bluuebunny/crossref_metadata_2025 huggingface dataset:
Proposal of a Nature-Inspired Shape for a Vertical Axis Wind Turbine and Comparison of Its Performance with a Semicircular Blade Profile
Authors: Blanco Javier , Rodriguez Juan de Dios , Couce Antonio , Lamas Maria Isabel
Published: July 2021

In order to improve the efficiency of the Savonius type vertical axis wind turbine, the present work analyzes an improvement based on an innovative rotor geometry. The rotor blades are inspired on an organic shape mathematically analyzed, the Fibonacci’s spiral, presented in many nature systems as well as in art. This rotor was analyzed in a wind tunnel and through a CFD model. The power coefficients at different tip speed ratios (TSR) were characterized and compared for the Savonius turbine and two versions using the Fibonacci’s spiral. One of the proposed geometries improves the performance of the Savonius type. Particularly, the optimal configuration lead to an improvement in maximum power coefficient of 14.5% in the numerical model respect to a conventional Savonius turbine and 17.6% in the experimental model.
Employing Vertical Elasticity for Efficient Big Data Processing in Container-Based Cloud Environments
Authors: Choi Jin-young , Cho Minkyoung , Kim Jik-Soo
Published: July 2021

Recently, “Big Data” platform technologies have become crucial for distributed processing of diverse unstructured or semi-structured data as the amount of data generated increases rapidly. In order to effectively manage these Big Data, Cloud Computing has been playing an important role by providing scalable data storage and computing resources for competitive and economical Big Data processing. Accordingly, server virtualization technologies that are the cornerstone of Cloud Computing have attracted a lot of research interests. However, conventional hypervisor-based virtualization can cause performance degradation problems due to its heavily loaded guest operating systems and rigid resource allocations. On the other hand, container-based virtualization technology can provide the same level of service faster with a lightweight capacity by effectively eliminating the guest OS layers. In addition, container-based virtualization enables efficient cloud resource management by dynamically adjusting the allocated computing resources (e.g., CPU and memory) during the runtime through “Vertical Elasticity”. In this paper, we present our practice and experience of employing an adaptive resource utilization scheme for Big Data workloads in container-based cloud environments by leveraging the vertical elasticity of Docker, a representative container-based virtualization technique. We perform extensive experiments running several Big Data workloads on representative Big Data platforms: Apache Hadoop and Spark. During the workload executions, our adaptive resource utilization scheme periodically monitors the resource usage patterns of running containers and dynamically adjusts allocated computing resources that could result in substantial improvements in the overall system throughput.
Simulations of the East Asian Winter Monsoon on Subseasonal to Seasonal Time Scales Using the Model for Prediction Across Scales
Authors: Hsu Li-Huan , Chen Dan-Rong , Chiang Chou-Chun , Chu Jung-Lien , Yu Yi-Chiang , Wu Chia-Chun
Published: July 2021

The Model for Prediction Across Scales (MPAS) is used to simulate the East Asian winter monsoon (EAWM) over the 2011–2020 winter. The 45 day hindcasts are made with 30 km horizontal resolution and constructed to a time-lagged ensemble system. The climatology, the major modes of EAWM variability, and the blocking activities are examined. The evaluation results reveal that MPAS can simulate the climatologic characteristics of EAWM reasonably, with a surface cold bias of 4% and a positive rainfall bias of 9% over East Asia. MPAS can perform skillfully in the forecasts of surface temperature probability of East Asia and is more reliable in detecting below normal and above normal events. The features that influence the EAWM variability are also analyzed. MPAS simulates reasonably in the occurrence frequency of blocking high in both locations and duration time. The empirical orthogonal function analysis also shows that MPAS can capture the two major modes of the surface temperature of EAWM. On the other hand, it is also found that a biased sea surface temperature may modify the circulations over the Western Pacific and affect the simulated occurrence frequency of cold events near Taiwan during winter.
Mapping of Flood Areas Using Landsat with Google Earth Engine Cloud Platform
Authors: Mehmood Hamid , Conway Crystal , Perera Duminda
Published: July 2021

The Earth Observation (EO) domain can provide valuable information products that can significantly reduce the cost of mapping flood extent and improve the accuracy of mapping and monitoring systems. In this study, Landsat 5, 7, and 8 were utilized to map flood inundation areas. Google Earth Engine (GEE) was used to implement Flood Mapping Algorithm (FMA) and process the Landsat data. FMA relies on developing a “data cube”, which is spatially overlapped pixels of Landsat 5, 7, and 8 imagery captured over a period of time. This data cube is used to identify temporary and permanent water bodies using the Modified Normalized Difference Water Index (MNDWI) and site-specific elevation and land use data. The results were assessed by calculating a confusion matrix for nine flood events spread over the globe. The FMA had a high true positive accuracy ranging from 71–90% and overall accuracy in the range of 74–89%. In short, observations from FMA in GEE can be used as a rapid and robust hindsight tool for mapping flood inundation areas, training AI models, and enhancing existing efforts towards flood mitigation, monitoring, and management.
Cloud Radar Observations of Diurnal and Seasonal Cloudiness over Reunion Island
Authors: Durand Jonathan , Lees Edouard , Bousquet Olivier , Delanoë Julien , Bonnardot François
Published: July 2021

In November 2016, a 95 GHz cloud radar was permanently deployed in Reunion Island to investigate the vertical distribution of tropical clouds and monitor the temporal variability of cloudiness in the frame of the pan-European research infrastructure Aerosol, Clouds and Trace gases Research InfraStructure (ACTRIS). In the present study, reflectivity observations collected during the two first years of operation (2016–2018) of this vertically pointing cloud radar are relied upon to investigate the diurnal and seasonal cycle of cloudiness in the northern part of this island. During the wet season (December–March), cloudiness is particularly pronounced between 1–3 km above sea level (with a frequency of cloud occurrence of 45% between 12:00–19:00 LST) and 8–12 km (with a frequency of cloud occurrence of 15% between 14:00–19:00 LST). During the dry season (June–September), this bimodal vertical mode is no longer observed and the vertical cloud extension is essentially limited to a height of 3 km due to both the drop-in humidity resulting from the northward migration of the ITCZ and the capping effect of the trade winds inversion. The frequency of cloud occurrence is at its maximum between 13:00–18:00 LST, with a probability of 35% at 15 LST near an altitude of 2 km. The analysis of global navigation satellite system (GNSS)-derived weather data also shows that the diurnal cycle of low- (1–3 km) and mid-to-high level (5–10 km) clouds is strongly correlated with the diurnal evolution of tropospheric humidity, suggesting that additional moisture is advected towards the island by the sea breeze regime. The detailed analysis of cloudiness observations collected during the four seasons sampled in 2017 and 2018 also shows substantial differences between the two years, possibly associated with a strong positive Indian Ocean Southern Dipole (IOSD) event extending throughout the year 2017.
Interactions of Ions and Ultracold Neutral Atom Ensembles in Composite Optical Dipole Traps: Developments and Perspectives
Authors: Karpa Leon
Published: July 2021

Ion–atom interactions are a comparatively recent field of research that has drawn considerable attention due to its applications in areas including quantum chemistry and quantum simulations. In first experiments, atomic ions and neutral atoms have been successfully overlapped by devising hybrid apparatuses combining established trapping methods, Paul traps for ions and optical or magneto-optical traps for neutral atoms, respectively. Since then, the field has seen considerable progress, but the inherent presence of radiofrequency (rf) fields in such hybrid traps was found to have a limiting impact on the achievable collision energies. Recently, it was shown that suitable combinations of optical dipole traps (ODTs) can be used for trapping both atoms and atomic ions alike, allowing to carry out experiments in absence of any rf fields. Here, we show that the expected cooling in such bichromatic traps is highly sensitive to relative position fluctuations between the two optical trapping beams, suggesting that this is the dominant mechanism limiting the currently observed cooling performance. We discuss strategies for mitigating these effects by using optimized setups featuring adapted ODT configurations. This includes proposed schemes that may mitigate three-body losses expected at very low temperatures, allowing to access the quantum dominated regime of interaction.
Inertial Accelerated Algorithm for Fixed Point of Asymptotically Nonexpansive Mapping in Real Uniformly Convex Banach Spaces
Authors: Harbau Murtala Haruna , Ugwunnadi Godwin Chidi , Jolaoso Lateef Olakunle , Abdulwahab Ahmad
Published: July 2021

In this work, we introduce a new inertial accelerated Mann algorithm for finding a point in the set of fixed points of asymptotically nonexpansive mapping in a real uniformly convex Banach space. We also establish weak and strong convergence theorems of the scheme. Finally, we give a numerical experiment to validate the performance of our algorithm and compare with some existing methods. Our results generalize and improve some recent results in the literature.
Field-Deployable Recombinase Polymerase Amplification Assay for Specific, Sensitive and Rapid Detection of the US Select Agent and Toxigenic Bacterium, Rathayibacter toxicus
Authors: Arif Mohammad , Busot Grethel Y. , Mann Rachel , Rodoni Brendan , Stack James P.
Published: July 2021

Rathayibacter toxicus is a toxigenic bacterial pathogen of several grass species and is responsible for massive livestock deaths in Australia and South Africa. Due to concern for animal health and livestock industries, it was designated a U.S. Select Agent. A rapid, accurate, and sensitive in-field detection method was designed to assist biosecurity surveillance surveys and to support export certification of annual ryegrass hay and seed. Complete genomes from all known R. toxicus populations were explored, unique diagnostic sequences identified, and target-specific primers and a probe for recombinase polymerase amplification (RPA) and endpoint PCR were designed. The RPA reaction ran at 37 °C and a lateral flow device (LFD) was used to visualize the amplified products. To enhance reliability and accuracy, primers and probes were also designed to detect portions of host ITS regions. RPA assay specificity and sensitivity were compared to endpoint PCR using appropriate inclusivity and exclusivity panels. The RPA assay sensitivity (10 fg) was 10 times more sensitive than endpoint PCR with and without a host DNA background. In comparative tests, the RPA assay was unaffected by plant-derived amplification inhibitors, unlike the LAMP and end-point PCR assays. In-field validation of the RPA assay at multiple sites in South Australia confirmed the efficiency, specificity, and applicability of the RPA assay. The RPA assay will support disease management and evidence-based in-field biosecurity decisions.
Nociceptin Increases Antioxidant Expression in the Kidney, Liver and Brain of Diabetic Rats
Authors: Adeghate Ernest , D’Souza Crystal M. , Saeed Zulqarnain , Al Jaberi Saeeda , Tariq Saeed , Kalász Huba , Tekes Kornélia , Adeghate Ernest A.
Published: July 2021

Nociceptin (NC) consists of 17 amino acids (aa) and takes part in the processing of learning and memory. The role of NC in the induction of endogenous antioxidants in still unclear. We examined the effect of NC on the expression of endogenous antioxidants in kidney, liver, cerebral cortex (CC), and hippocampus after the onset of diabetes mellitus, using enzyme-linked immunosorbent assay and immunohistochemistry. Exogenous NC (aa chain 1–17; 10 µg/kg body weight) was given intraperitoneally to normal and diabetic rats for 5 days. Our results showed that catalase (CAT) is present in the proximal (PCT) and distal (DCT) convoluted tubules of kidney, hepatocytes, and neurons of CC and hippocampus. The expression of CAT was significantly (p < 0.05) reduced in the kidney of normal and diabetic rats after treatment with NC. However, NC markedly (p < 0.001) increased the expression CAT in the liver and neurons of CC of diabetic rats. Superoxide dismutase (SOD) is widely distributed in the PCT and DCT of kidney, hepatocytes, and neurons of CC and hippocampus. NC significantly (p < 0.001) increased the expression of SOD in hepatocytes and neurons of CC and the hippocampus but not in the kidney. Glutathione reductase (GRED) was observed in kidney tubules, hepatocytes and neurons of the brain. NC markedly increased (p < 0.001) the expression of GRED in PCT and DCT cells of the kidney and hepatocytes of liver and neurons of CC. In conclusion, NC is a strong inducer of CAT, SOD, and GRED expression in the kidney, liver and brain of diabetic rats.
Receptor Interactions of Angiotensin II and Angiotensin Receptor Blockers—Relevance to COVID-19
Authors: Moore Graham J. , Pires Jose M. , Kelaidonis Konstantinos , Gadanec Laura Kate , Zulli Anthony , Apostolopoulos Vasso , Matsoukas John M.
Published: July 2021

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino group occupying position 2 of Ang II. These findings suggest that Tyr is preferred over His for bearing the negative charge and that the CRS is stabilized by the guanidino group. Recent crystallography studies provided details of the binding of nonpeptide angiotensin receptor blockers (ARBs) to the Ang II type 1 (AT1) receptor, and these insights were applied to Ang II. A model of binding and receptor activation that explains the surmountable and insurmountable effects of Ang II analogues sarmesin and sarilesin, respectively, was developed and enabled the discovery of a new generation of ARBs called bisartans. Finally, we determined the ability of the bisartan BV6(TFA) to act as a potential ARB, demonstrating similar effects to candesartan, by reducing vasoconstriction of rabbit iliac arteries in response to cumulative doses of Ang II. Recent clinical studies have shown that Ang II receptor blockers have protective effects in hypertensive patients infected with SARS-CoV-2. Therefore, the usage of ARBS to block the AT1 receptor preventing the binding of toxic angiotensin implicated in the storm of cytokines in SARS-CoV-2 is a target treatment and opens new avenues for disease therapy.
Brain-Derived Exosomal Proteins as Effective Biomarkers for Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Authors: Kim Ka Young , Shin Ki Young , Chang Keun-A
Published: July 2021

Alzheimer’s disease (AD), a progressive neurodegenerative disease, affects approximately 50 million people worldwide, which warrants the search for reliable new biomarkers for early diagnosis of AD. Brain-derived exosomal (BDE) proteins, which are extracellular nanovesicles released by all cell lineages of the central nervous system, have been focused as biomarkers for diagnosis, screening, prognosis prediction, and monitoring in AD. This review focused on the possibility of BDE proteins as AD biomarkers. The articles published prior to 26 January 2021 were searched in PubMed, EMBASE, Web of Science, and Cochrane Library to identify all relevant studies that reported exosome biomarkers in blood samples of patients with AD. From 342 articles, 20 studies were selected for analysis. We conducted a meta-analysis of six BDE proteins and found that levels of amyloid-β42 (standardized mean difference (SMD) = 1.534, 95% confidence interval [CI]: 0.595–2.474), total-tau (SMD = 1.224, 95% CI: 0.534–1.915), tau phosphorylated at threonine 181 (SMD = 4.038, 95% CI: 2.312-5.764), and tau phosphorylated at serine 396 (SMD = 2.511, 95% CI: 0.795–4.227) were significantly different in patients with AD compared to those in control. Whereas, those of p-tyrosine-insulin receptor substrate-1 and heat shock protein 70 did not show significant differences. This review suggested that Aβ42, t-tau, p-T181-tau, and p-S396-tau could be effective in diagnosing AD as blood biomarkers, despite the limitation in the meta-analysis based on the availability of data. Therefore, certain BDE proteins could be used as effective biomarkers for AD.
Activity of Anti-Microbial Peptides (AMPs) against Leishmania and Other Parasites: An Overview
Authors: El-Dirany Rima , Shahrour Hawraa , Dirany Zeinab , Abdel-Sater Fadi , Gonzalez-Gaitano Gustavo , Brandenburg Klaus , Martinez de Tejada Guillermo , Nguewa Paul A.
Published: July 2021

Anti-microbial peptides (AMPs), small biologically active molecules, produced by different organisms through their innate immune system, have become a considerable subject of interest in the request of novel therapeutics. Most of these peptides are cationic-amphipathic, exhibiting two main mechanisms of action, direct lysis and by modulating the immunity. The most commonly reported activity of AMPs is their anti-bacterial effects, although other effects, such as anti-fungal, anti-viral, and anti-parasitic, as well as anti-tumor mechanisms of action have also been described. Their anti-parasitic effect against leishmaniasis has been studied. Leishmaniasis is a neglected tropical disease. Currently among parasitic diseases, it is the second most threating illness after malaria. Clinical treatments, mainly antimonial derivatives, are related to drug resistance and some undesirable effects. Therefore, the development of new therapeutic agents has become a priority, and AMPs constitute a promising alternative. In this work, we describe the principal families of AMPs (melittin, cecropin, cathelicidin, defensin, magainin, temporin, dermaseptin, eumenitin, and histatin) exhibiting a potential anti-leishmanial activity, as well as their effectiveness against other microorganisms.
TFEB Signalling-Related MicroRNAs and Autophagy
Authors: Corà Davide , Bussolino Federico , Doronzo Gabriella
Published: July 2021

The oncogenic Transcription Factor EB (TFEB), a member of MITF-TFE family, is known to be the most important regulator of the transcription of genes responsible for the control of lysosomal biogenesis and functions, autophagy, and vesicles flux. TFEB activation occurs in response to stress factors such as nutrient and growth factor deficiency, hypoxia, lysosomal stress, and mitochondrial damage. To reach the final functional status, TFEB is regulated in multimodal ways, including transcriptional rate, post-transcriptional regulation, and post-translational modifications. Post-transcriptional regulation is in part mediated by miRNAs. miRNAs have been linked to many cellular processes involved both in physiology and pathology, such as cell migration, proliferation, differentiation, and apoptosis. miRNAs also play a significant role in autophagy, which exerts a crucial role in cell behaviour during stress or survival responses. In particular, several miRNAs directly recognise TFEB transcript or indirectly regulate its function by targeting accessory molecules or enzymes involved in its post-translational modifications. Moreover, the transcriptional programs triggered by TFEB may be influenced by the miRNA-mediated regulation of TFEB targets. Finally, recent important studies indicate that the transcription of many miRNAs is regulated by TFEB itself. In this review, we describe the interplay between miRNAs with TFEB and focus on how these types of crosstalk affect TFEB activation and cellular functions.
Primary Soft Tissue Sarcoma of the Heart: An Emerging Chapter in Cardio-Oncology
Authors: Scicchitano Pietro , Sergi Maria Chiara , Cameli Matteo , Miglioranza Marcelo H. , Ciccone Marco Matteo , Gentile Marica , Porta Camillo , Tucci Marco
Published: July 2021

Primary malignant cardiac tumors are rare, with a prevalence of about 0.01% among all cancer histotypes. At least 60% of them are primary soft tissue sarcomas of the heart (pSTS-h) that represent almost 1% of all STSs. The cardiac site of origin is the best way to classify pSTS-h as it is directly linked to the surgical approach for cancer removal. Indeed, histological differentiation should integrate the classification to provide insights into prognosis and survival expectancy of the patients. The prognosis of pSTS-h is severe and mostly influenced by the primary localization of the tumor, the difficulty in achieving complete surgical and pharmacological eradication, and the aggressive biological features of malignant cells. This review aims to provide a detailed literature overview of the most relevant issues on primary soft tissue sarcoma of the heart and highlight potential diagnostic and therapeutic future perspectives.
High Performance of a Metal Layer-Assisted Guided-Mode Resonance Biosensor Modulated by Double-Grating
Authors: Zhang Chengrui , Zhou Yi , Mi Lan , Ma Jiong , Wu Xiang , Fei Yiyan
Published: July 2021

Guided-mode resonance (GMR) sensors are widely used as biosensors with the advantages of simple structure, easy detection schemes, high efficiency, and narrow linewidth. However, their applications are limited by their relatively low sensitivity (<200 nm/RIU) and in turn low figure of merit (FOM, <100 1/RIU). Many efforts have been made to enhance the sensitivity or FOM, separately. To enhance the sensitivity and FOM simultaneously for more sensitive sensing, we proposed a metal layer-assisted double-grating (MADG) structure with the evanescent field extending to the sensing region enabled by the metal reflector layer underneath the double-grating. The influence of structural parameters was systematically investigated. Bulk sensitivity of 550.0 nm/RIU and FOM of 1571.4 1/RIU were obtained after numerical optimization. Compared with a single-grating structure, the surface sensitivity of the double-grating structure for protein adsorption increases by a factor of 2.4 times. The as-proposed MADG has a great potential to be a biosensor with high sensitivity and high accuracy.
Point-of-Care Detection of Salivary Nitrite Based on the Surface Plasmon-Assisted Catalytic Coupling Reaction of Aromatic Amines
Authors: Zhao Chen , Shi Ruyi , Wu Jiale , Luo Xuan , Liu Xiangjiang
Published: July 2021

Rapid quantification of nitrite (NO2−) in food, drink and body fluids is of significant importance for both food safety and point-of-care (POA) applications. However, conventional nitrite analytical methods are complicated, constrained to sample content, and time-consuming. Inspired by a nitrite-triggered surface plasmon-assisted catalysis (SPAC) reaction, a rapid point-of-care detection salivary nitrate was developed in this work. NO2− ions can trigger the rapid conversion of p-aminothiophenol (PATP) to p,p′-dimercaptozaobenzene (DMAB) on gold nanoparticles (GNPs) under light illumination, and the emerged new bands at ca. 1140, 1390, 1432 cm−1 originating from DMAB can be used to the quantification of nitrite. Meanwhile, to make the method entirely suitable for on-site fast screen or point-of-care application, the technique is needed to be further optimized. The calibration graph for nitrates was linear in the range of 1–100 µM with a correlation coefficient of 0.9579. The limit of detection was 1 µM. The facile method could lead to a further understanding of the progression and treatment of periodontitis and to guide professionals in planning on-site campaigns to effectively control periodontal diseases.
Improving the IAQ for Learning Efficiency with Indoor Plants in University Classrooms in Ajman, United Arab Emirates
Authors: Jung Chuloh , Awad Jihad
Published: July 2021

The objective of this paper is to investigate the effect of improving indoor air quality with indoor plants. As a methodology, two target classrooms with the same size (120.64 m2) and 32 students per room were selected. Then, 48 areca palm pots (average leaf area of 300 cm2/pot) were placed, and the plant density was 14.68% of the floor area. Subjective assessment for general questions, learning motivation, perceived air quality, and SBS symptoms was conducted at 5 min after the class started and 5 min before the class ended. The results showed that the CO2 concentration by respiration of the students (average of 1873 ppm) exceeded the regulatory standard (1000 ppm), but the students did not recognize the indoor CO2 concentration. The increase in CO2 concentration in the classroom was lower in the case with plant placement (624 ppm) compared with the case without plant placement (about 1205 ppm). It was statistically proven that the CO2 concentration by respiration could be reduced by 50% if the indoor plant leaf area density were maintained at about 14.68% of the floor area. In the case with plant placement, the students perceived the indoor air quality to be 40% fresher and showed a 140% higher acceptability. Moreover, the complaining of SBS symptoms was improved by 108%, and the students’ perception that it was better to focus on learning increased by about 120%. As the awareness of sustainability increases, indoor plants will be more actively placed in the United Arab Emirates. Indoor plants not only provide a visual green effect to improve human comfort but also purify indoor air pollutants.
Comprehensive Somatic Copy Number Analysis Using Aqueous Humor Liquid Biopsy for Retinoblastoma
Authors: Kim Mary E. , Polski Ashley , Xu Liya , Prabakar Rishvanth K. , Peng Chen-Ching , Reid Mark W. , Shah Rachana , Kuhn Peter , Cobrinik David , Hicks James , Berry Jesse L.
Published: July 2021

Aqueous humor (AH) liquid biopsy has been established as a surrogate tumor biopsy for retinoblastoma (RB). Previous AH studies have focused on highly recurrent RB somatic copy number alterations (SCNAs) including gain of 1q, 2p, 6p, and loss of 13q and 16q. In this retrospective study, we provide a comprehensive, whole-genome analysis of RB SCNAs and evaluate associated clinical features for 68 eyes of 64 RB patients from whom AH was obtained between December 2014 and October 2020. Shallow whole-genome sequencing of AH cell-free DNA was performed to assess for SCNAs. The prevalence of specific non-highly recurrent SCNAs, such as 20q gain and 8p loss, differed between primarily and secondarily enucleated eyes. Increases in chromosomal instability predict more advanced seeding morphology (p = 0.015); later age of diagnosis (p < 0.0001); greater odds of an endophytic tumor growth pattern (without retinal detachment; p = 0.047); tumor heights >10 mm (p = 0.09); and containing 6p gain, a biomarker of poor ocular prognosis (p = 0.004). The AH liquid biopsy platform is a high-yield method of whole-genome RB SCNA analysis, and SCNAs are associated with numerous clinical findings in RB eyes. Prospective analyses are encouraged to further elucidate the clinical relevance of specific SCNAs in RB.
Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma
Authors: Kim Chul , Xi Liqiang , Cultraro Constance M. , Wei Fang , Jones Gregory , Cheng Jordan , Shafiei Ahmad , Pham Trinh Hoc-Tran , Roper Nitin , Akoth Elizabeth , Ghafoor Azam , Misra Vikram , Monkash Nina , Strom Charles , Tu Michael , Liao Wei , Chia David , Morris Clive , Steinberg Seth M. , Bagheri Hadi , Wong David T. W. , Raffeld Mark , Guha Udayan
Published: July 2021

Background: We assessed whether serial ctDNA monitoring of plasma and saliva predicts response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma. Three ctDNA technologies—blood-based droplet-digital PCR (ddPCR), next-generation sequencing (NGS), and saliva-based EFIRM liquid biopsy (eLB)—were employed to investigate their complementary roles. Methods: Plasma and saliva samples were collected from patients enrolled in a prospective clinical trial of osimertinib and local ablative therapy upon progression (NCT02759835). Plasma was analyzed by ddPCR and NGS. Saliva was analyzed by eLB. Results: A total of 25 patients were included. We analyzed 534 samples by ddPCR (n = 25), 256 samples by NGS (n = 24) and 371 samples by eLB (n = 22). Among 20 patients who progressed, ctDNA progression predated RECIST 1.1 progression by a median of 118 days (range: 61–272 days) in 11 (55%) patients. Of nine patients without ctDNA progression by ddPCR, two patients had an increase in mutant EGFR by eLB and two patients were found to have ctDNA progression by NGS. Levels of ctDNA measured by ddPCR and NGS at early time points, but not volumetric tumor burden, were associated with PFS. EGFR/ERBB2/MET/KRAS amplifications, EGFR C797S, PIK3CA E545K, PTEN V9del, and CTNNB1 S45P were key resistance mechanisms identified by NGS. Conclusion: Serial assessment of ctDNA in plasma and saliva predicts response and resistance to osimertinib, with each assay having supplementary roles.
Identification of a Novel Tumor Microenvironment Prognostic Signature for Advanced-Stage Serous Ovarian Cancer
Authors: Zheng Mingjun , Long Junyu , Chelariu-Raicu Anca , Mullikin Heather , Vilsmaier Theresa , Vattai Aurelia , Heidegger Helene Hildegard , Batz Falk , Keckstein Simon , Jeschke Udo , Trillsch Fabian , Mahner Sven , Kaltofen Till
Published: July 2021

(1) Background: The tumor microenvironment is involved in the growth and proliferation of malignant tumors and in the process of resistance towards systemic and targeted therapies. A correlation between the gene expression profile of the tumor microenvironment and the prognosis of ovarian cancer patients is already known. (2) Methods: Based on data from The Cancer Genome Atlas (379 RNA sequencing samples), we constructed a prognostic 11-gene signature (SNRPA1, CCL19, CXCL11, CDC5L, APCDD1, LPAR2, PI3, PLEKHF1, CCDC80, CPXM1 and CTAG2) for Fédération Internationale de Gynécologie et d’Obstétrique stage III and IV serous ovarian cancer through lasso regression. (3) Results: The established risk score was able to predict the 1-, 3- and 5-year prognoses more accurately than previously known models. (4) Conclusions: We were able to confirm the predictive power of this model when we applied it to cervical and urothelial cancer, supporting its pan-cancer usability. We found that immune checkpoint genes correlate negatively with a higher risk score. Based on this information, we used our risk score to predict the biological response of cancer samples to an anti-programmed death ligand 1 immunotherapy, which could be useful for future clinical studies on immunotherapy in ovarian cancer.
The mir-423-5p/MMP-2 Axis Regulates the Nerve Growth Factor-Induced Promotion of Chondrosarcoma Metastasis
Authors: Tzeng Huey-En , Lin Syuan-Ling , Thadevoos Louis-Anoop , Ko Chih-Yuan , Liu Ju-Fang , Huang Yu-Wen , Lin Chih-Yang , Fong Yi-Chin , Tang Chih-Hsin
Published: July 2021

A chondrosarcoma is a common tumor of the soft tissue and bone that has a high propensity to metastasize to distant organs. Nerve growth factor (NGF) is capable of promoting the progression and metastasis of several different types of tumors although the effects of NGF in a chondrosarcoma are not confirmed. Here, we found that the levels of NGF and matrix metalloproteinase-2 (MMP-2) correlated with the tumor stage in patients with a chondrosarcoma. NGF facilitated the MMP-2-dependent cellular migration in human chondrosarcoma JJ012 cells while the overexpression of NGF enhanced the lung metastasis in a mouse model of a chondrosarcoma. NGF promoted the MMP-2 synthesis and cell migration by inhibiting miR-423-5p expression through the FAK and c-Src signaling cascades. NGF appears to be a worthwhile therapeutic target in the treatment of a metastatic chondrosarcoma.
Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?
Authors: McCann Christopher , Kerr Emma M.
Published: July 2021

Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical “cell death” machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities.
Treatment Options and Post-Treatment Malignant Transformation Rate of Actinic Cheilitis: A Systematic Review
Authors: Bakirtzi Katerina , Papadimitriou Ilias , Andreadis Dimitrios , Sotiriou Elena
Published: July 2021

Actinic cheilitis is a premalignant condition that may evolve to squamous cell carcinoma. A consensus on its management has not been established, and large clinical trials are lacking. We aimed to review the existing data regarding the treatment of actinic cheilitis with various modalities regarding safety, efficacy, recursions, and post-treatment malignant transformation. A systematic review was conducted through Pubmed, Ovid and the Cochrane library for studies in English language and the references of included papers from inception to January 2021. Case series were considered if ≥6 patients were included. Of the 698 articles, 36 studies and, overall, 699 patients were eventually reviewed. Laser ablation and vermilionectomy provided the best clinical and aesthetic outcomes with few recurrences, while photodynamic therapy was linked to more relapses. Generally, the adverse events were minor and there was no risk of post-treatment malignant transformation. The limitations of our review include the heterogeneity and the small number of patients across studies. Conclusively, invasive treatments demonstrated superior therapeutic and safety profile. Nevertheless, high-quality head-to-head studies that assess different modalities for actinic cheilitis and report patient preferences are lacking.
Evaluation of In Vitro Phototoxicity of a Minibody-IR700 Conjugate Using Cell Monolayer and Multicellular Tumor Spheroid Models
Authors: Sioud Mouldy , Juzenas Petras , Zhang Qindong , Kleinauskas Andrius , Peng Qian
Published: July 2021

Photodynamic therapy (PDT) is a treatment strategy that utilizes photosensitizers (PSs) and light of a specific wavelength to kill cancer cells. However, limited tumor specificity is still a drawback for the clinical application of PDT. To increase the therapeutic efficacy and specificity of PDT, a novel human minibody (MS5) that recognizes a cell surface receptor expressed on various cancer cells was labeled with the hydrophilic phthalocyanine PS IR700 to generate an MS5-IR700 conjugate that is activated by near-infrared (NIR) light. The phototoxicity of the conjugate was mainly tested against the PC3 prostate cancer cell line. The MS5-IR700 conjugate killed PC3 cells after NIR light irradiation as compared to untreated cells or cells treated with IR700 alone. Time-course analysis of cell viability revealed a high percentage of cell death during the first hour in PC3 cells exposed to the MS5-IR700 conjugate and NIR light irradiation. After irradiation, the MS5-IR700 conjugate-treated PC3 cells displayed cellular swelling, round shape, and rupture of the cell and nuclear membranes. In a co-culture model, the MS5-IR700 conjugate killed MS5-positive Ramos lymphoma cells specifically, while leaving MS5-negative cells unaffected. In line with the data obtained with the monolayer cultures, the MS5-IR700 conjugate also killed PC3 cancer cell spheroids. The treatment induced relocation of heat shock protein 70 and calreticulin to the cell surface, implying the induction of immunogenic cell death. Overall, the data suggest that the developed MS5-IR700 conjugate is a promising therapeutic agent that warrants further preclinical studies.
Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation
Authors: Zheng Hongmei , Siddharth Sumit , Parida Sheetal , Wu Xinhong , Sharma Dipali
Published: July 2021

Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.
Combination of the G-8 Screening Tool and Hand-Grip Strength to Predict Long-Term Overall Survival in Non-Small Cell Lung Cancer Patients Undergoing Stereotactic Body Radiotherapy
Authors: Bentsen Kristian Kirkelund , Hansen Olfred , Ryg Jesper , Giger Ann-Kristine Weber , Jeppesen Stefan Starup
Published: July 2021

The Geriatric 8 (G-8) is a known predictor of overall survival (OS) in older cancer patients, but is mainly based on nutritional aspects. This study aimed to assess if the G-8 combined with a hand-grip strength test (HGST) in patients with NSCLC treated with stereotactic body radiotherapy can predict long-term OS better than the G-8 alone. A total of 46 SBRT-treated patients with NSCLC of stage T1-T2N0M0 were included. Patients were divided into three groups: fit (normal G-8 and HGST), vulnerable (abnormal G-8 or HGST), or frail (abnormal G-8 and HGST). Statistically significant differences were found in 4-year OS between the fit, vulnerable, and frail groups (70% vs. 46% vs. 25%, p = 0.04), as well as between the normal and abnormal G-8 groups (69% vs. 39%, p = 0.02). In a multivariable analysis of OS, being vulnerable with a hazard ratio (HR) of 2.03 or frail with an HR of 3.80 indicated poorer OS, but this did not reach statistical significance. This study suggests that there might be a benefit of adding a physical test to the G-8 for more precisely predicting overall survival in SBRT-treated patients with localized NSCLC. However, this should be confirmed in a larger study population.
Comparative Analysis of Universal Protein Extraction Methodologies for Screening of Lipase Activity from Agricultural Products
Authors: Ha Jisu , Park Jun-Young , Choi Yoonseok , Chang Pahn-Shick , Park Kyung-Min
Published: July 2021

Protein extraction techniques are absolutely required for the research of biological catalysts. The present study compared four universal protein extraction methodologies (ammonium sulfate precipitation, TCA/acetone precipitation, and two commercial kits) to provide practical information on protein extraction in order to discover a novel lipase in agricultural products. Yields of protein extraction from 24 domestic agricultural products and their specific activities were evaluated and compared with each other. TCA/acetone precipitation showed a relatively higher extraction yield (on average, 3.41 ± 1.08 mg protein/0.1 g sample) in crude protein extraction, whereas the Pierce™ Plant Total Protein Extraction Kit showed the highest specific lipase activity on average in both spectrophotometric (266.61 ± 235.78 μU/mg protein) and fluorometric (41.52 ± 32.63 μU/mg protein) assays. Our results suggest that commercial kits for the rapid extraction of soluble functional proteins would be a better choice than conventional precipitation techniques to perform the high-throughput screening of enzyme activity from plant sources. Finally, several agricultural products such as cordyceps, pepper, bracken, and hemp, all of which exhibited an excellent specific lipase activity, were proposed as promising candidates for a source of novel lipases.
Function and Biomarkers of the Blood-Brain Barrier in a Neonatal Germinal Matrix Haemorrhage Model
Authors: Andersson Erik Axel , Rocha-Ferreira Eridan , Hagberg Henrik , Mallard Carina , Ek Carl Joakim
Published: July 2021

Germinal matrix haemorrhage (GMH), caused by rupturing blood vessels in the germinal matrix, is a prevalent driver of preterm brain injuries and death. Our group recently developed a model simulating GMH using intrastriatal injections of collagenase in 5-day-old rats, which corresponds to the brain development of human preterm infants. This study aimed to define changes to the blood-brain barrier (BBB) and to evaluate BBB proteins as biomarkers in this GMH model. Regional BBB functions were investigated using blood to brain 14C-sucrose uptake as well as using biotinylated BBB tracers. Blood plasma and cerebrospinal fluids were collected at various times after GMH and analysed with ELISA for OCLN and CLDN5. The immunoreactivity of BBB proteins was assessed in brain sections. Tracer experiments showed that GMH produced a defined region surrounding the hematoma where many vessels lost their integrity. This region expanded for at least 6 h following GMH, thereafter resolution of both hematoma and re-establishment of BBB function occurred. The sucrose experiment indicated that regions somewhat more distant to the hematoma also exhibited BBB dysfunction; however, BBB function was normalised within 5 days of GMH. This shows that GMH leads to a temporal dysfunction in the BBB that may be important in pathological processes as well as in connection to therapeutic interventions. We detected an increase of tight-junction proteins in both CSF and plasma after GMH making them potential biomarkers for GMH.
Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia
Authors: Toupenet Marchesi Liriopé , Leblanc Marion , Stevanin Giovanni
Published: July 2021

Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary. The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems. In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP.
Myostatin Deficiency Protects C2C12 Cells from Oxidative Stress by Inhibiting Intrinsic Activation of Apoptosis
Authors: Drysch Marius , Schmidt Sonja Verena , Becerikli Mustafa , Reinkemeier Felix , Dittfeld Stephanie , Wagner Johannes Maximilian , Dadras Mehran , Sogorski Alexander , von Glinski Maxi , Lehnhardt Marcus , Behr Björn , Wallner Christoph
Published: July 2021

Ischemia reperfusion (IR) injury remains an important topic in clinical medicine. While a multitude of prophylactic and therapeutic strategies have been proposed, recent studies have illuminated protective effects of myostatin inhibition. This study aims to elaborate on the intracellular pathways involved in myostatin signaling and to explore key proteins that convey protective effects in IR injury. We used CRISPR/Cas9 gene editing to introduce a myostatin (Mstn) deletion into a C2C12 cell line. In subsequent experiments, we evaluated overall cell death, activation of apoptotic pathways, ROS generation, lipid peroxidation, intracellular signaling via mitogen-activated protein kinases (MAPKs), cell migration, and cell proliferation under hypoxic conditions followed by reoxygenation to simulate an IR situation in vitro (hypoxia reoxygenation). It was found that mitogen-activated protein kinase kinase 3/6, also known as MAPK/ERK Kinase 3/6 (MEK3/6), and subsequent p38 MAPK activation were blunted in C2C12-Mstn−/− cells in response to hypoxia reoxygenation (HR). Similarly, c-Jun N-terminal kinase (JNK) activation was negated. We also found the intrinsic activation of apoptosis to be more important in comparison with the extrinsic activation. Additionally, intercepting myostatin signaling mitigated apoptosis activation. Ultimately, this research validated protective effects of myostatin inhibition in HR and identified potential mediators worth further investigation. Intercepting myostatin signaling did not inhibit ROS generation overall but mitigated cellular injury. In particular, intrinsic activation of apoptosis origination from mitochondria was alleviated. This was presumably mediated by decreased activation of p38 caused by the diminished kinase activity increase of MEK3/6. Overall, this work provides important insights into HR signaling in C2C12-Mstn−/− cells and could serve as basis for further research.
RhoA Signaling in Immune Cell Response and Cardiac Disease
Authors: Kilian Lucia Sophie , Frank Derk , Rangrez Ashraf Yusuf
Published: July 2021

Chronic inflammation, the activation of immune cells and their cross-talk with cardiomyocytes in the pathogenesis and progression of heart diseases has long been overlooked. However, with the latest research developments, it is increasingly accepted that a vicious cycle exists where cardiomyocytes release cardiocrine signaling molecules that spiral down to immune cell activation and chronic state of low-level inflammation. For example, cardiocrine molecules released from injured or stressed cardiomyocytes can stimulate macrophages, dendritic cells, neutrophils and even T-cells, which then subsequently increase cardiac inflammation by co-stimulation and positive feedback loops. One of the key proteins involved in stress-mediated cardiomyocyte signal transduction is a small GTPase RhoA. Importantly, the regulation of RhoA activation is critical for effective immune cell response and is being considered as one of the potential therapeutic targets in many immune-cell-mediated inflammatory diseases. In this review we provide an update on the role of RhoA at the juncture of immune cell activation, inflammation and cardiac disease.