bluuebunny/crossref_metadata_2025 huggingface dataset:
A Fuzzy Rule-Based GIS Framework to Partition an Urban System Based on Characteristics of Urban Greenery in Relation to the Urban Context
Authors: Cardone Barbara , Di Martino Ferdinando
Published: December 2020

We present a Geographical Information System (GIS)-based framework implementing a Mamdani fuzzy rule-based system to partition in an unsupervised mode an urban system in urban green areas. The proposed framework is characterized by high usability and flexibility. The study area is partitioned into homogeneous regions regarding the characteristics of public green areas and relations with the residents and buildings. The urban system is initially partitioned into microzones, given the smallest areas in which a census of the urban system is taken in terms of resident population, type and number of buildings and properties, and industrial and service activities. During a pre-processing phase, the values of specific indicators defined by a domain expert, which characterize the type of urban green area and the relationship with the residents and buildings, are calculated for each microzone. Subsequently, the fuzzy rule-based system component is executed to classify each microzone based on the fuzzy rule set constructed by the domain expert. Spatially adjoining microzones belonging to the same class are dissolved to form homogeneous areas called urban green contexts. The membership degrees of the microzones to the fuzzy set of their class are used to evaluate the reliability of the classification of the urban green context. We test our framework on the municipality of Pozzuoli, Italy, comparing the results with the ones obtained in a supervised manner by the expert appropriately partitioning and classifying the urban study area based on his knowledge of it.
CNN Classification Architecture Study for Turbulent Free-Space and Attenuated Underwater Optical OAM Communications
Authors: Neary Patrick L. , Watnik Abbie T. , Judd Kyle Peter , Lindle James R. , Flann Nicholas S.
Published: December 2020

Turbulence and attenuation are signal degrading factors that can severely hinder free-space and underwater OAM optical pattern demultiplexing. A variety of state-of-the-art convolutional neural network architectures are explored to identify which, if any, provide optimal performance under these non-ideal environmental conditions. Hyperparameter searches are performed on the architectures to ensure that near-ideal settings are used for training. Architectures are compared in various scenarios and the best performing, with their settings, are provided. We show that from the current state-of-the-art architectures, DenseNet outperforms all others when memory is not a constraint. When memory footprint is a factor, ShuffleNet is shown to performed the best.
The House that Lars Built. The Architecture of Transgression
Authors: Stępnik Małgorzata
Published: December 2020

This article discusses the motif of the “architecture of transgression”, which is present most implicitly, in Lars von Trier’s The House that Jack Built. The analysis concerns both the construction of cinematic narrative itself and the subtle allusions, inserted in the script, to two architectural metaphors: the Nietzschean (and Jungian) labyrinth and the Heideggerian die Hütte. Von Trier’s film may be read as an oeuvre immersed in literary tradition—from Dante’s Divine Comedy to the modern Bildungsroman—as well as inspired by modern philosophy, particularly George Bataille’s philosophy of transgression, (as expound in his Erotism and his short 1929 essay on Architecture).
Atmospheric Nitrogen Deposition to a Southeast Tibetan Forest Ecosystem
Authors: Wang Wei , Guan Lixue , Wen Zhang , Ma Xin , Fang Jiangping , Liu Xuejun
Published: December 2020

With atmospheric reactive nitrogen (Nr) emissions increasing globally, research into Nr deposition has attracted increasing attention, especially in remote environments. These ecosystems are very sensitive to global change, especially enhanced Nr deposition. Forest environments, in particular, are highlighted because of their important ecological function. We quantified atmospheric Nr concentrations and deposition over four years of continuous monitoring in a southeast Tibetan boreal forest ecosystem, an ecosystem in which forest biomass and carbon density are high around the world. Average annual bulk Nr deposition was 3.00 kg N ha−1 y−1, with those of reduced and oxidized species estimated at 1.60 and 1.40 kg N ha−1 y−1, respectively. Bulk deposition of both NH4+ and NO3− were controlled by precipitation amount: both Nr deposition and precipitation were highest in summer and lowest in winter. Dry deposition of NH3 and NO2 were 1.18 and 0.05 kg N ha−1 y−1, respectively. Atmospheric NH3 concentrations were in the range 1.15–3.53 mg N L−1, highest in summer and lowest in winter. In contrast, no clear trend in seasonal NO2 concentrations was observed. Monthly NO2 concentrations were 0.79–1.13 mg N L−1. Total Nr deposition (bulk plus dry) was 4.23 (3.00 + 1.23) kg N ha−1 y−1 in the forest. Reduced nitrogen was the dominant species. In conclusion, Nr deposition was in the range at which forest net productivity and carbon sequestration are sensitive to any variation in nitrogen input, so quantification of Nr deposition should continue and with greater detail.
Comparative Assessment of Intrinsic Disorder Predictions with a Focus on Protein and Nucleic Acid-Binding Proteins
Authors: Katuwawala Akila , Kurgan Lukasz
Published: December 2020

With over 60 disorder predictors, users need help navigating the predictor selection task. We review 28 surveys of disorder predictors, showing that only 11 include assessment of predictive performance. We identify and address a few drawbacks of these past surveys. To this end, we release a novel benchmark dataset with reduced similarity to the training sets of the considered predictors. We use this dataset to perform a first-of-its-kind comparative analysis that targets two large functional families of disordered proteins that interact with proteins and with nucleic acids. We show that limiting sequence similarity between the benchmark and the training datasets has a substantial impact on predictive performance. We also demonstrate that predictive quality is sensitive to the use of the well-annotated order and inclusion of the fully structured proteins in the benchmark datasets, both of which should be considered in future assessments. We identify three predictors that provide favorable results using the new benchmark set. While we find that VSL2B offers the most accurate and robust results overall, ESpritz-DisProt and SPOT-Disorder perform particularly well for disordered proteins. Moreover, we find that predictions for the disordered protein-binding proteins suffer low predictive quality compared to generic disordered proteins and the disordered nucleic acids-binding proteins. This can be explained by the high disorder content of the disordered protein-binding proteins, which makes it difficult for the current methods to accurately identify ordered regions in these proteins. This finding motivates the development of a new generation of methods that would target these difficult-to-predict disordered proteins. We also discuss resources that support users in collecting and identifying high-quality disorder predictions.
Degradation of Intrinsically Disordered Proteins by the NADH 26S Proteasome
Authors: Tsvetkov Peter , Myers Nadav , Adler Julia , Shaul Yosef
Published: December 2020

The 26S proteasome is the endpoint of the ubiquitin- and ATP-dependent degradation pathway. Over the years, ATP was regarded as completely essential for 26S proteasome function due to its role in ubiquitin-signaling, substrate unfolding and ensuring its structural integrity. We have previously reported that physiological concentrations of NADH are efficient in replacing ATP to maintain the integrity of an enzymatically functional 26S PC. However, the substrate specificity of the NADH-stabilized 26S proteasome complex (26S PC) was never assessed. Here, we show that the binding of NADH to the 26S PC inhibits the ATP-dependent and ubiquitin-independent degradation of the structured ODC enzyme. Moreover, the NADH-stabilized 26S PC is efficient in degrading intrinsically disordered protein (IDP) substrates that might not require ATP-dependent unfolding, such as p27, Tau, c-Fos and more. In some cases, NADH-26S proteasomes were more efficient in processing IDPs than the ATP-26S PC. These results indicate that in vitro, physiological concentrations of NADH can alter the processivity of ATP-dependent 26S PC substrates such as ODC and, more importantly, the NADH-stabilized 26S PCs promote the efficient degradation of many IDPs. Thus, ATP-independent, NADH-dependent 26S proteasome activity exemplifies a new principle of how mitochondria might directly regulate 26S proteasome substrate specificity.
Tim17 Updates: A Comprehensive Review of an Ancient Mitochondrial Protein Translocator
Authors: Chaudhuri Minu , Darden Chauncey , Soto Gonzalez Fidel , Singha Ujjal K. , Quinones Linda , Tripathi Anuj
Published: December 2020

The translocases of the mitochondrial outer and inner membranes, the TOM and TIMs, import hundreds of nucleus-encoded proteins into mitochondria. TOM and TIMs are multi-subunit protein complexes that work in cooperation with other complexes to import proteins in different sub-mitochondrial destinations. The overall architecture of these protein complexes is conserved among yeast/fungi, animals, and plants. Recent studies have revealed unique characteristics of this machinery, particularly in the eukaryotic supergroup Excavata. Despite multiple differences, homologues of Tim17, an essential component of one of the TIM complexes and a member of the Tim17/Tim22/Tim23 family, have been found in all eukaryotes. Here, we review the structure and function of Tim17 and Tim17-containing protein complexes in different eukaryotes, and then compare them to the single homologue of this protein found in Trypanosoma brucei, a unicellular parasitic protozoan.
Effects of Histamine Receptor Antagonist Cetirizine on Orthodontic Tooth Movement
Authors: Sperl Gregor , Gattner Johanna , Deschner James , Wolf Michael , Proff Peter , Schröder Agnes , Kirschneck Christian
Published: December 2020

Many patients regularly take histamine receptor antagonists, such as cetirizine, to prevent allergic reactions, but these antiallergic drugs may have inadvertent effects on orthodontic treatment. In previous studies, histamine has been shown to modulate the sterile inflammatory reaction underlying orthodontic tooth movement. Pertinent effects of histamine antagonization via cetirizine during orthodontic treatment, however, have not been adequately investigated. We thus treated male Fischer344 rats either with tap water (control group) or cetirizine by daily oral gavage corresponding to the clinically used human dosage adjusted to the rat metabolism (0.87 mg/kg) or to a previously published high dosage of cetirizine (3 mg/kg). Experimental anterior movement of the first upper left molar was induced by insertion of a nickel-titanium (NiTi) coil spring (0.25 N) between the molar and the upper incisors. Cone-beam computed tomography (CBCT), micro-computed tomography (µCT) images, as well as histological hematoxylin-eosin (HE), and tartrate-resistant acid phosphatase (TRAP) stainings were used to assess the extent of tooth movement, cranial growth, periodontal bone loss, root resorptions, and osteoclast activity in the periodontal ligament. Both investigated cetirizine dosages had no impact on the weight gain of the animals and, thus, animal welfare. Neither the extent of tooth movement, nor cranial growth, nor root resorption, nor periodontal bone loss were significantly influenced by the cetirizine dosages investigated. We, thus, conclude that histamine receptor antagonist cetirizine can be used during orthodontic treatment to prevent allergic reactions without clinically relevant side effects on orthodontic tooth movement.
Emission Reduction Potential of Different Types of Finnish Buildings through Energy Retrofits
Authors: Hirvonen Janne , Jokisalo Juha , Sankelo Paula , Niemelä Tuomo , Kosonen Risto
Published: December 2020

Energy retrofitting of buildings shows great potential in reducing CO2 emissions. However, most retrofitting studies only focus on a single building type. This paper shows the relative potential in six Finnish building types, to identify possible focus areas for future retrofits in Finland. Data from previous optimization studies was used to provide optimal cases for comparison. Energy demand of the buildings was generated through dynamic simulation with the IDA-ICE software. The cases were compared according to emissions reduction, investment and life cycle cost. It was found that, in all buildings, it was possible to reduce emissions cost-neutrally by 20% to 70% in buildings with district heating and by 70% to 95% using heat pumps. Single-family homes with oil or wood boilers switching to heat pumps had the greatest emission reduction potential. More stringent requirements for energy efficiency could be mandated during building renovation.
Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials
Authors: Riesco-Martinez Maria C. , Fernandez-Martos Carlos , Gravalos-Castro Cristina , Espinosa-Olarte Paula , La Salvia Anna , Robles-Diaz Luis , Modrego-Sanchez Andrea , Garcia-Carbonero Rocio
Published: December 2020

Multimodality treatment is a standard of care for LARC, but the optimal sequencing of the treatment modalities remains unclear. Several randomized clinical trials (RCTs) compared total neoadjuvant treatment (TNT) vs. standard neoadjuvant chemoradiotherapy (CRT) with inconsistent results. A systematic review and meta-analysis was performed to evaluate the efficacy of TNT in terms of complete pathological response (pCR) rate, disease-free and overall survival vs. standard CRT in LARC. A systematic search was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and meeting abstracts up to May 2020. RCTs comparing CRT vs. TNT followed by surgery in LARC were eligible for the study. Study selection and data extraction were done following PRISMA guidelines by two independent reviewers. The Mantel–Haenzel method was used to obtain a fixed-effects model of pooled odds or hazard ratios for the main outcomes. Eight RCTs, including 2301 patients, met the eligibility criteria. TNT significantly improved pCR rate (OR = 1.99, 95% confidence interval (CI) 1.59–2.49; p < 0.001), 3-year disease-free-survival (DFS) (HR = 0.82, 95%CI 0.71–0.95; p = 0.01) and 3-year overall survival (OS) (hazard ratio (HR) = 0.81, p = 0.04). Grade 3–4 adverse events were not significantly different in both strategies (OR = 1.58; p = 0.14). An improved pCR rate was documented regardless of the type of radiotherapy administered (long vs. short fractionation schedules). No significant heterogeneity was found. The results of this meta-analysis show that TNT improves pCR and survival rates vs. standard preoperative CRT in patients with LARC. TNT may become a new standard of care in LARC, although longer follow-up is needed to properly assess its long-term impact on survival.
Predictive Modeling for Voxel-Based Quantification of Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma (PDAC): A Multi-Institutional Study
Authors: Zaid Mohamed , Widmann Lauren , Dai Annie , Sun Kevin , Zhang Jie , Zhao Jun , Hurd Mark W. , Varadhachary Gauri R. , Wolff Robert A. , Maitra Anirban , Katz Matthew H. G. , Herman Joseph M. , Wang Huamin , Knopp Michael V. , Williams Terence M. , Bhosale Priya , Tamm Eric P. , Koay Eugene J.
Published: December 2020

Previously, we characterized qualitative imaging-based subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed tomography (CT) scans. Conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we developed a quantitative classification of this imaging-based subtype (quantitative delta; q-delta). Retrospectively, baseline pancreatic protocol CT scans of three cohorts (cohort#1 = 101, cohort#2 = 90 and cohort#3 = 16 [external validation]) of patients with PDAC were qualitatively classified into high and low delta. We used a voxel-based method to volumetrically quantify tumor enhancement while referencing normal-pancreatic-parenchyma and used machine learning-based analysis to build a predictive model. In addition, we quantified the stromal content using hematoxylin- and eosin-stained treatment-naïve PDAC sections. Analyses revealed that PDAC quantitative enhancement values are predictive of the qualitative delta scoring and were used to build a classification model (q-delta). Compared to high q-delta, low q-delta tumors were associated with improved outcomes, and the q-delta class was an independent prognostic factor for survival. In addition, low q-delta tumors had higher stromal content and lower cellularity compared to high q-delta tumors. Our results suggest that q-delta classification provides a clinically and biologically relevant tool that may be integrated into ongoing and future clinical trials.
Mapping the Relative Biological Effectiveness of Proton, Helium and Carbon Ions with High-Throughput Techniques
Authors: Bronk Lawrence , Guan Fada , Patel Darshana , Ma Duo , Kroger Benjamin , Wang Xiaochun , Tran Kevin , Yiu Joycelyn , Stephan Clifford , Debus Jürgen , Abdollahi Amir , Jäkel Oliver , Mohan Radhe , Titt Uwe , Grosshans David R.
Published: December 2020

Large amounts of high quality biophysical data are needed to improve current biological effects models but such data are lacking and difficult to obtain. The present study aimed to more efficiently measure the spatial distribution of relative biological effectiveness (RBE) of charged particle beams using a novel high-accuracy and high-throughput experimental platform. Clonogenic survival was selected as the biological endpoint for two lung cancer cell lines, H460 and H1437, irradiated with protons, carbon, and helium ions. Ion-specific multi-step microplate holders were fabricated such that each column of a 96-well microplate is spatially situated at a different location along a particle beam path. Dose, dose-averaged linear energy transfer (LETd), and dose-mean lineal energy (yd) were calculated using an experimentally validated Geant4-based Monte Carlo system. Cells were irradiated at the Heidelberg Ion Beam Therapy Center (HIT). The experimental results showed that the clonogenic survival curves of all tested ions were yd-dependent. Both helium and carbon ions achieved maximum RBEs within specific yd ranges before biological efficacy declined, indicating an overkill effect. For protons, no overkill was observed, but RBE increased distal to the Bragg peak. Measured RBE profiles strongly depend on the physical characteristics such as yd and are ion specific.
Identifying Cross-Scale Associations between Radiomic and Pathomic Signatures of Non-Small Cell Lung Cancer Subtypes: Preliminary Results
Authors: Alvarez-Jimenez Charlems , Sandino Alvaro A. , Prasanna Prateek , Gupta Amit , Viswanath Satish E. , Romero Eduardo
Published: December 2020

(1) Background: Despite the complementarity between radiology and histopathology, both from a diagnostic and a prognostic perspective, quantitative analyses of these modalities are usually performed in disconnected silos. This work presents initial results for differentiating two major non-small cell lung cancer (NSCLC) subtypes by exploring cross-scale associations between Computed Tomography (CT) images and corresponding digitized pathology images. (2) Methods: The analysis comprised three phases, (i) a multi-resolution cell density quantification to identify discriminant pathomic patterns for differentiating adenocarcinoma (ADC) and squamous cell carcinoma (SCC), (ii) radiomic characterization of CT images by using Haralick descriptors to quantify tumor textural heterogeneity as represented by gray-level co-occurrences to discriminate the two pathological subtypes, and (iii) quantitative correlation analysis between the multi-modal features to identify potential associations between them. This analysis was carried out using two publicly available digitized pathology databases (117 cases from TCGA and 54 cases from CPTAC) and a public radiological collection of CT images (101 cases from NSCLC-R). (3) Results: The top-ranked cell density pathomic features from the histopathology analysis were correlation, contrast, homogeneity, sum of entropy and difference of variance; which yielded a cross-validated AUC of 0.72 ± 0.02 on the training set (CPTAC) and hold-out validation AUC of 0.77 on the testing set (TCGA). Top-ranked co-occurrence radiomic features within NSCLC-R were contrast, correlation and sum of entropy which yielded a cross-validated AUC of 0.72 ± 0.01. Preliminary but significant cross-scale associations were identified between cell density statistics and CT intensity values using matched specimens available in the TCGA cohort, which were used to significantly improve the overall discriminatory performance of radiomic features in differentiating NSCLC subtypes (AUC = 0.78 ± 0.01). (4) Conclusions: Initial results suggest that cross-scale associations may exist between digital pathology and CT imaging which can be used to identify relevant radiomic and histopathology features to accurately distinguish lung adenocarcinomas from squamous cell carcinomas.
Gamma Knife Radiosurgery for Brain Metastases in Non-Small Cell Lung Cancer Patients Treated with Immunotherapy or Targeted Therapy
Authors: Cho Anna , Untersteiner Helena , Hirschmann Dorian , Shaltout Abdallah , Göbl Philipp , Dorfer Christian , Rössler Karl , Marik Wolfgang , Kirchbacher Klaus , Kapfhammer Irene , Zöchbauer-Müller Sabine , Gatterbauer Brigitte , Hochmair Maximilian J. , Frischer Josa M.
Published: December 2020

The combination of Gamma Knife radiosurgery (GKRS) and systemic immunotherapy (IT) or targeted therapy (TT) is a novel treatment method for brain metastases (BMs) in non-small cell lung cancer (NSCLC). To elucidate the safety and efficacy of concomitant IT or TT on the outcome after GKRS, 496 NSCLC patients with BMs, who were treated with GKRS were retrospectively reviewed. The median time between the initial lung cancer diagnosis and the diagnosis of brain metastases was one month. The survival after the initial BM diagnosis was significantly longer than the survival predicted by prognostic BM scores. After the first Gamma Knife radiosurgery treatment (GKRS1), the estimated median survival was 9.9 months (95% CI = 8.3–11.4). Patients with concurrent IT or TT presented with a significantly longer survival after GKRS1 than patients without IT or TT (p < 0.001). These significant differences in the survival were also apparent among the four treatment groups and remained significant after adjustment for Karnofsky performance status scale (KPS), recursive partitioning analysis (RPA) class, sex, and multiple BMs. About half of all our patients (46%) developed new distant BMs after GKRS1. Of note, no statistically significant differences in the occurrence of radiation reaction, radiation necrosis, or intralesional hemorrhage in association with IT or TT at or after GKRS1 were observed. In NSCLC-BM patients, the concomitant use of GKRS and IT or TT showed an increase in overall survival without increased complications related to GKRS. Therefore, the combined treatment with GKRS and IT or TT seems to be a safe and powerful treatment option and emphasizes the role of radiosurgery in modern BM treatment.
Getting Lost in the Cell–Lysosomal Entrapment of Chemotherapeutics
Authors: Zhai Xingjian , El Hiani Yassine
Published: December 2020

Despite extensive research, resistance to chemotherapy still poses a major obstacle in clinical oncology. An exciting strategy to circumvent chemoresistance involves the identification and subsequent disruption of cellular processes that are aberrantly altered in oncogenic states. Upon chemotherapeutic challenges, lysosomes are deemed to be essential mediators that enable cellular adaptation to stress conditions. Therefore, lysosomes potentially hold the key to disarming the fundamental mechanisms of chemoresistance. This review explores modes of action of classical chemotherapeutic agents, adaptive response of the lysosomes to cell stress, and presents physiological and pharmacological insights pertaining to drug compartmentalization, sequestration, and extracellular clearance through the lens of lysosomes.
S100A10 Has a Critical Regulatory Function in Mammary Tumor Growth and Metastasis: Insights Using MMTV-PyMT Oncomice and Clinical Patient Sample Analysis
Authors: Bharadwaj Alamelu G. , Dahn Margaret L. , Liu Rong-Zong , Colp Patricia , Thomas Lynn N. , Holloway Ryan W. , Marignani Paola A. , Too Catherine K. L. , Barnes Penelope J. , Godbout Roseline , Marcato Paola , Waisman David M.
Published: December 2020

S100A10 (p11) is a plasminogen receptor that regulates cellular plasmin generation by cancer cells. In the current study, we used the MMTV-PyMT mouse breast cancer model, patient tumor microarray, and immunohistochemical (IHC) analysis to investigate the role of p11 in oncogenesis. The genetic deletion of p11 resulted in significantly decreased tumor onset, growth rate, and spontaneous pulmonary metastatic burden in the PyMT/p11-KO (knock-out) mice. This phenotype was accompanied by substantial reduction in Ki67 positivity, macrophage infiltration, decreased vascular density in the primary tumors, and decrease in invasive carcinoma and pulmonary metastasis. Surprisingly, IHC analysis of wild-type MMTV-PyMT mice failed to detect p11 expression in the tumors or metastatic tumor cells and loss of p11 did not decrease plasmin generation in the PyMT tumors and cells. Furthermore, tumor cells expressing p11 displayed dramatically reduced lung metastasis when injected into p11-depleted mice, further strengthening the stromal role of p11 in tumor growth and metastasis. Transcriptome analysis of the PyMT tumors from p11-KO mice showed marked reduction in genes such as Areg, Muc1, and S100a8 involved in breast cancer development, progression, and inflammation. The PyMT/p11-KO tumors displayed a remarkable increase in inflammatory cytokines such as interleukin (Il)-6, Il-10, and interferon (Ifn)-γ. Gene expression profiling and IHC of primary breast cancer samples showed that p11 mRNA and protein levels were significantly higher in tumor tissues compared to normal mammary tissue. P11 mRNA expression was significantly associated with poor patient prognosis and significantly elevated in high grade, triple negative (TN) tumors, and tumors with high proliferative index. This is the first study examining the crucial role of p11 in breast tumor development and metastasis, thus emphasizing its potential as a diagnostic and prognostic biomarker in breast cancer.
Translational Research in Ovarian Cancer
Authors: Di Renzo Maria Flavia , Valabrega Giorgio
Published: December 2020

Ovarian cancer is still the most lethal gynecologic malignancy with a median five-year survival of 48%, including the less malignant and early diagnosed cases [...]
Investigating Serum and Tissue Expression Identified a Cytokine/Chemokine Signature as a Highly Effective Melanoma Marker
Authors: Cesati Marco , Scatozza Francesca , D’Arcangelo Daniela , Antonini-Cappellini Gian Carlo , Rossi Stefania , Tabolacci Claudio , Nudo Maurizio , Palese Enzo , Lembo Luigi , Di Lella Giovanni , Facchiano Francesco , Facchiano Antonio
Published: December 2020

The identification of reliable and quantitative melanoma biomarkers may help an early diagnosis and may directly affect melanoma mortality and morbidity. The aim of the present study was to identify effective biomarkers by investigating the expression of 27 cytokines/chemokines in melanoma compared to healthy controls, both in serum and in tissue samples. Serum samples were from 232 patients recruited at the IDI-IRCCS hospital. Expression was quantified by xMAP technology, on 27 cytokines/chemokines, compared to the control sera. RNA expression data of the same 27 molecules were obtained from 511 melanoma- and healthy-tissue samples, from the GENT2 database. Statistical analysis involved a 3-step approach: analysis of the single-molecules by Mann–Whitney analysis; analysis of paired-molecules by Pearson correlation; and profile analysis by the machine learning algorithm Support Vector Machine (SVM). Single-molecule analysis of serum expression identified IL-1b, IL-6, IP-10, PDGF-BB, and RANTES differently expressed in melanoma (p < 0.05). Expression of IL-8, GM-CSF, MCP-1, and TNF-α was found to be significantly correlated with Breslow thickness. Eotaxin and MCP-1 were found differentially expressed in male vs. female patients. Tissue expression analysis identified very effective marker/predictor genes, namely, IL-1Ra, IL-7, MIP-1a, and MIP-1b, with individual AUC values of 0.88, 0.86, 0.93, 0.87, respectively. SVM analysis of the tissue expression data identified the combination of these four molecules as the most effective signature to discriminate melanoma patients (AUC = 0.98). Validation, using the GEPIA2 database on an additional 1019 independent samples, fully confirmed these observations. The present study demonstrates, for the first time, that the IL-1Ra, IL-7, MIP-1a, and MIP-1b gene signature discriminates melanoma from control tissues with extremely high efficacy. We therefore propose this 4-molecule combination as an effective melanoma marker.
Interrogation of IDH1 Status in Gliomas by Fourier Transform Infrared Spectroscopy
Authors: Cameron James M. , Conn Justin J. A. , Rinaldi Christopher , Sala Alexandra , Brennan Paul M. , Jenkinson Michael D. , Caldwell Helen , Cinque Gianfelice , Syed Khaja , Butler Holly J. , Hegarty Mark G. , Palmer David S. , Baker Matthew J.
Published: December 2020

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene are found in a high proportion of diffuse gliomas. The presence of the IDH1 mutation is a valuable diagnostic, prognostic and predictive biomarker for the management of patients with glial tumours. Techniques involving vibrational spectroscopy, e.g., Fourier transform infrared (FTIR) spectroscopy, have previously demonstrated analytical capabilities for cancer detection, and have the potential to contribute to diagnostics. The implementation of FTIR microspectroscopy during surgical biopsy could present a fast, label-free method for molecular genetic classification. For example, the rapid determination of IDH1 status in a patient with a glioma diagnosis could inform intra-operative decision-making between alternative surgical strategies. In this study, we utilized synchrotron-based FTIR microanalysis to probe tissue microarray sections from 79 glioma patients, and distinguished the positive class (IDH1-mutated) from the IDH1-wildtype glioma, with a sensitivity and specificity of 82.4% and 83.4%, respectively. We also examined the ability of attenuated total reflection (ATR)-FTIR spectroscopy in detecting the biomolecular events and global epigenetic and metabolic changes associated with mutations in the IDH1 enzyme, in blood serum samples collected from an additional 72 brain tumour patients. Centrifugal filtration enhanced the diagnostic ability of the classification models, with balanced accuracies up to ~69%. Identification of the molecular status from blood serum prior to biopsy could further direct some patients to alternative treatment strategies.
Living with Metastatic Cancer: A Roadmap for Future Research
Authors: Tometich Danielle B. , Hyland Kelly A. , Soliman Hatem , Jim Heather S. L. , Oswald Laura
Published: December 2020

Living with metastatic cancer, or metavivorship, differs from cancer survivorship and has changed as novel treatments have increased survival time. The purpose of this narrative review is to describe factors that impact challenges in metavivorship within a conceptual framework to guide future research. This review focuses on the specific metavivorship outcomes of progressive disease, survival time, symptoms, distress, financial toxicity, and quality of life. We describe the predisposing, precipitating, and perpetuating (3P) model of metavivorship. Understanding the biological, psychological, and social 3P factors that contribute to the development and maintenance of challenges in metavivorship provides a roadmap for future research. Implications of this model include prevention by targeting predisposing factors, management of precipitating factors after onset of metastatic disease, and treatment of perpetuating factors to reduce symptoms and improve quality of life during the chronic phase of metavivorship. This can be accomplished through biopsychosocial screening efforts, monitoring of patient-reported outcomes, education and communication interventions, interdisciplinary symptom management, advance care planning, and behavioral interventions to cultivate psychological resilience.
Identifying Ovarian Cancer in Symptomatic Women: A Systematic Review of Clinical Tools
Authors: Funston Garth , Hardy Victoria , Abel Gary , Crosbie Emma J. , Emery Jon , Hamilton Willie , Walter Fiona M.
Published: December 2020

In the absence of effective ovarian cancer screening programs, most women are diagnosed following the onset of symptoms. Symptom-based tools, including symptom checklists and risk prediction models, have been developed to aid detection. The aim of this systematic review was to identify and compare the diagnostic performance of these tools. We searched MEDLINE, EMBASE and Cochrane CENTRAL, without language restriction, for relevant studies published between 1 January 2000 and 3 March 2020. We identified 1625 unique records and included 16 studies, evaluating 21 distinct tools in a range of settings. Fourteen tools included only symptoms; seven also included risk factors or blood tests. Four tools were externally validated—the Goff Symptom Index (sensitivity: 56.9–83.3%; specificity: 48.3–98.9%), a modified Goff Symptom Index (sensitivity: 71.6%; specificity: 88.5%), the Society of Gynaecologic Oncologists consensus criteria (sensitivity: 65.3–71.5%; specificity: 82.9–93.9%) and the QCancer Ovarian model (10% risk threshold—sensitivity: 64.1%; specificity: 90.1%). Study heterogeneity precluded meta-analysis. Given the moderate accuracy of several tools on external validation, they could be of use in helping to select women for ovarian cancer investigations. However, further research is needed to assess the impact of these tools on the timely detection of ovarian cancer and on patient survival.
Recent Advances in Synthesis and Applications of Carbon-Doped TiO2 Nanomaterials
Authors: Hua Li , Yin Zhengliang , Cao Shunsheng
Published: December 2020

TiO2 has been widely used as a photocatalyst and an electrode material toward the photodegradation of organic pollutants and electrochemical applications, respectively. However, the properties of TiO2 are not enough up to meet practical needs because of its intrinsic disadvantages such as a wide bandgap and low conductivity. Incorporation of carbon into the TiO2 lattice is a promising tool to overcome these limitations because carbon has metal-like conductivity, high separation efficiency of photogenerated electron/hole pairs, and strong visible-light absorption. This review would describe and discuss a variety of strategies to develop carbon-doped TiO2 with enhanced photoelectrochemical performances in environmental, energy, and catalytic fields. Emphasis is given to highlight current techniques and recent progress in C-doped TiO2-based materials. Meanwhile, how to tackle the challenges we are currently facing is also discussed. This understanding will allow the process to continue to evolve and provide facile and feasible techniques for the design and development of carbon-doped TiO2 materials.
Transformation of Contaminants of Emerging Concern (CECs) during UV-Catalyzed Processes Assisted by Chlorine
Authors: Kudlek Edyta
Published: December 2020

Every compound that potentially can be harmful to the environment is called a Contaminant of Emerging Concern (CEC). Compounds classified as CECs may undergo different transformations, especially in the water environment. The intermediates formed in this way are considered to be toxic against living organisms even in trace concentrations. We attempted to identify the intermediates formed during single chlorination and UV-catalyzed processes supported by the action of chlorine and hydrogen peroxide or ozone of selected contaminants of emerging concern. The analysis of post-processing water samples containing benzocaine indicated the formation of seven compound intermediates, while ibuprofen, acridine and β-estradiol samples contained 5, 5, and 3 compound decomposition by-products, respectively. The number and also the concentration of the intermediates decreased with the time of UV irradiation. The toxicity assessment indicated that the UV-catalyzed processes lead to decreased toxicity nature of post-processed water solutions.
Infection of Mammals and Mosquitoes by Alphaviruses: Involvement of Cell Death
Authors: Cappuccio Lucie , Maisse Carine
Published: December 2020

Alphaviruses, such as the chikungunya virus, are emerging and re-emerging viruses that pose a global public health threat. They are transmitted by blood-feeding arthropods, mainly mosquitoes, to humans and animals. Although alphaviruses cause debilitating diseases in mammalian hosts, it appears that they have no pathological effect on the mosquito vector. Alphavirus/host interactions are increasingly studied at cellular and molecular levels. While it seems clear that apoptosis plays a key role in some human pathologies, the role of cell death in determining the outcome of infections in mosquitoes remains to be fully understood. Here, we review the current knowledge on alphavirus-induced regulated cell death in hosts and vectors and the possible role they play in determining tolerance or resistance of mosquitoes.
Propagation and Maintenance of Cancer Stem Cells: A Major Influence of the Long Non-Coding RNA H19
Authors: Lecerf Clément , Peperstraete Evodie , Le Bourhis Xuefen , Adriaenssens Eric
Published: December 2020

Cancer stem cells (CSCs) represent a rare population of tumor cells that exhibit stem cell properties with the abilities of self-renewal and differentiation. These cells are now widely accepted to be responsible for tumor initiation, development, resistance to conventional therapies, and recurrence. Thus, a better understanding of the molecular mechanisms involved in the control of CSCs is essential to improve patient management in terms of diagnostics and therapies. CSCs are regulated by signals of the tumor microenvironment as well as intrinsic genetic and epigenetic modulators. H19, the first identified lncRNA is involved in the development and progression of many different cancer types. Recently, H19 has been demonstrated to be implicated in the regulation of CSCs in different types of cancers. The aim of this review is to provide an overview of the role and mechanisms of action of H19 in the regulation of CSCs. We summarize how H19 may regulate CSC division and cancer cell reprogramming, thus affecting metastasis and drug resistance. We also discuss the potential clinical implications of H19.
Maturation of T and B Lymphocytes in the Assessment of the Immune Status in COVID-19 Patients
Authors: Kwiecień Iwona , Rutkowska Elżbieta , Kłos Krzysztof , Więsik-Szewczyk Ewa , Jahnz-Różyk Karina , Rzepecki Piotr , Chciałowski Andrzej
Published: December 2020

Cell response to novel coronavirus disease 19 (COVID-19) is currently a widely researched topic. The assessment of leukocytes population and the maturation of both B and T lymphocytes may be important in characterizing the immunological profile of COVID-19 patients. The aim of the present study was to evaluate maturation of B and T cells in COVID-19 patients with interstitial lesions on chest X-ray (COVID-19 X-ray (+)), without changes on X-ray (COVID-19 X-ray (−)) and in healthy control. The study group consisted of 23 patients divided on two groups: COVID-19 X-ray (+) n = 14 and COVID-19 X-ray (−) n = 9 and control n = 20. The flow cytometry method was performed. We observed a significantly higher percentage of plasmablasts and lower CD4+ lymphocytes in COVID-19 X-ray (+) patients than in COVID-19 X-ray (−) and control. In the COVID-19 X-ray (+) patients, there was a lower proportion of effector CD4+ T cells, naïve CD8+ T cells and higher central memory CD4+ cells and effector CD8+ T cells than control. The above results showed that the assessment of selected cells of B and T lymphocytes by flow cytometry can distinguish patients with COVID-19 and differentiate patients with and without changes on chest X-ray.
Correction: Rigiracciolo, D.C., et al., IGF-1/IGF-1R/FAK/YAP Transduction Signaling Prompts Growth Effects in Triple-Negative Breast Cancer (TNBC) Cells. Cells 2020, 9, 1010
Authors: Rigiracciolo Damiano Cosimo , Nohata Nijiro , Lappano Rosamaria , Cirillo Francesca , Talia Marianna , Scordamaglia Domenica , Gutkind J. Silvio , Maggiolini Marcello
Published: December 2020

The authors wish to make the following changes to their paper [...]
Erratum: Viswanathan, A., et al. Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect (Running Title: Cancer Cells Death Signalling Activation). Cells 2019, 8, 1624
Authors: Viswanathan Anisha , Musa Aliyu , Murugesan Akshaya , Vale João R. , Afonso Carlos A. M. , Mani Saravanan Konda , Yli-Harja Olli , Candeias Nuno R. , Kandhavelu Meenakshisundaram
Published: December 2020

There is an error in the title of the paper [...]
Leukocytes, Systemic Inflammation and Immunopathology in Acute-on-Chronic Liver Failure
Authors: Casulleras Mireia , Zhang Ingrid W. , López-Vicario Cristina , Clària Joan
Published: December 2020

Acute-on-chronic liver failure (ACLF) is a complex syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure(s) and high short-term mortality. ACLF frequently occurs in close temporal relationship to a precipitating event, such as acute alcoholic, drug-induced or viral hepatitis or bacterial infection and, in cases without precipitating events, probably related to intestinal translocation of bacterial products. Dysbalanced immune function is central to its pathogenesis and outcome with an initial excessive systemic inflammatory response that drives organ failure and mortality. This hyperinflammatory state ultimately impairs the host defensive mechanisms of immune cells, rendering ACLF patients immunocompromised and more vulnerable to secondary infections, and therefore to higher organ dysfunction and mortality. In this review, we describe the prevailing characteristics of the hyperinflammatory state in patients with acutely decompensated cirrhosis developing ACLF, with special emphasis on cells of the innate immune system (i.e., monocytes and neutrophils), their triggers (pathogen- and damage-associated molecular patterns [PAMPs and DAMPs]), their effector molecules (cytokines, chemokines, growth factors and bioactive lipid mediators) and the consequences on tissue immunopathology. In addition, this review includes a chapter discussing new emerging therapies based on the modulation of leukocyte function by the administration of pleiotropic proteins such as albumin, Toll-like receptor 4 antagonists, interleukin-22 or stem cell therapy. Finally, the importance of finding an appropriate intervention that reduces inflammation without inducing immunosuppression is highlighted as one of the main therapeutic challenges in cirrhosis.
Cooperation and Interplay between EGFR Signalling and Extracellular Vesicle Biogenesis in Cancer
Authors: Zanetti-Domingues Laura C. , Bonner Scott E. , Iyer R. Sumanth , Martin-Fernandez Marisa L. , Huber Veronica
Published: December 2020

Epidermal growth factor receptor (EGFR) takes centre stage in carcinogenesis throughout its entire cellular trafficking odyssey. When loaded in extracellular vesicles (EVs), EGFR is one of the key proteins involved in the transfer of information between parental cancer and bystander cells in the tumour microenvironment. To hijack EVs, EGFR needs to play multiple signalling roles in the life cycle of EVs. The receptor is involved in the biogenesis of specific EV subpopulations, it signals as an active cargo, and it can influence the uptake of EVs by recipient cells. EGFR regulates its own inclusion in EVs through feedback loops during disease progression and in response to challenges such as hypoxia, epithelial-to-mesenchymal transition and drugs. Here, we highlight how the spatiotemporal rules that regulate EGFR intracellular function intersect with and influence different EV biogenesis pathways and discuss key regulatory features and interactions of this interplay. We also elaborate on outstanding questions relating to EGFR-driven EV biogenesis and available methods to explore them. This mechanistic understanding will be key to unravelling the functional consequences of direct anti-EGFR targeted and indirect EGFR-impacting cancer therapies on the secretion of pro-tumoural EVs and on their effects on drug resistance and microenvironment subversion.
Detection of EGFR Mutations in Plasma Cell-Free Tumor DNA of TKI-Treated Advanced-NSCLC Patients by Three Methodologies: Scorpion-ARMS, PNAClamp, and Digital PCR
Authors: Siggillino Annamaria , Ulivi Paola , Pasini Luigi , Reda Maria Sole , Chiadini Elisa , Tofanetti Francesca Romana , Baglivo Sara , Metro Giulio , Crinó Lucio , Delmonte Angelo , Minotti Vincenzo , Roila Fausto , Ludovini Vienna
Published: December 2020

Analysis of circulating cell-free tumor DNA (cftDNA) has emerged as a specific and sensitive blood-based approach to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients. Still, there is some debate on what should be the preferential clinical method for plasma-derived cftDNA analysis. We tested 31 NSCLC patients treated with anti-EGFR tyrosine kinase inhibitors (TKIs), at baseline and serially during therapy, by comparing three methodologies in detecting EGFR mutations (L858R, exon 19 deletion, and T790M) from plasma: scorpions-amplification refractory mutation system (ARMS) methodology by using EGFR Plasma RGQ PCR Kit-QIAGEN, peptide nucleic acid (PNA) clamp and PANA RealTyper integration by using PNAClamp EGFR-PANAGENE, and digital real time PCR by using QuantStudio 3D Digital PCR System-Thermo Fisher Scientific. Specificity was 100% for all three mutations, independently from the platform used. The sensitivity for L858R (42.86%) and T790M (100%) did not change based on the method, while the sensitivity for Del 19 differed markedly (Scorpion-ARMS 45%, PNAClamp 75%, and Digital PCR 85%). The detection rate was also higher (94.23%) as measured by Digital PCR, and when we monitored the evolution of EGFR mutations over time, it evidenced the extreme inter-patient heterogeneity in terms of levels of circulating mutated copies. In our study, Digital PCR showed the best correlation with tissue biopsy and the highest sensitivity to attain the potential clinical utility of monitoring plasma levels of EGFR mutations.
Some Aspects of Time-Reversal in Chemical Kinetics
Authors: Maas Ulrich
Published: December 2020

Chemical kinetics govern the dynamics of chemical systems leading towards chemical equilibrium. There are several general properties of the dynamics of chemical reactions such as the existence of disparate time scales and the fact that most time scales are dissipative. This causes a transient relaxation to lower dimensional attracting manifolds in composition space. In this work, we discuss this behavior and investigate how a time reversal effects this behavior. For this, both macroscopic chemical systems as well as microscopic chemical systems (elementary reactions) are considered.