation of the inflammatory and immune responses, associated with submesothelial immune infiltrates, angiogenesis, loss of the mesothelial layer due to cell death and mesothelial to mesenchymal transition, and collagen accumulation in the submesothelial compact zone. These processes lead to fibrosis and loss of peritoneal membrane function. Peritoneal inflammation and membrane failure are strongly associated with additional problems in PD patients, mainly with a very high risk of cardiovascular disease. Among the inflammatory mediators involved in peritoneal damage, cytokine IL-17A has recently been proposed as a potential therapeutic target for chronic inflammatory diseases, including CKD. Although IL-17A is the hallmark cytokine of Th17 immune cells, many other cells can also produce or secrete IL-17A. In the peritoneum of PD patients, IL-17A-secreting cells comprise Th17 cells, γδ T cells, mast cells, and neutrophils. Experimental studies demonstrated that IL-17A blockade ameliorated peritoneal damage caused by exposure to PD fluids. This article provides a comprehensive review of recent advances on the role of IL-17A in peritoneal membrane injury during PD and other PD-associated complications.
Clustering and Fibril Formation during GNNQQNY Aggregation: A Molecular Dynamics Study
Authors: Szała-Mendyk Beata , Molski Andrzej
Published: September 2020

The precise kinetic pathways of peptide clustering and fibril formation are not fully understood. Here we study the initial clustering kinetics and transient cluster morphologies during aggregation of the heptapeptide fragment GNNQQNY from the yeast prion protein Sup35. We use a mid-resolution coarse-grained molecular dynamics model of Bereau and Deserno to explore the aggregation pathways from the initial random distribution of free monomers to the formation of large clusters. By increasing the system size to 72 peptides we could follow directly the molecular events leading to the formation of stable fibril-like structures. To quantify those structures we developed a new cluster helicity parameter. We found that the formation of fibril-like structures is a cooperative processes that requires a critical number of monomers, M⋆≈25, in a cluster. The terminal tyrosine residue is the structural determinant in the formation of helical fibril-like structures. This work supports and quantifies the two-step aggregation model where the initially formed amorphous clusters grow and, when they are large enough, rearrange into mature twisted structures. However, in addition to the nucleated fibrillation, growing aggregates undergo further internal reorganization, which leads to more compact structures of large aggregates.
Recovery of Bioactive Compounds from Hazelnuts and Walnuts Shells: Quantitative–Qualitative Analysis and Chromatographic Purification
Authors: Herrera René , Hemming Jarl , Smeds Annika , Gordobil Oihana , Willför Stefan , Labidi Jalel
Published: September 2020

Hazelnut (HS) and walnut (WS) shells, an abundant by-product of the processing industries of these edible nuts, are traditionally considered as a low-value waste. However, they are a source of valuable compounds with an interesting chemical profile for the chemical and pharmaceutical sectors. In this study, the lipophilic and hydrophilic extracts present in HS and WS were quantified and identified, then the polar fractions were chromatographically separated, and their antioxidant capacity was studied. The experimental work includes the isolation of crude lipophilic and hydrophilic extracts by an accelerated extraction process, chromatographic analysis (gas chromatography-flame ionization (GC-FID), GC-mass spectroscopy (GC-MS), high-performance size-exclusion chromatography (HPSEC), thin-layer chromatography (TLC)), and quantification of the components. In addition, a thorough compositional characterization of the subgroups obtained by flash chromatography and their antioxidant capacity was carried out. The gravimetric concentrations showed different lipophilic/hydrophilic ratios (0.70 for HS and 0.23 for WS), indicating a higher proportion of polar compounds in WS than in HS. Moreover, the lipophilic extracts were principally composed of short-chain fatty acids (stearic, palmitic, and oleic acid), triglycerides, and sterols. The polar fractions were screened by thin-layer chromatography and then separated by flash chromatography, obtaining fractions free of fatty acids and sugar derivatives (97:3 in HS and 95:5 in WS), and mixtures richer in phenolic compounds and flavonoids such as guaiacyl derivatives, quercetin, pinobanksin, and catechin. The most polar fractions presented a higher antioxidant capacity than that of the crude extracts.
Point of Care Diagnostics in Resource-Limited Settings: A Review of the Present and Future of PoC in Its Most Needed Environment
Authors: Heidt Benjamin , Siqueira Williane , Eersels Kasper , Diliën Hanne , van Grinsven Bart , Fujiwara Ricardo , Cleij Thomas
Published: September 2020

Point of care (PoC) diagnostics are at the focus of government initiatives, NGOs and fundamental research alike. In high-income countries, the hope is to streamline the diagnostic procedure, minimize costs and make healthcare processes more efficient and faster, which, in some cases, can be more a matter of convenience than necessity. However, in resource-limited settings such as low-income countries, PoC-diagnostics might be the only viable route, when the next laboratory is hours away. Therefore, it is especially important to focus research into novel diagnostics for these countries in order to alleviate suffering due to infectious disease. In this review, the current research describing the use of PoC diagnostics in resource-limited settings and the potential bottlenecks along the value chain that prevent their widespread application is summarized. To this end, we will look at literature that investigates different parts of the value chain, such as fundamental research and market economics, as well as actual use at healthcare providers. We aim to create an integrated picture of potential PoC barriers, from the first start of research at universities to patient treatment in the field. Results from the literature will be discussed with the aim to bring all important steps and aspects together in order to illustrate how effectively PoC is being used in low-income countries. In addition, we discuss what is needed to improve the situation further, in order to use this technology to its fullest advantage and avoid “leaks in the pipeline”, when a promising device fails to take the next step of the valorization pathway and is abandoned.
Quantifying the Predictive Role of Temperament Dimensions and Attachment Styles on the Five Factor Model of Personality
Authors: Barel Efrat , Mizrachi Yonathan , Nachmani Maayan
Published: September 2020

Background: The present study investigated the role of temperament and attachment security in predicting individual differences in the five factor personality traits among adults. As previous studies suggested the potential moderating role of attachment in the association between temperament and personality traits, the present study sought to examine an interactionist model combining attachment and temperament in explaining individual differences in personality traits. Methods: A sample of 1871 participants (1151 women and 719 men) completed self-report measures of adult attachment style (the Relationships Questionnaire—RQ), temperament dimension (the Fisher Temperament Inventory—FTI), and personality domain (the Five Factor Model—FFM). Results: Partial correlational analyses revealed associations between attachment security and each of the five domains of the FFM, and few associations between some temperament dimensions and several domains of the FFM. Moderated regression analyses showed that attachment security moderated the associations between temperament dimensions and the Agreeableness domain of the FFM. Among secure individuals, those with higher scores on the Curious/Energetic, Cautious/Social Norm Compliant and Prosocial/Empathetic scales exhibited higher Agreeableness scores, whereas among insecure individuals, those with higher scores on the Analytic/Tough-minded scale exhibited lower scores on the Agreeableness scale. Conclusion: Overall, the current study provides evidence in support of the substantive role of social-environmental factors (Adult Attachment) as a moderating element bridging temperament-related personality elements and a number of their FFM manifestations.
Decision Support in Building Construction: A Systematic Review of Methods and Application Areas
Authors: Marcher Carmen , Giusti Andrea , Matt Dominik T.
Published: September 2020

Decision making is a relevant task in the building construction sector, and various systems and methods for decision support are emerging. By means of a systematic literature review, this article identifies the methods for decision making in building construction and the lifecycle phases for which decision support systems are proposed. The selected articles are analyzed and grouped according to the adopted decision-making methods and the defined lifecycle phases. The findings show that multiple criteria decision analysis is the most used method for decision support in building construction and that the construction phase is the most addressed phase within the relevant existing works. The findings related to the construction phase are further refined by grouping the articles into application areas and by reviewing in detail the proposed methods therein. The scarce availability of data and project cases is identified as the most common barrier for the successful development and implementation of decision support systems in the building construction sector. This work provides a basis for scientists and practitioners for identifying suitable methods for decision-making support in a specific lifecycle phase of a building.
Landscape of Genome-Wide DNA Methylation of Colorectal Cancer Metastasis
Authors: Ili Carmen , Buchegger Kurt , Demond Hannah , Castillo-Fernandez Juan , Kelsey Gavin , Zanella Louise , Abanto Michel , Riquelme Ismael , López Jaime , Viscarra Tamara , García Patricia , Bellolio Enrique , Saavedra David , Brebi Priscilla
Published: September 2020

Colorectal cancer is a heterogeneous disease caused by both genetic and epigenetics factors. Analysing DNA methylation changes occurring during colorectal cancer progression and metastasis formation is crucial for the identification of novel epigenetic markers of patient prognosis. Genome-wide methylation sequencing of paired samples of colon (normal adjacent, primary tumour and lymph node metastasis) showed global hypomethylation and CpG island (CGI) hypermethylation of primary tumours compared to normal. In metastasis we observed high global and non-CGI regions methylation, but lower CGI methylation, compared to primary tumours. Gene ontology analysis showed shared biological processes between hypermethylated CGIs in metastasis and primary tumours. After complementary analysis with The Cancer Genome Atlas (TCGA) cohort, FIGN, HTRA3, BDNF, HCN4 and STAC2 genes were found associated with poor survival. We mapped the methylation landscape of colon normal tissues, primary tumours and lymph node metastasis, being capable of identified methylation changes throughout the genome. Furthermore, we found five genes with potential for methylation biomarkers of poor prognosis in colorectal cancer patients.
Deregulated microRNAs Are Associated with Patient Survival and Predicted to Target Genes That Modulate Lung Cancer Signaling Pathways
Authors: Souza Cristiano P. , Cinegaglia Naiara C. , Felix Tainara F. , Evangelista Adriane F. , Oliveira Rogério A. , Hasimoto Erica N. , Cataneo Daniele C. , Cataneo Antônio J. M. , Scapulatempo Neto Cristovam , Viana Cristiano R. , Paula Flávia E. de , Drigo Sandra A. , Carvalho Robson F. , Marques Márcia M. C. , Reis Rui M. , Reis Patricia P.
Published: September 2020

(1) Background: Although the advances in diagnostic and treatment strategies, lung cancer remains the leading cause of cancer-related deaths, worldwide, with survival rates as low as 16% in developed countries. Low survival rates are mainly due to late diagnosis and the lack of effective treatment. Therefore, the identification of novel, clinically useful biomarkers is still needed for patients with advanced disease stage and poor survival. Micro(mi)RNAs are non-coding RNAs and potent regulators of gene expression with a possible role as diagnostic, prognostic and predictive biomarkers in cancer. (2) Methods: We applied global miRNA expression profiling analysis using TaqMan® arrays in paired tumor and normal lung tissues (n = 38) from treatment-naïve patients with lung adenocarcinoma (AD; n = 23) and lung squamous cell carcinoma (SCC; n = 15). miRNA target genes were validated using The Cancer Genome Atlas (TCGA) lung AD (n = 561) and lung SCC (n = 523) RNA-Seq datasets. (3) Results: We identified 33 significantly deregulated miRNAs (fold change, FC ≥ 2.0 and p < 0.05) in tumors relative to normal lung tissues, regardless of tumor histology. Enrichment analysis confirmed that genes targeted by the 33 miRNAs are aberrantly expressed in lung AD and SCC, and modulate known pathways in lung cancer. Additionally, high expression of miR-25-3p was significantly associated (p < 0.05) with poor patient survival, when considering both tumor histologies. (4) Conclusions: miR-25-3p may be a potential prognostic biomarker in non-small cell lung cancer. Genes targeted by miRNAs regulate EGFR and TGFβ signaling, among other known pathways relevant to lung tumorigenesis.
Hormonal Receptor Status Determines Prognostic Significance of FGFR2 in Invasive Breast Carcinoma
Authors: Braun Marcin , Piasecka Dominika , Tomasik Bartlomiej , Mieczkowski Kamil , Stawiski Konrad , Zielinska Aleksandra , Kopczynski Janusz , Nejc Dariusz , Kordek Radzislaw , Sadej Rafal , Romanska Hanna M.
Published: September 2020

Interaction between fibroblast growth factor receptor 2 (FGFR2) and estrogen/progesterone receptors (ER/PR) affects resistance to anti-ER therapies, however the prognostic value of FGFR2 in breast cancer (BCa) remains largely unexplored. We have recently showed in vitro that FGFR2-mediated signaling alters PR activity and response to anti-ER treatment. Herein, prognostic significance of FGFR2 in BCa was evaluated in relation to both ER/PR protein status and a molecular signature designed to reflect PR transcriptional activity. FGFR2 was examined in 353 BCa cases using immunohistochemistry and Nanostring-based RNA quantification. FGFR2 expression was higher in ER+PR+ and ER+PR- compared to ER−PR− cases (p < 0.001). Low FGFR2 was associated with higher grade (p < 0.001), higher Ki67 proliferation index (p < 0.001), and worse overall and disease-free survival (HR = 2.34 (95% CI: 1.26–4.34), p = 0.007 and HR = 2.22 (95% CI: 1.25–3.93), p = 0.006, respectively). The poor prognostic value of low FGFR2 was apparent in ER+PR+, but not in ER+PR− patients, and it did not depend on the expression level of PR-dependent genes. Despite the functional link between FGFR2 and ER/PR revealed by preclinical studies, the data showed a link between FGFR2 expression and poor prognosis in BCa patients.
Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma
Authors: Zugbi Santiago , Ganiewich Daiana , Bhattacharyya Arpita , Aschero Rosario , Ottaviani Daniela , Sampor Claudia , Cafferata Eduardo , Mena Marcela , Sgroi Mariana , Winter Ursula , Lamas Gabriela , Suñol Mariona , Daroqui Manuel , Baialardo Edgardo , Salas Beatriz , Das Anirban , Fandiño Adriana , Francis Jasmine , Lubieniecki Fabiana , Lavarino Cinzia , Garippa Ralph , Podhajcer Osvaldo , Abramson David , Radvanyi François , Chantada Guillermo , Llera Andrea , Schaiquevich Paula
Published: September 2020

An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in RB1 gene with high-level amplification of MYCN (MCYNamplRB1+/+) has only been described as intra-ocular cases treated with initial enucleation. Here, we present a comprehensive clinical, genomic, and pharmacological analysis of two cases of MCYNamplRB1+/+ with orbital and cervical lymph node involvement, but no central nervous system spread, rapidly progressing to fatal disease due to chemoresistance. Both patients showed in common MYCN high amplification and chromosome 16q and 17p loss. A somatic mutation in TP53, in homozygosis by LOH, and high chromosomal instability leading to aneuploidy was identified in the primary ocular tumor and sites of dissemination of one patient. High-throughput pharmacological screening was performed in a primary cell line derived from the lymph node dissemination of one case. This cell line showed resistance to broad spectrum chemotherapy consistent with the patient’s poor response but sensitivity to the synergistic effects of panobinostat–bortezomib and carboplatin–panobinostat associations. From these cells we established a cell line derived xenograft model that closely recapitulated the tumor dissemination pattern of the patient and served to evaluate whether triple chemotherapy significantly prolonged survival of the animals. We report novel genomic alterations in two cases of metastatic MCYNamplRB1+/+ that may be associated with chemotherapy resistance and in vitro/in vivo models that serve as basis for tailoring therapy in these cases.
Menin and Menin-Associated Proteins Coregulate Cancer Energy Metabolism
Authors: Chou Chih-Wei , Tan Xi , Hung Chia-Nung , Lieberman Brandon , Chen Meizhen , Kusi Meena , Mitsuya Kohzoh , Lin Chun-Lin , Morita Masahiro , Liu Zhijie , Chen Chun-Liang , Huang Tim Hui-Ming
Published: September 2020

The interplay between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) is central to maintain energy homeostasis. It remains to be determined whether there is a mechanism governing metabolic fluxes based on substrate availability in microenvironments. Here we show that menin is a key transcription factor regulating the expression of OXPHOS and glycolytic genes in cancer cells and primary tumors with poor prognosis. A group of menin-associated proteins (MAPs), including KMT2A, MED12, WAPL, and GATA3, is found to restrain menin’s full function in this transcription regulation. shRNA knockdowns of menin and MAPs result in reduced ATP production with proportional alterations of cellular energy generated through glycolysis and OXPHOS. When shRNA knockdown cells are exposed to metabolic stress, the dual functionality can clearly be distinguished among these metabolic regulators. A MAP can negatively counteract the regulatory mode of menin for OXPHOS while the same protein positively influences glycolysis. A close-proximity interaction between menin and MAPs allows transcriptional regulation for metabolic adjustment. This coordinate regulation by menin and MAPs is necessary for cells to rapidly adapt to fluctuating microenvironments and to maintain essential metabolic functions.
Radiation-Induced Hypothyroidism in Patients with Oropharyngeal Cancer Treated with IMRT: Independent and External Validation of Five Normal Tissue Complication Probability Models
Authors: Nowicka Zuzanna , Tomasik Bartłomiej , Papis-Ubych Anna , Bibik Robert , Graczyk Łukasz , Latusek Tomasz , Rutkowski Tomasz , Wyka Krystyna , Fijuth Jacek , Schoenfeld Jonathan D. , Chałubińska-Fendler Justyna , Fendler Wojciech
Published: September 2020

We aimed to externally validate five normal tissue complication probability (NTCP) models for radiation-induced hypothyroidism (RIHT) in a prospectively recruited cohort of 108 patients with oropharyngeal cancer (OPC). NTCP scores were calculated using original published formulas. Plasma thyrotropin (TSH) level was additionally assessed in the short-term after RT. After a median of 28 months of follow-up, thirty one (28.7%) patients developed RIHT. Thyroid mean dose and thyroid volume were significant predictors of RIHT: odds ratio equal to 1.11 (95% CI 1.03–1.19) for mean thyroid dose and 0.87 (95%CI 0.81–0.93) for thyroid volume in univariate analyses. Two of the evaluated NTCP models, published by Rønjom et al. and by Boomsma et al., had satisfactory performance with accuracies of 0.87 (95%CI 0.79–0.93) and 0.84 (95%CI: 0.76–0.91), respectively. Three remaining models, by Cella et al., Bakhshandeh et al. and Vogelius et al., performed significantly worse, overestimating the risk of RIHT in this patient cohort. A short-term TSH level change relative to baseline was not indicative of RIHT development in the follow-up (OR 0.96, 95%CI: 0.65–1.42, p = 0.825). In conclusion, the models by Rønjom et al. and by Boomsma et al. demonstrated external validity and feasibility for long-term prediction of RIHT in survivors of OPC treated with Intensity-Modulated Radiation Therapy (IMRT).
The Undervalued Avenue to Reinstate Tumor Suppressor Functionality of the p53 Protein Family for Improved Cancer Therapy-Drug Repurposing
Authors: Zawacka-Pankau Joanna E.
Published: September 2020

p53 and p73 are critical tumor suppressors that are often inactivated in human cancers through various mechanisms. Owing to their high structural homology, the proteins have many joined functions and recognize the same set of genes involved in apoptosis and cell cycle regulation. p53 is known as the ‘guardian of the genome’ and together with p73 forms a barrier against cancer development and progression. The TP53 is mutated in more than 50% of all human cancers and the germline mutations in TP53 predispose to the early onset of multiple tumors in Li–Fraumeni syndrome (LFS), the inherited cancer predisposition. In cancers where TP53 gene is intact, p53 is degraded. Despite the ongoing efforts, the treatment of cancers remains challenging. This is due to late diagnoses, the toxicity of the current standard of care and marginal benefit of newly approved therapies. Presently, the endeavors focus on reactivating p53 exclusively, neglecting the potential of the restoration of p73 protein for cancer eradication. Taken that several small molecules reactivating p53 failed in clinical trials, there is a need to develop new treatments targeting p53 proteins in cancer. This review outlines the most advanced strategies to reactivate p53 and p73 and describes drug repurposing approaches for the efficient reinstatement of the p53 proteins for cancer therapy.
SFMBT2-Mediated Infiltration of Preadipocytes and TAMs in Prostate Cancer
Authors: Gwak Jungsug , Jeong Hayan , Lee Kwanghyun , Shin Jee Yoon , Sim Taejun , Na Jungtae , Kim Jongchan , Ju Bong-Gun
Published: September 2020

Infiltration of diverse cell types into tumor microenvironment plays a critical role in cancer progression including metastasis. We previously reported that SFMBT2 (Scm-like with four mbt domains 2) regulates the expression of matrix metalloproteinases (MMPs) and migration and invasion of cancer cells in prostate cancer. Here we investigated whether the down-regulation of SFMBT2 regulates the infiltration of preadipocytes and tumor-associated macrophages (TAMs) in prostate cancer. We found that the down-regulation of SFMBT2 promotes the infiltration of preadipocytes and TAMs through up-regulation of CXCL8, CCL2, CXCL10, and CCL20 expression in prostate cancer. Expression of CXCL8, CCL2, CXCL10, and CCL20 was also elevated in prostate cancer patients having a higher Gleason score (≥8), which had substantially lower SFMBT2 expression. We also found that the up-regulation of CXCL8, CCL2, CXCL10, and CCL20 expression is dependent on NF-κB activation in prostate cancer cells expressing a low level of SFMBT2. Moreover, increased IL-6 from infiltrated preadipocytes and TAMs promoted migration and invasion of prostate cancer cells expressing a low level of SFMBT2. Our study may suggest that SFMBT2 a critical regulator for the infiltration of preadipocytes and TAMs into the prostate tumor microenvironment. Thus, the regulation of SFMBT2 may provide a new therapeutic strategy to inhibit prostate cancer metastasis, and SFMBT2 could be used as a potential biomarker in prostate cancer metastasis.
Establishment of Prostate Tumor Growth and Metastasis Is Supported by Bone Marrow Cells and Is Mediated by PIP5K1α Lipid Kinase
Authors: Karlsson Richard , Larsson Per , Miftakhova Regina , Syed Khaja Azharuddin Sajid , Sarwar Martuza , Semenas Julius , Chen Sa , Hedblom Andreas , Wang Tianyan , Ekström-Holka Kristina , Simoulis Athanasios , Kumar Anjani , Ødum Niels , Grundström Thomas , Persson Jenny L.
Published: September 2020

Cancer cells facilitate growth and metastasis by using multiple signals from the cancer-associated microenvironment. However, it remains poorly understood whether prostate cancer (PCa) cells may recruit and utilize bone marrow cells for their growth and survival. Furthermore, the regulatory mechanisms underlying interactions between PCa cells and bone marrow cells are obscure. In this study, we isolated bone marrow cells that mainly constituted populations that were positive for CD11b and Gr1 antigens from xenograft PC-3 tumor tissues from athymic nu/nu mice. We found that the tumor-infiltrated cells alone were unable to form tumor spheroids, even with increased amounts and time. By contrast, the tumor-infiltrated cells together with PCa cells formed large numbers of tumor spheroids compared with PCa cells alone. We further utilized xenograft athymic nu/nu mice bearing bone metastatic lesions. We demonstrated that PCa cells were unable to survive and give rise to colony-forming units (CFUs) in media that were used for hematopoietic cell colony-formation unit (CFU) assays. By contrast, PC-3M cells survived when bone marrow cells were present and gave rise to CFUs. Our results showed that PCa cells required bone marrow cells to support their growth and survival and establish bone metastasis in the host environment. We showed that PCa cells that were treated with either siRNA for PIP5K1α or its specific inhibitor, ISA-2011B, were unable to survive and produce tumor spheroids, together with bone marrow cells. Given that the elevated expression of PIP5K1α was specific for PCa cells and was associated with the induced expression of VEGF receptor 2 in PCa cells, our findings suggest that cancer cells may utilize PIP5K1α-mediated receptor signaling to recruit growth factors and ligands from the bone marrow-derived cells. Taken together, our study suggests a new mechanism that enables PCa cells to gain proliferative and invasive advantages within their associated host microenvironment. Therapeutic interventions using PIP5K1α inhibitors may not only inhibit tumor invasion and metastasis but also enhance the host immune system.
Development and Internal Validation of a Multivariable Prediction Model for Adrenocortical-Carcinoma-Specific Mortality
Authors: Ettaieb Madeleine H. T. , van Kuijk Sander M. J. , de Wit-Pastoors Annelies , Feelders Richard A. , Corssmit Eleonora P. M. , Eekhoff Elisabeth M. W. , van der Valk Paul , Timmers Henri J. L. M. , Kerstens Michiel N. , Klümpen Heinz-Josef , van Leeuwaarde Rachel S. , Havekes Bas , Haak Harm R.
Published: September 2020

Adrenocortical carcinoma (ACC) has an incidence of about 1.0 per million per year. In general, survival of patients with ACC is limited. Predicting survival outcome at time of diagnosis is a clinical challenge. The aim of this study was to develop and internally validate a clinical prediction model for ACC-specific mortality. Data for this retrospective cohort study were obtained from the nine centers of the Dutch Adrenal Network (DAN). Patients who presented with ACC between 1 January 2004 and 31 October 2013 were included. We used multivariable Cox proportional hazards regression to compute the coefficients for the prediction model. Backward stepwise elimination was performed to derive a more parsimonious model. The performance of the initial prediction model was quantified by measures of model fit, discriminative ability, and calibration. We undertook an internal validation step to counteract the possible overfitting of our model. A total of 160 patients were included in the cohort. The median survival time was 35 months, and interquartile range (IQR) 50.7 months. The multivariable modeling yielded a prediction model that included age, modified European Network for the Study of Adrenal Tumors (mENSAT) stage, and radical resection. The c-statistic was 0.77 (95% Confidence Interval: 0.72, 0.81), indicating good predictive performance. We developed a clinical prediction model for ACC-specific mortality. ACC mortality can be estimated using a relatively simple clinical prediction model with good discriminative ability and calibration.
Epstein–Barr Virus Infection of Pseudostratified Nasopharyngeal Epithelium Disrupts Epithelial Integrity
Authors: Yu Fenggang , Lu Yanan , Li Yingying , Uchio Yuji , Pangnguriseng Utomo Andi , Kartika Andy Visi , Iizasa Hisashi , Yoshiyama Hironori , Loh Kwok Seng
Published: September 2020

Epstein–Barr virus (EBV) is a human oncogenic virus that causes several types of tumor, such as Burkitt’s lymphoma and nasopharyngeal carcinoma (NPC). NPC tumor cells are clonal expansions of latently EBV-infected epithelial cells. However, the mechanisms by which EBV transforms the nasopharyngeal epithelium is hampered, because of the lack of good in vitro model to pursue oncogenic process. Our primary nasopharyngeal epithelial cell cultures developed pseudostratified epithelium at the air-liquid interface, which was susceptible to EBV infection. Using the highly sensitive RNA in situ hybridization technique, we detected viral infection in diverse cell types, including ciliated cells, goblet cells, and basal cells. EBV-encoded small RNA-positive cells were more frequently detected in the suprabasal layer than in the basal layer. We established the most physiologically relevant EBV infection model of nasopharyngeal epithelial cells. This model will advance our understanding of EBV pathogenesis in the development of NPC.
Neutralization of B-Cell Activating Factor (BAFF) by Belimumab Reinforces Small Molecule Inhibitor Treatment in Chronic Lymphocytic Leukemia
Authors: Tandler Claudia , Schmidt Moritz , Heitmann Jonas S. , Hierold Julia , Schmidt Jonas , Schneider Pascal , Dörfel Daniela , Walz Juliane , Salih Helmut R.
Published: September 2020

The introduction of idelalisib, ibrutinib and venetoclax for treatment of chronic lymphocytic leukemia (CLL) has greatly improved long term survival of patients. However, many patients do not achieve complete remission and suffer from development of resistance upon treatment with these small molecule inhibitors. Here we report that the TNF family member B-cell activating factor (BAFF) mediates resistance of CLL cells to idelalisib, ibrutinib and venetoclax by sustaining survival and preventing apoptosis of the malignant B cells as revealed by analysis of cellular ATP levels and mitochondrial membrane integrity as well as caspase activation, respectively. As BAFF also plays a prominent role in autoimmune diseases, the BAFF-neutralizing antibody belimumab was developed and approved for treatment of systemic lupus erythematosus (SLE). When we employed belimumab in the context of CLL treatment with idelalisib, ibrutinib and venetoclax, BAFF neutralization was found to significantly increase the sensitivity of the leukemic cells to all three small molecule inhibitors. Notably, BAFF neutralization proved to be beneficial independently of clinical stage according to Binet and Rai or IgVH mutational status. Our results identify drug repurposing of belimumab for neutralization of BAFF to complement small molecule inhibitor treatment as a promising therapeutic approach in CLL that is presently undergoing clinical evaluation.
LncRNA Profiling Reveals That the Deregulation of H19, WT1-AS, TCL6, and LEF1-AS1 Is Associated with Higher-Risk Myelodysplastic Syndrome
Authors: Szikszai Katarina , Krejcik Zdenek , Klema Jiri , Loudova Nikoleta , Hrustincova Andrea , Belickova Monika , Hruba Monika , Vesela Jitka , Stranecky Viktor , Kundrat David , Pecherkova Pavla , Cermak Jaroslav , Jonasova Anna , Dostalova Merkerova Michaela
Published: September 2020

Background: myelodysplastic syndrome (MDS) is a hematopoietic stem cell disorder with an incompletely known pathogenesis. Long noncoding RNAs (lncRNAs) play multiple roles in hematopoiesis and represent a new class of biomarkers and therapeutic targets, but information on their roles in MDS is limited. Aims: here, we aimed to characterize lncRNAs deregulated in MDS that may function in disease pathogenesis. In particular, we focused on the identification of lncRNAs that could serve as novel potential biomarkers of adverse outcomes in MDS. Methods: we performed microarray expression profiling of lncRNAs and protein-coding genes (PCGs) in the CD34+ bone marrow cells of MDS patients. Expression profiles were analyzed in relation to different aspects of the disease (i.e., diagnosis, disease subtypes, cytogenetic and mutational aberrations, and risk of progression). LncRNA-PCG networks were constructed to link deregulated lncRNAs with regulatory mechanisms associated with MDS. Results: we found several lncRNAs strongly associated with disease pathogenesis (e.g., H19, WT1-AS, TCL6, LEF1-AS1, EPB41L4A-AS1, PVT1, GAS5, and ZFAS1). Of these, downregulation of LEF1-AS1 and TCL6 and upregulation of H19 and WT1-AS were associated with adverse outcomes in MDS patients. Multivariate analysis revealed that the predominant variables predictive of survival are blast count, H19 level, and TP53 mutation. Coexpression network data suggested that prognosis-related lncRNAs are predominantly related to cell adhesion and differentiation processes (H19 and WT1-AS) and mechanisms such as chromatin modification, cytokine response, and cell proliferation and death (LEF1-AS1 and TCL6). In addition, we observed that transcriptional regulation in the H19/IGF2 region is disrupted in higher-risk MDS, and discordant expression in this locus is associated with worse outcomes. Conclusions: we identified specific lncRNAs contributing to MDS pathogenesis and proposed cellular processes associated with these transcripts. Of the lncRNAs associated with patient prognosis, the level of H19 transcript might serve as a robust marker comparable to the clinical variables currently used for patient stratification.
Dual Targeting of Endothelial and Cancer Cells Potentiates In Vitro Nanobody-Targeted Photodynamic Therapy
Authors: Mashayekhi Vida , Xenaki Katerina T. , van Bergen en Henegouwen Paul M.P. , Oliveira Sabrina
Published: September 2020

Photodynamic therapy (PDT) induces cell death through local light activation of a photosensitizer, although sub-optimal tumor specificity and side effects have hindered its clinical application. We introduced a new strategy named nanobody-targeted PDT in which photosensitizers are delivered to tumor cells by means of nanobodies. As efficacy of targeted PDT can be hampered by heterogeneity of target expression and/or moderate/low target expression levels, we explored the possibility of combined targeting of endothelial and cancer cells in vitro. We developed nanobodies binding to the mouse VEGFR2, which is overexpressed on tumor vasculature, and combined these with nanobodies specific for the cancer cell target EGFR. The nanobodies were conjugated to the photosensitizer IRDye700DX and specificity of the newly developed nanobodies was verified using several endothelial cell lines. The cytotoxicity of these conjugates was assessed in monocultures and in co-cultures with cancer cells, after illumination with an appropriate laser. The results show that the anti-VEGFR2 conjugates are specific and potent PDT agents. Nanobody-targeted PDT on co-culture of endothelial and cancer cells showed improved efficacy, when VEGFR2 and EGFR targeting nanobodies were applied simultaneously. Altogether, dual targeting of endothelial and cancer cells is a promising novel therapeutic strategy for more effective nanobody-targeted PDT.
Loco-Regional and Systemic Chemotherapies for Hepato-Pancreatic Tumors: Integrated Treatments
Authors: Ranieri Girolamo , Laface Carmelo
Published: September 2020

This Special Issue of Cancers, titled “Loco-Regional Arterial Chemotherapies Alone or in Combination with Systemic Treatments for Primary and Secondary Hepato-Pancreatic Tumors”, focuses on new possible strategies to treat only liver disease (or mainly liver disease) through the combination of loco-regional and systemic chemotherapies [...]