bluuebunny/crossref_metadata_2025 huggingface dataset:
Fire Parameters of Spruce (Picea abies Karst. (L.)) Dust Layer from Different Wood Technologies Slovak Case Study
Authors: Mračková Eva , Schmidtová Jarmila , Marková Iveta , Jaďuďová Jana , Tureková Ivana , Hitka Miloš
Published: January 2022

The issue of the formation of wood dust particles in the work environment is still an actual topic in terms of its impact on employee health and the risk of fire or explosion in a woodworking operation. This article deals with the characteristics of spruce dust (Picea abies Karst. (L.)), which was taken from several types of wood technology. Experimental samples of spruce dust were taken from four types of sawing technologies, including grinding, briquetting and from the suction device container. The physical parameters of the samples taken were monitored and the particle size analysis was determined. The granulometric composition of the samples is significantly different. The sample of spruce wood dust from sawing has the most numerous fraction (250 µm), while the sample from grinding has the most numerous fraction 63–250 µm (87%).The aim of the paper was to monitor the minimum ignition temperature of the settled spruce dust layer and to look for a significant dependence of the minimum ignition temperature and ignition time on the type of spruce dust sample. A significant dependence was not confirmed. Significant moisture dependence of the samples was confirmed; the highest humidity was observed in the container, the lowest in sawing.
Properties of CAD/CAM 3D Printing Dental Materials and Their Clinical Applications in Orthodontics: Where Are We Now?
Authors: Scribante Andrea , Gallo Simone , Pascadopoli Maurizio , Canzi Pietro , Marconi Stefania , Montasser Mona A. , Bressani Davide , Gandini Paola , Sfondrini Maria Francesca
Published: January 2022

In the last years, both medicine and dentistry have come across a revolution represented by the introduction of more and more digital technologies for both diagnostic and therapeutic purposes. Additive manufacturing is a relatively new technology consisting of a computer-aided design and computer-aided manufacturing (CAD/CAM) workflow, which allows the substitution of many materials with digital data. This process requires three fundamental steps represented by the digitalization of an item through a scanner, the editing of the data acquired using a software, and the manufacturing technology to transform the digital data into a final product, respectively. This narrative review aims to discuss the recent introduction in dentistry of the abovementioned digital workflow. The main advantages and disadvantages of the process will be discussed, along with a brief description of the possible applications on orthodontics.
A New Method to Determine the Steel Fibre Content of Existing Structures—Test Setup and Numerical Simulation
Authors: Cleven Simon , Raupach Michael , Matschei Thomas
Published: January 2022

The diagnostics of constructions built with steel fibre reinforced concrete are extremely difficult to conduct because, typically, no information on the actual amount and orientation of the fibres is available. Therefore, it is of great interest to engineers to have the possibility to determine the steel fibre content and, at best, also the orientation of the fibres in existing structures. For this purpose, an easy-to-use test setup was developed and tested, in the course of laboratory investigations. This method can be used for cylinders, for example drilling cores, that can later be taken of existing structures, to determine both the fibre content and orientation. Based on these results, a model for cylindrical specimens was derived, which can be used for varying concrete compositions with steel fibre contents of up to 80 kg/m3. In the case of missing information concerning the concrete composition, it allows an initial estimation for the fibre content. In case additional information about the concrete composition is available, a much higher accuracy of the projected steel fibre content and therefore, an assessment of the building’s condition is possible.
Visual SLAM Based Spatial Recognition and Visualization Method for Mobile AR Systems
Authors: Song Jooeun , Kook Joongjin
Published: January 2022

The simultaneous localization and mapping (SLAM) market is growing rapidly with advances in Machine Learning, Drones, and Augmented Reality (AR) technologies. However, due to the absence of an open source-based SLAM library for developing AR content, most SLAM researchers are required to conduct their own research and development to customize SLAM. In this paper, we propose an open source-based Mobile Markerless AR System by building our own pipeline based on Visual SLAM. To implement the Mobile AR System of this paper, we use ORB-SLAM3 and Unity Engine and experiment with running our system in a real environment and confirming it in the Unity Engine’s Mobile Viewer. Through this experimentation, we can verify that the Unity Engine and the SLAM System are tightly integrated and communicate smoothly. In addition, we expect to accelerate the growth of SLAM technology through this research.
Simulation and Evaluation of Statistical Downscaling of Regional Daily Precipitation over North China Based on Self-Organizing Maps
Authors: Wang Yongdi , Sun Xinyu
Published: January 2022

A statistical downscaling method based on Self-Organizing Maps (SOM), of which the SOM Precipitation Statistical Downscaling Method (SOM-SD) is named, has received increasing attention. Herein, its applicability of downscaling daily precipitation over North China is evaluated. Six indices (total season precipitation, daily precipitation intensity, mean number of precipitation days, percentage of rainfall from events beyond the 95th percentile value of overall precipitation, maximum consecutive wet days, and maximum consecutive dry days) are selected, which represent the statistics of daily precipitation with regards to both precipitation amount and frequency, as well as extreme event. The large-scale predictors were extracted from the National Center for Environmental Prediction/National Center for Atmospheric Research (NCEP/NCAR) daily reanalysis data, while the prediction was the high resolution gridded daily observed precipitation. The results show that the method can establish certain conditional transformation relationships between large-scale atmospheric circulation and local-scale surface precipitation in a relatively simple way. This method exhibited a high skill in reproducing the climatologic statistical properties of the observed precipitation. The simulated daily precipitation probability distribution characteristics can be well matched with the observations. The values of Brier scores are between 0 and 1.5 × 10−4 and the significance scores are between 0.8 and 1 for all stations. The SOM-SD method, which is evaluated with the six selected indicators, shows a strong simulation capability. The deviations of the simulated daily precipitation are as follows: Total season precipitation (−7.4%), daily precipitation intensity (−11.6%), mean number of rainy days (−3.1 days), percentage of rainfall from events beyond the 95th percentile value of overall precipitation (+3.4%), maximum consecutive wet days (−1.1 days), and maximum consecutive dry days (+3.5 days). In addition, the frequency difference of wet-dry nodes is defined in the evaluation. It is confirmed that there was a significant positive correlation between frequency difference and precipitation. The findings of this paper imply that the SOM-SD method has a good ability to simulate the probability distribution of daily precipitation, especially the tail of the probability distribution curve. It is more capable of simulating extreme precipitation fields. Furthermore, it can provide some guidance for future climate projections over North China.
Methyl Orange Biodegradation by Immobilized Consortium Microspheres: Experimental Design Approach, Toxicity Study and Bioaugmentation Potential
Authors: Ibrahim Amany , El-Fakharany Esmail M. , Abu-Serie Marwa M. , ElKady Marwa F. , Eltarahony Marwa
Published: January 2022

Methyl orange (MO) is categorized among the recalcitrant and refractory xenobiotics, representing a significant burden in the ecosystem. To clean-up the surrounding environment, advances in microbial degradation have been made. The main objective of this study was to investigate the extent to which an autochthonous consortium immobilized in alginate beads can promote an efficient biodegradation of MO. By employing response surface methodology (RSM), a parametric model explained the interaction of immobilized consortium (Raoultella planticola, Ochrobactrum thiophenivorans, Bacillus flexus and Staphylococcus xylosus) to assimilate 200 mg/L of MO in the presence of 40 g/L of NaCl within 120 h. Physicochemical analysis, including UV-Vis spectroscopy and FTIR, and monitoring of the degrading enzymes (azoreductase, DCIP reductase, NADH reductase, laccase, LiP, MnP, nitrate reductase and tyrosinase) were used to evaluate MO degradation. In addition, the toxicity of MO-degradation products was investigated by means of phytotoxicity and cytotoxicity. Chlorella vulgaris retained its photosynthetic performance (>78%), as shown by the contents of chlorophyll-a, chlorophyll-b and carotenoids. The viability of normal lung and kidney cell lines was recorded to be 90.63% and 99.23%, respectively, upon exposure to MO-metabolic outcomes. These results reflect the non-toxicity of treated samples, implying their utilization in ferti-irrigation applications and industrial cooling systems. Moreover, the immobilized consortium was employed in the bioremediation of MO from artificially contaminated agricultural and industrial effluents, in augmented and non-augmented systems. Bacterial consortium remediated MO by 155 and 128.5 mg/L in augmented systems of agricultural and industrial effluents, respectively, within 144 h, revealing its mutual synergistic interaction with both indigenous microbiotas despite differences in their chemical, physical and microbial contents. These promising results encourage the application of immobilized consortium in bioaugmentation studies using different resources.
Synthesis of C2-Alkoxy-Substituted 19-Nor Vitamin D3 Derivatives: Stereoselectivity and Biological Activity
Authors: Mizumoto Yuka , Sakamoto Ryota , Nagata Akiko , Sakane Suzuka , Kittaka Atsushi , Odagi Minami , Tera Masayuki , Nagasawa Kazuo
Published: January 2022

The active form of vitamin D3 (D3), 1a,25-dihydroxyvitamn D3 (1,25D3), plays a central role in calcium and bone metabolism. Many structure–activity relationship (SAR) studies of D3 have been conducted, with the aim of separating the biological activities of 1,25D3 or reducing its side effects, such as hypercalcemia, and SAR studies have shown that the hypercalcemic activity of C2-substituted derivatives and 19-nor type derivatives is significantly suppressed. In the present paper, we describe the synthesis of 19-nor type 1,25D3 derivatives with alkoxy groups at C2, by means of the Julia–Kocienski type coupling reaction between a C2 symmetrical A ring ketone and a CD ring synthon. The effect of C2 substituents on the stereoselectivity of the coupling reaction was evaluated. The biological activities of the synthesized derivatives were evaluated in an HL-60 cell-based assay. The a-methoxy-substituted C2α-7a was found to show potent cell-differentiating activity, with an ED50 value of 0.38 nM, being 26-fold more potent than 1,25D3.
Single-Cellular Biological Effects of Cholesterol-Catabolic Bile Acid-Based Nano/Micro Capsules as Anti-Inflammatory Cell Protective Systems
Authors: Mooranian Armin , Ionescu Corina Mihaela , Walker Daniel , Jones Melissa , Wagle Susbin Raj , Kovacevic Bozica , Chester Jacqueline , Foster Thomas , Johnston Edan , Kuthubutheen Jafri , Brown Daniel , Atlas Marcus D. , Mikov Momir , Al-Salami Hani
Published: January 2022

Recent studies in our laboratories have shown promising effects of bile acids in ➀ drug encapsulation for oral targeted delivery (via capsule stabilization) particularly when encapsulated with Eudragit NM30D® and ➁ viable-cell encapsulation and delivery (via supporting cell viability and biological activities, postencapsulation). Accordingly, this study aimed to investigate applications of bile acid-Eudragit NM30D® capsules in viable-cell encapsulation ready for delivery. Mouse-cloned pancreatic β-cell line was cultured and cells encapsulated using bile acid-Eudragit NM30D® capsules, and capsules’ images, viability, inflammation, and bioenergetics of encapsulated cells assessed. The capsules’ thermal and chemical stability assays were also assessed to ascertain an association between capsules’ stability and cellular biological activities. Bile acid-Eudragit NM30D® capsules showed improved cell viability (e.g., F1 < F2 & F8; p < 0.05), insulin, inflammatory profile, and bioenergetics as well as thermal and chemical stability, compared with control. These effects were formulation-dependent and suggest, overall, that changes in ratios of bile acids to Eudragit NM30D® can change the microenvironment of the capsules and subsequent cellular biological activities.
Fibrates: A Possible Treatment Option for Patients with Abdominal Aortic Aneurysm?
Authors: Amioka Naofumi , Miyoshi Toru
Published: January 2022

Abdominal aortic aneurysm (AAA) is a life-threatening disease; however, there is no established treatment for patients with AAA. Fibrates are agonists of peroxisome proliferator-activated receptor alpha (PPARα) that are widely used as therapeutic agents to treat patients with hypertriglyceridemia. They can regulate the pathogenesis of AAA in multiple ways, for example, by exerting anti-inflammatory and anti-oxidative effects and suppressing the expression of matrix metalloproteinases. Previously, basic and clinical studies have evaluated the effects of fenofibrate on AAA. In this paper, we summarize the results of these studies and discuss the problems associated with using fenofibrate as a therapeutic agent for patients with AAA. In addition, we discuss a new perspective on the regulation of AAA by PPARα agonists.
Recent Advances in Strategies for Addressing Hypoxia in Tumor Photodynamic Therapy
Authors: Hong Liang , Li Jiangmin , Luo Yali , Guo Tao , Zhang Chenshuang , Ou Sha , Long Yaohang , Hu Zuquan
Published: January 2022

Photodynamic therapy (PDT) is a treatment modality that uses light to target tumors and minimize damage to normal tissues. It offers advantages including high spatiotemporal selectivity, low side effects, and maximal preservation of tissue functions. However, the PDT efficiency is severely impeded by the hypoxic feature of tumors. Moreover, hypoxia may promote tumor metastasis and tumor resistance to multiple therapies. Therefore, addressing tumor hypoxia to improve PDT efficacy has been the focus of antitumor treatment, and research on this theme is continuously emerging. In this review, we summarize state-of-the-art advances in strategies for overcoming hypoxia in tumor PDTs, categorizing them into oxygen-independent phototherapy, oxygen-economizing PDT, and oxygen-supplementing PDT. Moreover, we highlight strategies possessing intriguing advantages such as exceedingly high PDT efficiency and high novelty, analyze the strengths and shortcomings of different methods, and envision the opportunities and challenges for future research.
A Comprehensive Review of Receptor-Type Tyrosine-Protein Phosphatase Gamma (PTPRG) Role in Health and Non-Neoplastic Disease
Authors: Boni Christian , Laudanna Carlo , Sorio Claudio
Published: January 2022

Protein tyrosine phosphatase receptor gamma (PTPRG) is known to interact with and regulate several tyrosine kinases, exerting a tumor suppressor role in several type of cancers. Its wide expression in human tissues compared to the other component of group 5 of receptor phosphatases, PTPRZ expressed as a chondroitin sulfate proteoglycan in the central nervous system, has raised interest in its role as a possible regulatory switch of cell signaling processes. Indeed, a carbonic anhydrase-like domain (CAH) and a fibronectin type III domain are present in the N-terminal portion and were found to be associated with its role as [HCO3−] sensor in vascular and renal tissues and a possible interaction domain for cell adhesion, respectively. Studies on PTPRG ligands revealed the contactins family (CNTN) as possible interactors. Furthermore, the correlation of PTPRG phosphatase with inflammatory processes in different normal tissues, including cancer, and the increasing amount of its soluble form (sPTPRG) in plasma, suggest a possible role as inflammatory marker. PTPRG has important roles in human diseases; for example, neuropsychiatric and behavioral disorders and various types of cancer such as colon, ovary, lung, breast, central nervous system, and inflammatory disorders. In this review, we sum up our knowledge regarding the latest discoveries in order to appreciate PTPRG function in the various tissues and diseases, along with an interactome map of its relationship with a group of validated molecular interactors.
Role of Sulphur and Heavier Chalcogens on the Antioxidant Power and Bioactivity of Natural Phenolic Compounds
Authors: Alfieri Maria Laura , Panzella Lucia , Amorati Riccardo , Cariola Alice , Valgimigli Luca , Napolitano Alessandra
Published: January 2022

The activity of natural phenols is primarily associated to their antioxidant potential, but is ultimately expressed in a variety of biological effects. Molecular scaffold manipulation of this large variety of compounds is a currently pursued approach to boost or modulate their properties. Insertion of S/Se/Te containing substituents on phenols may increase/decrease their H-donor/acceptor ability by electronic and stereo-electronic effects related to the site of substitution and geometrical constrains. Oxygen to sulphur/selenium isosteric replacement in resveratrol or ferulic acid leads to an increase in the radical scavenging activity with respect to the parent phenol. Several chalcogen-substituted phenols inspired by Vitamin E and flavonoids have been prepared, which in some cases prove to be chain-breaking antioxidants, far better than the natural counterparts. Conjugation of catechols with biological thiols (cysteine, glutathione, dihydrolipoic acid) is easily achieved by addition to the corresponding ortho-quinones. Noticeable examples of compounds with potentiated antioxidant activities are the human metabolite 5-S-cysteinyldopa, with high iron-induced lipid peroxidation inhibitory activity, due to strong iron (III) binding, 5-S-glutathionylpiceatannol a most effective inhibitor of nitrosation processes, and 5-S-lipoylhydroxytyrosol, and its polysulfides that proved valuable oxidative-stress protective agents in various cellular models. Different methodologies have been used for evaluation of the antioxidant power of these compounds against the parent compounds. These include kinetics of inhibition of lipid peroxidation alkylperoxyl radicals, common chemical assays of radical scavenging, inhibition of the OH• mediated hydroxylation/oxidation of model systems, ferric- or copper-reducing power, scavenging of nitrosating species. In addition, computational methods allowed researchers to determine the Bond Dissociation Enthalpy values of the OH groups of chalcogen modified phenolics and predict the best performing derivative. Finally, the activity of Se and Te containing compounds as mimic of glutathione peroxidase has been evaluated, together with other biological activities including anticancer action and (neuro)protective effects in various cellular models. These and other achievements are discussed and rationalized to guide future development in the field.
Anti-Inflammatory Effects of Heliangin from Jerusalem Artichoke (Helianthus tuberosus) Leaves Might Prevent Atherosclerosis
Authors: Saiki Papawee , Yoshihara Mizuki , Kawano Yasuhiro , Miyazaki Hitoshi , Miyazaki Koyomi
Published: January 2022

Atherosclerosis is considered the major cause of cardiovascular and cerebrovascular diseases, which are the leading causes of death worldwide. Excessive nitric oxide production and inflammation result in dysfunctional vascular endothelial cells, which are critically involved in the initiation and progression of atherosclerosis. The present study aimed to identify a bioactive compound from Jerusalem artichoke leaves with anti-inflammatory activity that might prevent atherosclerosis. We isolated bioactive heliangin that inhibited NO production in LPS-induced macrophage-like RAW 264.7 cells. Heliangin suppressed ICAM-1, VCAM-1, E-selectin, and MCP-1 expression, as well as NF-κB and IκBα phosphorylation, in vascular endothelial cells stimulated with TNF-α. These results suggested that heliangin suppresses inflammation by inhibiting excessive NO production in macrophages and the expression of the factors leading to the development of atherosclerosis via the NF-κB signaling pathway in vascular endothelial cells. Therefore, heliangin in Jerusalem artichoke leaves could function in the prevention of atherosclerosis that is associated with heart attacks and strokes.
Personality, Defense Mechanisms and Psychological Distress in Women with Fibromyalgia
Authors: Romeo Annunziata , Benfante Agata , Geminiani Giuliano Carlo , Castelli Lorys
Published: January 2022

Background: Previous studies have shown that many personality traits are associated with fibromyalgia (FM), worsening both the quality of life and psychological distress of patients. Despite the high comorbidity of psychopathological disorders in this syndrome and their association with immature defense styles, few studies have examined the defense mechanisms used by FM patients. The main aim of our study was to investigate personality traits and defense mechanisms in FM patients compared to in a healthy control group (HC). Moreover, we investigated the effect of personality traits and defense mechanisms on psychological distress in both FM and HC groups. Methods: A total of 54 women with FM and 54 healthy women completed the (1) Temperament and Character Inventory—Revised; (2) the Toronto Alexithymia Scale; (3) the Defense Style Questionnaire; and (4) the Hospital Anxiety and Depression Scale. Results: The results indicated that FM patients display higher alexithymia, higher harm avoidance, lower self-directedness, lower persistence, and the higher use of a maladaptive defense style compared to HC. We found that alexithymia, harm avoidance, and maladaptive defense style are significant predictors of patients’ psychological distress. Moreover, harm avoidance and adaptive defense style significantly predicted psychological distress in the HC group. Conclusion: The present study is the first to explore the contribution of both defense mechanisms and personality characteristics on the psychological distress of FM patients. Our findings have important clinical implications and may help diagnose and treat FM patients more in depth.
The BIM-Based Building Permit Process: Factors Affecting Adoption
Authors: Ullah Kaleem , Witt Emlyn , Lill Irene
Published: January 2022

Public organizations responsible for building permits are increasingly considering the potential applications of Building Information Modelling (BIM) in their workflows, but BIM adoption still remains a complex challenge. This research aims to investigate the factors affecting BIM adoption for building permits through a case study of a public organization currently developing and piloting a BIM-based building permit process. A thematic analysis of semi-structured interview data revealed ten factors that influence BIM adoption for building permits: complexity (in both development and use) of a BIM-based building permit system; relative advantages/disadvantages of BIM for building permits; the existing building permit system; management support for a BIM-based building permit process; organizational culture; BIM awareness; training and learning; available expertise for a BIM-based building permit process; external pressure; and legal context. The findings are important for public authorities’ understanding of both the enablers and challenges of the BIM-based building permit process, and have practical implications for professionals in public authorities in particular, and also the Architecture Engineering Construction/Facilities Management (AEC/FM) industry in general, to guide their steps towards adopting BIM. This research also highlights the potential benefits of BIM adoption for the building permit process.
An Investigation on the Thermal Environment of Residential Courtyards in the Cold Area of Western Sichuan Plateau
Authors: Xu Sheng , Cheng Bin , Huang Zefeng , Shen Chenyang
Published: January 2022

Located on the east side of China’s Qinghai–Tibet Plateau is the Western Sichuan Plateau, the courtyard adopts a passive design to withstand the harsh climate in cold areas, and its internal thermal environment has a direct impact on the productivity and activities of the residents. This paper takes a plateau village (3500 m above sea level) beside the Sichuan–Tibet line as the research area, and selects four typical local courtyard layouts and an outdoor reference point for the measurement and comparison of the thermal environment. By comparing the measured parameters inside and outside the courtyard, and the correlation analysis, it was deduced as follows. (1) In the cold winter, traditional plateau residential courtyards can create a stable internal micro-climate, but the cold resistance of the courtyards is closely related to its layout. (2) Except for wind speed, other thermal environment parameters of the courtyard are all affected by solar radiation (3) The correlation analysis of the various environmental parameters and physiologically equivalent temperature (PET) showed that the correlation coefficient between the mean radiation temperature (Tmrt) and all courtyard PET values is <0.0001, showing a significant correlation. The indicators of mean temperature radiation are mainly affected by the temperature and the wind speed; furthermore, the temperature and solar radiation are positively correlated, which confirms that the solar radiation and wind speed within the courtyard are the main factors affecting the internal thermal environment in the courtyard. (4) Feedback the courtyard layout problems through the difference in the thermal environment parameters within different courtyards, and then determine some shortcomings in the current courtyard layout design. The inferences drawn from this work will provide a scientific basis for the design, layout, and construction of courtyards in other cold plateau areas.
A GP-Based Hierarchical Objectives Decision-Making Method for Building Energy Efficiency Optimization
Authors: Li Xiang , Liu Sha , Sun Yichao
Published: January 2022

Building energy efficiency, which is critical in reducing environmental impact, has become one of the most important objectives of building designs. In order to precisely express the goals of building designs, and help decision makers estimate the ultimate performance of design schemes in advance when searching for the optimal building design, the Goal Programming Model (GPM) is introduced in this study to provide a solution for explicit design objective delivery and multi-stakeholder involved decision-making support. In this proposed method, EnergyPlusTM works as a simulation engine to search for the relationship between design parameter combinations and building energy consumption. Simultaneously, Genetic Algorithm (GA) is used to improve the efficiency of overall building energy performance optimization by processing multiple iterations. A case study with five possible design scenarios was dedicated in this study to implement the proposed optimization method, and the optimization results verified the capacity of the established GP-based optimization method to satisfy various design requirements for decision makers and/or stakeholders, especially in facing the hierarchical objectives with different priorities. In this case, the envelope-related variables, including the exterior wall and window, serve as optimization objectives. The optimization is carried out under the ideal air conditioning system, considering different energy usage patterns. Meanwhile, comparing with the vague and restricted expression of objectives in multi-objective optimization, the proposed GP-based optimization method provides explicit trade-off relationships among various objectives for designers, which improves the practical value of the optimized designs, so as to ensure the project success and facilitate the development of green buildings.
Impact of Cancer Stem Cells and Cancer Stem Cell-Driven Drug Resiliency in Lung Tumor: Options in Sight
Authors: Cortes-Dericks Lourdes , Galetta Domenico
Published: January 2022

Causing a high mortality rate worldwide, lung cancer remains an incurable malignancy resistant to conventional therapy. Despite the discovery of specific molecular targets and new treatment strategies, there remains a pressing need to develop more efficient therapy to further improve the management of this disease. Cancer stem cells (CSCs) are considered the root of sustained tumor growth. This consensus corroborates the CSC model asserting that a distinct subpopulation of malignant cells within a tumor drives and maintains tumor progression with high heterogeneity. Besides being highly tumorigenic, CSCs are highly refractory to standard drugs; therefore, cancer treatment should be focused on eliminating these cells. Herein, we present the current knowledge of the existence of CSCs, CSC-associated mechanisms of chemoresistance, the ability of CSCs to evade immune surveillance, and potential CSC inhibitors in lung cancer, to provide a wider insight to drive a more efficient elimination of this pro-oncogenic and treatment-resistant cell fraction.
Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas
Authors: Tabebi Mouna , Łysiak Małgorzata , Dutta Ravi Kumar , Lomazzi Sandra , Turkina Maria V. , Brunaud Laurent , Gimm Oliver , Söderkvist Peter
Published: January 2022

Background: Somatic mutations, copy-number variations, and genome instability of mitochondrial DNA (mtDNA) have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is scarce information about pheochromocytomas and paragangliomas (PCCs/PGLs) formation. Material: To determine the potential roles of mtDNA alterations in sporadic PCCs/PGLs, we analyzed a panel of 26 nuclear susceptibility genes and the entire mtDNA sequence of seventy-seven human tumors, using next-generation sequencing, and compared the results with normal adrenal medulla tissues. We also performed an analysis of copy-number alterations, large mtDNA deletion, and gene and protein expression. Results: Our results revealed that 53.2% of the tumors harbor a mutation in at least one of the targeted susceptibility genes, and 16.9% harbor complementary mitochondrial mutations. More than 50% of the mitochondrial mutations were novel and predicted pathogenic, affecting mitochondrial oxidative phosphorylation. Large deletions were found in 26% of tumors, and depletion of mtDNA occurred in more than 87% of PCCs/PGLs. The reduction of the mitochondrial number was accompanied by a reduced expression of the regulators that promote mitochondrial biogenesis (PCG1α, NRF1, and TFAM). Further, P62 and LC3a gene expression suggested increased mitophagy, which is linked to mitochondrial dysfunction. Conclusion: The pathogenic role of these finding remains to be shown, but we suggest a complementarity and a potential contributing role in PCCs/PGLs tumorigenesis.
Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma
Authors: Comito Francesca , Pagani Rachele , Grilli Giada , Sperandi Francesca , Ardizzoni Andrea , Melotti Barbara
Published: January 2022

The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies.
Gastrointestinal Adenocarcinoma Incidence and Survival Trends in South Australia, 1990–2017
Authors: Schell Dominique , Ullah Shahid , Brooke-Smith Mark E. , Hollington Paul , Yeow Marina , Karapetis Christos S. , Watson David I. , Pandol Stephen J. , Roberts Claire T. , Barreto Savio G.
Published: January 2022

Background & Aims: Globally, there has been a concerning rise in the incidence of young-onset cancers. The aim of this study was to provide trends in the incidence and survival of gastrointestinal adenocarcinomas (oesophagus, stomach, pancreas, and colorectal) in South Australia over a 27-year period. Methods: This is a cross-sectional analysis of a prospective longitudinal database including all cases of gastrointestinal adenocarcinomas prospectively reported to the South Australian (State) Cancer Registry from 1990 to 2017. Results: A total of 28,566 patients diagnosed with oesophageal, stomach, pancreatic, or colorectal adenocarcinoma between 1990 and 2017 were included in the study. While the overall incidence for gastrointestinal adenocarcinomas in individuals >50 years has decreased since 2000 (IRR of 0.97 (95% CI 0.94–1.00; p = 0.06)) compared to 1990–1999, the rate amongst individuals aged 18–50 has significantly increased (IRR 1.41 (95% CI 1.27–1.57; p < 0.001)) during the same reference time period. Although noted in both sexes, the rate of increase in incidence was significantly greater in males (11.5 to 19.7/100,000; p < 0.001). The overall survival from adenocarcinomas across all subsites improved in the >50-year cohort in the last decade (HR 0.89 (95% CI 0.86–0.93; p < 0.001)) compared to 1990–1999. In individuals aged 18–50 years, there has only been a significant improvement in survival for colorectal cancer (HR 0.82 (95% CI 0.68–0.99; p < 0.04)), but not the other subsites. A lower overall survival was noted for males in both age cohorts (18–50 years—HR 1.24 (95% CI 1.09–1.13; p < 0.01) and >50 years—HR 1.13 (95% CI 1.10–1.16; p < 0.001), respectively) compared to females. Conclusions: This study from South Australia demonstrates a significant increase in young-onset gastrointestinal adenocarcinomas over the last 28 years, with a greater increase in the male sex. The only significant improvement in survival in this cohort has been noted in colorectal cancer patients.
Increased Expression and Altered Cellular Localization of Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) Are Associated with Prostate Cancer Progression
Authors: Yu Lan , Toriseva Mervi , Afshan Syeda , Cangiano Mario , Fey Vidal , Erickson Andrew , Seikkula Heikki , Alanen Kalle , Taimen Pekka , Ettala Otto , Nurmi Martti , Boström Peter J. , Kallajoki Markku , Tuomela Johanna , Mirtti Tuomas , Beumer Inès J. , Nees Matthias , Härkönen Pirkko
Published: January 2022

Fibroblast growth factor receptors (FGFRs) 1–4 are involved in prostate cancer (PCa) regulation, but the role of FGFR-like 1 (FGFRL1) in PCa is unclear. FGFRL1 expression was studied by qRT-PCR and immunohistochemistry of patient tissue microarrays (TMAs) and correlated with clinical patient data. The effects of FGFRL1 knockdown (KD) in PC3M were studied in in vitro culture models and in mouse xenograft tumors. Our results showed that FGFRL1 was significantly upregulated in PCa. The level of membranous FGFRL1 was negatively associated with high Gleason scores (GSs) and Ki67, while increased cytoplasmic and nuclear FGFRL1 showed a positive correlation. Cox regression analysis indicated that nuclear FGFRL1 was an independent prognostic marker for biochemical recurrence after radical prostatectomy. Functional studies indicated that FGFRL1-KD in PC3M cells increases FGFR signaling, whereas FGFRL1 overexpression attenuates it, supporting decoy receptor actions of membrane-localized FGFRL1. In accordance with clinical data, FGFRL1-KD markedly suppressed PC3M xenograft growth. Transcriptomics of FGFRL1-KD cells and xenografts revealed major changes in genes regulating differentiation, ECM turnover, and tumor–stromal interactions associated with decreased growth in FGFRL1-KD xenografts. Our results suggest that FGFRL1 upregulation and altered cellular compartmentalization contribute to PCa progression. The nuclear FGFRL1 could serve as a prognostic marker for PCa patients.
Transthyretin Gene Variants and Associated Phenotypes in Danish Patients with Amyloid Cardiomyopathy
Authors: Rasmussen Torsten B. , Ladefoged Bertil T. , Dybro Anne M. , Clemmensen Tor S. , Sørensen Rikke H. , Terkelsen Astrid J. , Mølgaard Henning , Vase Henrik , Poulsen Steen H.
Published: January 2022

Genotyping divides transthyretin cardiac amyloidosis (ATTR-CA) in hereditary (ATTRv) and wild type (ATTRwt) forms. This study investigated the prevalence and clinical presentation of ATTRv in a contemporary cohort of consecutive ATTR-CA patients diagnosed at a tertiary Danish amyloidosis center. Age at diagnosis, clinical- and echocardiographic data, and transthyretin (TTR) genotype were recorded. Relatives of ATTRv patients underwent clinical phenotyping and predictive gene testing. Genetic testing in 102 patients identified four TTR variant carriers: p.Pro63Ser, p.Ala65Ser (n = 2) and p.Val142Ile. The mean age of ATTRv index patients was significantly lower compared to ATTRwt patients: 70.2 ± 1.2 versus 80.0 ± 6.2, p-value: 0.005. Evaluation of ATTRv families identified seven TTR variant carriers with a median age of 65 years (range 48–76) and three were diagnosed with ATTR-CA by DPD-scintigraphy. Family members with ATTR-CA were all asymptomatic and had normal levels of cardiac biomarkers. In conclusion, the prevalence of ATTRv in a contemporary Danish ATTR-CA cohort is 4%. ATTRv index patients were significantly younger age at diagnosis than ATTRwt patients. Non-p.Leu131Met TTR variants have reduced penetrance at the age of 65 years in which approximately half of variant carriers have asymptomatic ATTR-CA with normal LV systolic function and cardiac biomarker analyses.
Realistic Modelling of Dynamics at Nanostructured Interfaces Relevant to Heterogeneous Catalysis
Authors: Rossi Kevin , Mineva Tzonka , Filhol Jean-Sebastien , Tielens Frederik , Guesmi Hazar
Published: January 2022

The focus of this short review is directed towards investigations of the dynamics of nanostructured metallic heterogeneous catalysts and the evolution of interfaces during reaction—namely, the metal–gas, metal–liquid, and metal–support interfaces. Indeed, it is of considerable interest to know how a metal catalyst surface responds to gas or liquid adsorption under reaction conditions, and how its structure and catalytic properties evolve as a function of its interaction with the support. This short review aims to offer the reader a birds-eye view of state-of-the-art methods that enable more realistic simulation of dynamical phenomena at nanostructured interfaces by exploiting resource-efficient methods and/or the development of computational hardware and software.
Recognition and Chaperoning by Pex19, Followed by Trafficking and Membrane Insertion of the Peroxisome Proliferation Protein, Pex11
Authors: Zientara-Rytter Katarzyna M. , Mahalingam Shanmuga S. , Farré Jean-Claude , Carolino Krypton , Subramani Suresh
Published: January 2022

Pex11, an abundant peroxisomal membrane protein (PMP), is required for division of peroxisomes and is robustly imported to peroxisomal membranes. We present a comprehensive analysis of how the Pichia pastoris Pex11 is recognized and chaperoned by Pex19, targeted to peroxisome membranes and inserted therein. We demonstrate that Pex11 contains one Pex19-binding site (Pex19-BS) that is required for Pex11 insertion into peroxisomal membranes by Pex19, but is non-essential for peroxisomal trafficking. We provide extensive mutational analyses regarding the recognition of Pex19-BS in Pex11 by Pex19. Pex11 also has a second, Pex19-independent membrane peroxisome-targeting signal (mPTS) that is preserved among Pex11-family proteins and anchors the human HsPex11γ to the outer leaflet of the peroxisomal membrane. Thus, unlike most PMPs, Pex11 can use two mechanisms of transport to peroxisomes, where only one of them depends on its direct interaction with Pex19, but the other does not. However, Pex19 is necessary for membrane insertion of Pex11. We show that Pex11 can self-interact, using both homo- and/or heterotypic interactions involving its N-terminal helical domains. We demonstrate that Pex19 acts as a chaperone by interacting with the Pex19-BS in Pex11, thereby protecting Pex11 from spontaneous oligomerization that would otherwise cause its aggregation and subsequent degradation.
N-Glycosylation Facilitates 4-1BB Membrane Localization by Avoiding Its Multimerization
Authors: Sun Ruoxuan , Kim Alyssa Min Jung , Murray Allison A. , Lim Seung-Oe
Published: January 2022

Leveraging the T cell immunity against tumors represents a revolutionary type of cancer therapy. 4-1BB is a well-characterized costimulatory immune receptor existing on activated T cells and mediating their proliferation and cytotoxicity under infectious diseases and cancers. Despite the accumulating interest in implementing 4-1BB as a therapeutic target for immune-related disorders, less is known about the pattern of its intracellular behaviors and regulations. It has been previously demonstrated that 4-1BB is heavily modified by N-glycosylation; however, the biological importance of this modification lacks detailed elucidation. Through biochemical, biophysical, and cell-biological approaches, we systematically evaluated the impact of N-glycosylation on the ligand interaction, stability, and localization of 4-1BB. We hereby highlighted that N-glycan functions by preventing the oligomerization of 4-1BB, thus permitting its membrane transportation and fast turn-over. Without N-glycosylation, 4-1BB could be aberrantly accumulated intracellularly and fail to be sufficiently inserted in the membrane. The N-glycosylation-guided intracellular processing of 4-1BB serves as the potential mechanism explicitly modulating the “on” and “off” of 4-1BB through the control of protein abundance. Our study will further solidify the understanding of the biological properties of 4-1BB and facilitate the clinical practice against this promising therapeutic target.
Co-Expression Analysis of microRNAs and Proteins in Brain of Alzheimer’s Disease Patients
Authors: Watson Callum N. , Begum Ghazala , Ashman Emma , Thorn Daniella , Yakoub Kamal M. , Hariri Moustafa Al , Nehme Ali , Mondello Stefania , Kobeissy Firas , Belli Antonio , Di Pietro Valentina
Published: January 2022

Alzheimer’s disease (AD) is the most common form of dementia globally; however, the aetiology of AD remains elusive hindering the development of effective therapeutics. MicroRNAs (miRNAs) are regulators of gene expression and have been of growing interest in recent studies in many pathologies including AD not only for their use as biomarkers but also for their implications in the therapeutic field. In this study, miRNA and protein profiles were obtained from brain tissues of different stage (Braak III-IV and Braak V-VI) of AD patients and compared to matched controls. The aim of the study was to identify in the late stage of AD, the key dysregulated pathways that may contribute to pathogenesis and then to evaluate whether any of these pathways could be detected in the early phase of AD, opening new opportunity for early treatment that could stop or delay the pathology. Six common pathways were found regulated by miRNAs and proteins in the late stage of AD, with one of them (Rap1 signalling) activated since the early phase. MiRNAs and proteins were also compared to explore an inverse trend of expression which could lead to the identification of new therapeutic targets. These results suggest that specific miRNA changes could represent molecular fingerprint of neurodegenerative processes and potential therapeutic targets for early intervention.
Engineered Liposomes Protect Immortalized Immune Cells from Cytolysins Secreted by Group A and Group G Streptococci
Authors: Besançon Hervé , Larpin Yu , Babiychuk Viktoria S. , Köffel René , Babiychuk Eduard B.
Published: January 2022

The increasing antibiotic resistance of bacterial pathogens fosters the development of alternative, non-antibiotic treatments. Antivirulence therapy, which is neither bacteriostatic nor bactericidal, acts by depriving bacterial pathogens of their virulence factors. To establish a successful infection, many bacterial pathogens secrete exotoxins/cytolysins that perforate the host cell plasma membrane. Recently developed liposomal nanotraps, mimicking the outer layer of the targeted cell membranes, serve as decoys for exotoxins, thus diverting them from attacking host cells. In this study, we develop a liposomal nanotrap formulation that is capable of protecting immortalized immune cells from the whole palette of cytolysins secreted by Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis—important human pathogens that can cause life-threatening bacteremia. We show that the mixture of cholesterol-containing liposomes with liposomes composed exclusively of phospholipids is protective against the combined action of all streptococcal exotoxins. Our findings pave the way for further development of liposomal antivirulence therapy in order to provide more efficient treatment of bacterial infections, including those caused by antibiotic resistant pathogens.
In Vitro Anticancer Screening and Preliminary Mechanistic Study of A-Ring Substituted Anthraquinone Derivatives
Authors: Morgan Ibrahim , Wessjohann Ludger A. , Kaluđerović Goran N.
Published: January 2022

Anthraquinone derivatives exhibit various biological activities, e.g., antifungal, antibacterial and in vitro antiviral activities. They are naturally produced in many fungal and plant families such as Rhamnaceae or Fabaceae. Furthermore, they were found to have anticancer activity, exemplified by mitoxantrone and pixantrone, and many are well known redox-active compounds. In this study, various nature inspired synthetic anthraquinone derivatives were tested against colon, prostate, liver and cervical cancer cell lines. Most of the compounds exhibit anticancer effects against all cell lines, therefore the compounds were further studied to determine their IC50-values. Of these compounds, 1,4-bis(benzyloxy)-2,3-bis(hydroxymethyl)anthracene-9,10-dione (4) exhibited the highest cytotoxicity against PC3 cells and was chosen for a deeper look into its mechanism of action. Based on flow cytometry, the compound was proven to induce apoptosis through the activation of caspases and to demolish the ROS/RNS and NO equilibrium in the PC3 cell line. It trapped cells in the G2/M phase. Western blotting was performed for several proteins related to the effects observed. Compound 4 enhanced the production of PARP and caspase-3. Moreover, it activated the conversion of LC3A/B-I to LC3A/B-II showing that also autophagy plays a role in its mechanism of action, and it caused the phosphorylation of p70 s6 kinase.