bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Assimilating Advanced Himawari Imager Channel 16 Data on Precipitation Prediction over the Haihe River Basin
Authors: Ouyang Hongxiang , Qin Zhengkun , Li Juan
Published: September 2021

Assimilation of high-resolution geostationary satellite data is of great value for precise precipitation prediction in regional basins. The operational geostationary satellite imager carried by the Himawari-8 satellite, Advanced Himawari Imager (AHI), has two additional water vapor channels and four other channels compared with its predecessor, MTSAT-2. However, due to the uncertainty in surface parameters, AHI surface-sensitive channels are usually not assimilated over land, except for the three water vapor channels. Previous research showed that the brightness temperature of AHI channel 16 is much more sensitive to the lower-tropospheric temperature than to surface emissivity, which is similar to the three water vapor channels 8–10. As a follow-up work, this paper evaluates the effectiveness of assimilating brightness temperature observations over land from both the three AHI water vapor channels and channel 16 to improve watershed precipitation forecasting through both case analysis (in the Haihe River basin, China) and batch tests. It is found that assimilating AHI channel 16 can improve the upstream near-surface atmospheric temperature forecast, which in turn affects the development of downstream weather systems. The precipitation forecasting test results indicate that adding the terrestrial observations of channel 16 to the assimilation of AHI data can improve short-term precipitation forecasting in the basin.
Variation of High and Low Level Circulation of Meiyu in Jiangsu Province in Recent 30 Years
Authors: Hu Ruoxin , Wang Lijuan
Published: September 2021

By using the NCEP/NCAR re-analysis data from 1990 to 2019 and the daily precipitation data of CN05.1 gridded observation dataset, the high and low level circulation characteristics and their influence on the onset and precipitation of Meiyu in Jiangsu Province in recent 30 years are studied. Comparing Meiyu in the 2010s with that in the 1990s, it is found that during the 2010s Meiyu was characterized by a late arrival and less precipitation. There were obviously earlier Meiyu years in the 1990s, while no extremely early Meiyu year existed in the 2010s, which was mainly caused by the late northward jump of the upper jet and the ridge line of the western Pacific subtropical high (WPSH hereinafter) in the 2010s. Compared with the 1990s, the 2010s witnessed an eastward position of the South Asia high and a westward position of the subtropical westerly jet during the Meiyu period, which are not conducive to precipitation in the Yangtze-Huaihe region. At the same time, the cold air flowing southward to the Yangtze-Huaihe region was hindered in the 2010s due to the change of blocking in the middle troposphere. In the 2010s, the water vapor transport and the vertical transportation weakened, resulting in the decrease of precipitation in the Yangtze-Huaihe region.
Global Stability Condition for the Disease-Free Equilibrium Point of Fractional Epidemiological Models
Authors: Almeida Ricardo , Martins Natália , Silva Cristiana J.
Published: September 2021

In this paper, we present a new result that allows for studying the global stability of the disease-free equilibrium point when the basic reproduction number is less than 1, in the fractional calculus context. The method only involves basic linear algebra and can be easily applied to study global asymptotic stability. After proving some auxiliary lemmas involving the Mittag–Leffler function, we present the main result of the paper. Under some assumptions, we prove that the disease-free equilibrium point of a fractional differential system is globally asymptotically stable. We then exemplify the procedure with some epidemiological models: a fractional-order SEIR model with classical incidence function, a fractional-order SIRS model with a general incidence function, and a fractional-order model for HIV/AIDS.
ADD: Attention-Based DeepFake Detection Approach
Authors: Khormali Aminollah , Yuan Jiann-Shiun
Published: September 2021

Recent advancements of Generative Adversarial Networks (GANs) pose emerging yet serious privacy risks threatening digital media’s integrity and trustworthiness, specifically digital video, through synthesizing hyper-realistic images and videos, i.e., DeepFakes. The need for ascertaining the trustworthiness of digital media calls for automatic yet accurate DeepFake detection algorithms. This paper presents an attention-based DeepFake detection (ADD) method that exploits the fine-grained and spatial locality attributes of artificially synthesized videos for enhanced detection. ADD framework is composed of two main components including face close-up and face shut-off data augmentation methods and is applicable to any classifier based on convolutional neural network architecture. ADD first locates potentially manipulated areas of the input image to extract representative features. Second, the detection model is forced to pay more attention to these forgery regions in the decision-making process through a particular focus on interpreting the sample in the learning phase. ADD’s performance is evaluated against two challenging datasets of DeepFake forensics, i.e., Celeb-DF (V2) and WildDeepFake. We demonstrated the generalization of ADD by evaluating four popular classifiers, namely VGGNet, ResNet, Xception, and MobileNet. The obtained results demonstrate that ADD can boost the detection performance of all four baseline classifiers significantly on both benchmark datasets. Particularly, ADD with ResNet backbone detects DeepFakes with more than 98.3% on Celeb-DF (V2), outperforming state-of-the-art DeepFake detection methods.
Prevalence of Hyperhomocysteinemia in China: An Updated Meta-Analysis
Authors: Zeng Yuan , Li Fei-Fei , Yuan Shu-Qian , Tang Hao-Kai , Zhou Jun-Hua , He Quan-Yuan , Baker Julien S. , Dong Yan-Hui , Yang Yi-De
Published: September 2021

We conducted a meta-analysis to systematically assess the prevalence of hyperhomocysteinemia (HHcy) in China, its change over time, and its determinants. Literature searches were conducted using English databases (PubMed, Embase, and Web of Science) and Chinese databases (CNKI, CBM, VIP, and Wanfang). The time ranges were from Jan 2014 to Mar 2021 in China. We adopted the random effects model to estimate the pooled positive rates of HHcy and corresponding 95% confidence intervals (95% CI). To find the sources of heterogeneity, we performed subgroup analysis and meta-regression. A total of 29 related articles were identified involving 338,660 participants with 128,147 HHcy cases. The estimated prevalence of HHcy in China was 37.2% (95% CI: 32.6–41.8%, I2 = 99.8%, p for heterogeneity < 0.001). The trend of HHcy prevalence was gradually upward over time, with increases during 2015–2016 (comparison to 2013–2014, p < 0.001), but steady between 2015–2016 and 2017–2018. Subgroup analysis showed that the prevalence was higher in the elderly over 55 years old, males, and residents in the north, inland, and rural China (for each comparison, p < 0.001). Meta-regression analysis revealed that age and area of study contributed to 42.3% of the heterogeneity between studies. The current meta-analysis provides strong evidence that the prevalence of HHcy is increasing in China, and varies substantially across different ages, genders, and geographic distribution. Accordingly, high-risk population groups should be focused on, and public health policies and strategies should be carried out to prevent and control HHcy in China.
COVID-19 Vaccines: Current Conditions and Future Prospects
Authors: Zieneldien Tarek , Kim Janice , Cao Jessica , Cao Chuanhai
Published: September 2021

It has been over a year since SARS-CoV-2 was first reported in December of 2019 in Wuhan, China. To curb the spread of the virus, many therapies and cures have been tested and developed, most notably mRNA and DNA vaccines. Federal health agencies (CDC, FDA) have approved emergency usage of these S gene-based vaccines with the intention of minimizing any further loss of lives and infections. It is crucial to assess which vaccines are the most efficacious by examining their effects on the immune system, and by providing considerations for new technological vaccine strategies in the future. This paper provides an overview of the current SARS-CoV-2 vaccines with their mechanisms of action, current technologies utilized in manufacturing of the vaccines, and limitations in this new field with emerging data. Although the most popular COVID-19 vaccines have been proven effective, time will be the main factor in dictating which vaccine will be able to best address mutations and future infection.
Bioprospecting Desert Plants for Endophytic and Biostimulant Microbes: A Strategy for Enhancing Agricultural Production in a Hotter, Drier Future
Authors: Zhang Qiuwei , White James F.
Published: September 2021

Deserts are challenging places for plants to survive in due to low nutrient availability, drought and heat stress, water stress, and herbivory. Endophytes—microbes that colonize and infect plant tissues without causing apparent disease—may contribute to plant success in such harsh environments. Current knowledge of desert plant endophytes is limited, but studies performed so far reveal that they can improve host nutrient acquisition, increase host tolerance to abiotic stresses, and increase host resistance to biotic stresses. When considered in combination with their broad host range and high colonization rate, there is great potential for desert endophytes to be used in a commercial agricultural setting, especially as croplands face more frequent and severe droughts due to climate change and as the agricultural industry faces mounting pressure to break away from agrochemicals towards more environmentally friendly alternatives. Much is still unknown about desert endophytes, but future studies may prove fruitful for the discovery of new endophyte-based biofertilizers, biocontrol agents, and abiotic stress relievers of crops.
Hydroxychloroquine Attenuates Acute Inflammation (LPS)-Induced Apoptosis via Inhibiting TRPV1 Channel/ROS Signaling Pathways in Human Monocytes
Authors: Güzel Mustafa , Akpınar Orhan
Published: September 2021

Acute inflammation (INF) and apoptosis are induced in monocytes by the generation of several factors, including the products of cytosolic oxygen free radicals (cROS) and the excessive influx of Ca2+ via the stimulation of TRPV1. These are main factors in the etiology of monocyte activation-induced inflammatory and neurodegenerative diseases. Importantly, the protective action of hydroxychloroquine (HCQ) treatment via the inhibition of TRPV1 on the levels of inflammatory factors, cROS, and apoptosis in acute INF (lipopolysaccharide, LPS)-exposed neuronal cells was recently reported. However, the relationships between acute INF via TRPV1 activation and HCQ in monocytes have not been fully clarified yet. The cell membrane of U937 human monocytes contains natural TRPV1. In the study plan, we used U937 cells in four main groups, namely control, HCQ (60 μM for 48 h), INF (1 μg/mL LPS for 16 h), and HCQ + INF. The current data indicate that LPS-induced acute INF caused the upregulation of excessive cytosolic Ca2+ accumulation via the stimulation of TRPV1 in the cells. The treatment of INF additionally upregulated the levels of apoptosis and cytokines (IL6, IL1β, and TNFα), due to upregulated cROS and lipid peroxidation levels as well as upregulated generation of caspase -3 (CAS3) and -9 (CAS9) but a decrease in glutathione and glutathione peroxidase. The expression levels of TRPV1, Bax, CAS3, and CAS9 were also upregulated by the treatment of LPS. However, treatment with HCQ and TRPV1 blocker (capsazepine) modulated the levels of cytokines, caspases, cROS, Ca2+ influx, and apoptosis through the modulation of TRPV1 in the U937 that were stimulated with LPS. In summary, the present data suggest TRPV1 activation through the acute INF (LPS)-induced inflammatory, oxidant, and apoptotic adverse actions in monocyte cells, whereas HCQ prevented adverse actions via the modulation of TRPV1. The results may be significant in the modulation of monocyte activation-caused inflammatory and neurodegenerative diseases.
Optimization of Fermentation Conditions for Carrageenase Production by Cellulophaga Species: A Comparative Study
Authors: Howlader Md Musa , Molz Jana , Sachse Nico , Tuvikene Rando
Published: September 2021

Carrageenases appear in various species of marine bacteria and are widely used for the degradation of carrageenans, the commercially significant sulphated polysaccharides. The carrageenase production ability of six different Cellulophaga species was identified, with ι-carrageenase being the most abundant carrageenolytic enzyme. C. algicola was the most potent strain, followed by C. fucicola and C. geojensis, whereas C. pacifica was the least effective carrageenase producer among the studied strains. The enzyme production was maximized using the one-factor-at-a-time optimization method. The optimal incubation temperature was identified as 25 °C and the incubation time was set as 48 h for all tested species. The optimal medium composition for Cellulophaga strains was determined as 30 g/L sea salt, 1.4 g/L furcellaran, and 3 g/L yeast extract. An ultrafiltered enzyme extracted from C. algicola had the highest activity at around 40 °C. The optimal pH for enzymatic degradation was determined as 7.8, and the enzyme was fairly stable at temperatures up to 40 °C.
The Combined Use of Platelet-Rich Plasma and Adipose-Derived Mesenchymal Stem Cells Promotes Healing. A Review of Experimental Models and Future Perspectives
Authors: Tatsis Dimitris , Vasalou Varvara , Kotidis Efstathios , Anestiadou Elissavet , Grivas Ioannis , Cheva Angeliki , Koliakos Georgios , Venetis Gregory , Pramateftakis Manousos-George , Ouzounidis Nikolaos , Angelopoulos Stamatis
Published: September 2021

Wound healing and tissue regeneration are a field of clinical medicine presenting high research interest, since various local and systematic factors can inhibit these processes and lead to an inferior result. New methods of healing enhancement constantly arise, which, however, require experimental validation before their establishment in everyday practice. Platelet-rich plasma (PRP) is a well-known autologous factor that promotes tissue healing in various surgical defects. PRP derives from the centrifugation of peripheral blood and has a high concentration of growth factors that promote healing. Recently, the use of adipose-derived mesenchymal stem cells (ADMSCs) has been thoroughly investigated as a form of wound healing enhancement. ADMSCs are autologous stem cells deriving from fat tissue, with a capability of differentiation in specific cells, depending on the micro-environment that they are exposed to. The aim of the present comprehensive review is to record the experimental studies that have been published and investigate the synergistic use of PRP and ADMSC in animal models. The technical aspects of experimentations, as well as the major results of each study, are discussed. In addition, the limited clinical studies including humans are also reported. Future perspectives are discussed, along with the limitations of current studies on the long-term follow up needed on efficacy and safety.
The Interactions of H2TMPyP, Analogues and Its Metal Complexes with DNA G-Quadruplexes—An Overview
Authors: Ramos Catarina I. V. , Monteiro Ana R. , Moura Nuno M. M. , Faustino Maria Amparo F. , Trindade Tito , Neves Maria Graça P. M. S.
Published: September 2021

The evidence that telomerase is overexpressed in almost 90% of human cancers justifies the proposal of this enzyme as a potential target for anticancer drug design. The inhibition of telomerase by quadruplex stabilizing ligands is being considered a useful approach in anticancer drug design proposals. Several aromatic ligands, including porphyrins, were exploited for telomerase inhibition by adduct formation with G-Quadruplex (GQ). 5,10,15,20-Tetrakis(N-methyl-4-pyridinium)porphyrin (H2TMPyP) is one of the most studied porphyrins in this field, and although reported as presenting high affinity to GQ, its poor selectivity for GQ over duplex structures is recognized. To increase the desired selectivity, porphyrin modifications either at the peripheral positions or at the inner core through the coordination with different metals have been handled. Herein, studies involving the interactions of TMPyP and analogs with different DNA sequences able to form GQ and duplex structures using different experimental conditions and approaches are reviewed. Some considerations concerning the structural diversity and recognition modes of G-quadruplexes will be presented first to facilitate the comprehension of the studies reviewed. Additionally, considering the diversity of experimental conditions reported, we decided to complement this review with a screening where the behavior of H2TMPyP and of some of the reviewed metal complexes were evaluated under the same experimental conditions and using the same DNA sequences. In this comparison under unified conditions, we also evaluated, for the first time, the behavior of the AgII complex of H2TMPyP. In general, all derivatives showed good affinity for GQ DNA structures with binding constants in the range of 106–107 M−1 and ligand-GQ stoichiometric ratios of 3:1 and 4:1. A promising pattern of selectivity was also identified for the new AgII derivative.
Correlative Light-Environmental Scanning Electron Microscopy of Plasma Membrane Efflux Carriers of Plant Hormone Auxin
Authors: Stelate Ayoub , Tihlaříková Eva , Schwarzerová Kateřina , Neděla Vilém , Petrášek Jan
Published: September 2021

Fluorescence light microscopy provided convincing evidence for the domain organization of plant plasma membrane (PM) proteins. Both peripheral and integral PM proteins show an inhomogeneous distribution within the PM. However, the size of PM nanodomains and protein clusters is too small to accurately determine their dimensions and nano-organization using routine confocal fluorescence microscopy and super-resolution methods. To overcome this limitation, we have developed a novel correlative light electron microscopy method (CLEM) using total internal reflection fluorescence microscopy (TIRFM) and advanced environmental scanning electron microscopy (A-ESEM). Using this technique, we determined the number of auxin efflux carriers from the PINFORMED (PIN) family (NtPIN3b-GFP) within PM nanodomains of tobacco cell PM ghosts. Protoplasts were attached to coverslips and immunostained with anti-GFP primary antibody and secondary antibody conjugated to fluorochrome and gold nanoparticles. After imaging the nanodomains within the PM with TIRFM, the samples were imaged with A-ESEM without further processing, and quantification of the average number of molecules within the nanodomain was performed. Without requiring any post-fixation and coating procedures, this method allows to study details of the organization of auxin carriers and other plant PM proteins.
Inhibition of Astrocytic Histamine N-Methyltransferase as a Possible Target for the Treatment of Alzheimer’s Disease
Authors: Flores-Clemente Cecilia , Nicolás-Vázquez María Inés , Mera Jiménez Elvia , Hernández-Rodríguez Maricarmen
Published: September 2021

Alzheimer’s disease (AD) represents the principal cause of dementia among the elderly. Great efforts have been established to understand the physiopathology of AD. Changes in neurotransmitter systems in patients with AD, including cholinergic, GABAergic, serotoninergic, noradrenergic, and histaminergic changes have been reported. Interestingly, changes in the histaminergic system have been related to cognitive impairment in AD patients. The principal pathological changes in the brains of AD patients, related to the histaminergic system, are neurofibrillary degeneration of the tuberomammillary nucleus, the main source of histamine in the brain, low histamine levels, and altered signaling of its receptors. The increase of histamine levels can be achieved by inhibiting its degrading enzyme, histamine N-methyltransferase (HNMT), a cytoplasmatic enzyme located in astrocytes. Thus, increasing histamine levels could be employed in AD patients as co-therapy due to their effects on cognitive functions, neuroplasticity, neuronal survival, neurogenesis, and the degradation of amyloid beta (Aβ) peptides. In this sense, the evaluation of the impact of HNMT inhibitors on animal models of AD would be interesting, consequently highlighting its relevance.
Structural Sizing and Topology Optimization Based on Weight Minimization of a Variable Tapered Span-Morphing Wing for Aerodynamic Performance Improvements
Authors: Elelwi Mohamed , Botez Ruxandra Mihaela , Dao Thien-My
Published: September 2021

This article proposes the integration of structural sizing, topology, and aerodynamic optimization for a morphing variable span of tapered wing (MVSTW) with the aim to minimize its weight. In order to evaluate the feasibility of the morphing wing optimization, this work creates a numerical environment by incorporating simultaneous structural sizing and topology optimization based on its aerodynamic analysis. This novel approach is proposed for an MVSTW. A problem-specific optimization approach to determine the minimum weight structure of the wing components for its fixed and moving segments is firstly presented. The optimization was performed using the OptiStruct solver inside HyperMesh. This investigation seeks to minimize total structure compliance while maximizing stiffness in order to satisfy the structural integrity requirements of the MVSTW. The aerodynamic load distribution along the wingspan at full wingspan extension and maximum speed were considered in the optimization processes. The wing components were optimized for size and topology, and all of them were built from aluminum alloy 2024-T3. The optimization results show that weight savings of up to 51.2% and 55.7% were obtained for fixed and moving wing segments, respectively. Based on these results, the optimized variable-span morphing wing can perform certain flight missions perfectly without experiencing any mechanical failures.
Functional Hyperconnectivity during a Stories Listening Task in Magnetoencephalography Is Associated with Language Gains for Children Born Extremely Preterm
Authors: Barnes-Davis Maria E. , Fujiwara Hisako , Drury Georgina , Merhar Stephanie L. , Parikh Nehal A. , Kadis Darren S.
Published: September 2021

Extreme prematurity (EPT, <28 weeks gestation) is associated with language problems. We previously reported hyperconnectivity in EPT children versus term children (TC) using magnetoencephalography (MEG). Here, we aim to ascertain whether functional hyperconnectivity is a marker of language resiliency for EPT children, validating our earlier work with a distinct sample of contemporary well-performing EPT and preterm children with history of language delay (EPT-HLD). A total of 58 children (17 EPT, 9 EPT-HLD, and 32 TC) participated in stories listening during MEG and functional magnetic resonance imaging (fMRI) at 4–6 years. We compared connectivity in EPT and EPT-HLD, investigating relationships with language over time. We measured fMRI activation during stories listening and parcellated the activation map to obtain “nodes” for MEG connectivity analysis. There were no significant group differences in age, sex, race, ethnicity, parental education, income, language scores, or language representation on fMRI. MEG functional connectivity (weighted phase lag index) was significantly different between groups. Preterm children had increased connectivity, replicating our earlier work. EPT and EPT-HLD had hyperconnectivity versus TC at 24–26 Hz, with EPT-HLD exhibiting greatest connectivity. Network strength correlated with change in standardized scores from 2 years to 4–6 years of age, suggesting hyperconnectivity is a marker of advancing language development.
A Low-Cost Prestress Monitoring Method for Post-Tensioned RC Beam Using Piezoelectric-Based Smart Strand
Authors: Le Thanh-Cao , Phan Thi Tuong Vy , Nguyen Trung-Hau , Ho Duc-Duy , Huynh Thanh-Canh
Published: September 2021

This study proposes a cost-effective prestress monitoring method for post-tensioned reinforced concrete (RC) beams using a smart strand. Firstly, the concept of a piezoelectric-based smart strand and its implementation for prestress force monitoring are developed. The smart strand is prepared by embedding inexpensive and high-sensitivity electromechanical impedance (EMI) sensors in a steel strand. Next, the feasibility of the proposed method is experimentally verified for prestress force monitoring of a simple supported post-tensioned RC beam. A smart strand prototype is fabricated and embedded into a 6.4 m RC beam which is then prestressed with different levels. For each prestress level, the EMI responses of the smart tendon are measured and the EMI features are extracted for prestress force monitoring. The results showed that the EMI signals of the smart strand showed strong resonant peaks that varied sensitively to the prestress level of the beam. The prestress change in the prestressed RC beam was successfully estimated by using linear regression models of the EMI features.
Energy Performance of 3D-Printed Concrete Walls: A Numerical Study
Authors: Suntharalingam Thadshajini , Upasiri Irindu , Gatheeshgar Perampalam , Poologanathan Keerthan , Nagaratnam Brabha , Santos Paulo , Rajanayagam Heshachanaa
Published: September 2021

Three-dimensional-printed concrete (3DPC), which is also termed as digital fabrication of concrete, offers potential development towards a sustainable built environment. This novel technique clearly reveals its development towards construction application with various global achievements, including structures such as bridges, houses, office buildings, and emergency shelters. However, despite the enormous efforts of academia and industry in the recent past, the application of the 3DPC method is still challenging, as existing knowledge about its performance is limited. The construction industry and building sectors have a significant share of the total energy consumed globally, and building thermal efficiency has become one of the main driving forces within the industry. Hence, it is important to study the thermal energy performance of the structures developed using the innovative 3DPC technique. Thermal characterization of walls is fundamental for the assessment of the energy performance, and thermal insulation plays an important role in performance enhancements. Therefore, in this study, different wall configurations were examined, and the conclusions were drawn based on their relative energy performance. The thermal performance of 32 different 3DPC wall configurations with and without cavity insulation were traced using validated finite element models by measuring the thermal transmittance value (U-value). Our study found that the considered 3DPC cavity walls had a low energy performance, as the U-values did not satisfy the standard regulations. Thus, their performance was improved with cavity insulation. The simulation resulted in a minimum thermal transmittance value of 0.34 W/m2·K. Additionally, a suitable equation was proposed to find the U-values of 100 mm-thick cavity wall panels with different configurations. Furthermore, this study highlights the importance of analytical and experimental solutions as an outline for further research
Robustness Analysis and Important Element Evaluation Method of Truss Structures
Authors: Feng Jian , Sun Yifu , Xu Yixiang , Wang Fang , Zhang Qian , Cai Jianguo
Published: September 2021

Robustness and vulnerability are important evaluation criteria for structural safety to improve progressive collapse resistance. Modeling rapid evaluation on important elements in the conceptual analysis stage is an essential and efficient way to ensure the robustness of a design. This paper proposes an evaluation method for element importance by using structural strain energy, which can reflect the influence of geometric topology and external load distribution on the structural safety status simultaneously. Three simple planar trusses are chosen to clarify the proposed method. Moreover, the influences of geometric topology, boundary condition, stiffness distribution and load distribution on the element importance are investigated. This evaluation method also extends to the two spatial truss structures, regular quadrangular pyramid grid structures and chessboard-shaped pyramid grid structures. The distribution characteristics of important elements are obtained. This work defines the element importance distribution law of typical structures. It provides a method for rapid robustness analysis of general truss structures, which can be effectively integrated into the existing analysis platform.
Heterogeneity of Melanoma Cell Responses to Sleep Apnea-Derived Plasma Exosomes and to Intermittent Hypoxia
Authors: Khalyfa Abdelnaby , Trzepizur Wojciech , Gileles-Hillel Alex , Qiao Zhuanhong , Sanz-Rubio David , Marin José M. , Martinez-Garcia Miguel A. , Campos-Rodriguez Francisco , Almendros Isaac , Farre Ramon , Sanchez-de-la-Torre Manuel , García-Río Francisco , Gozal David
Published: September 2021

Obstructive sleep apnea (OSA) is associated with increased cutaneous melanoma incidence and adverse outcomes. Exosomes are secreted by most cells, and play a role in OSA-associated tumor progression and metastasis. We aimed to study the effects of plasma exosomes from OSA patients before and after adherent treatment with continuous positive airway pressure (CPAP) on melanoma cells lines, and also to identify exosomal miRNAs from melanoma cells exposed to intermittent hypoxia (IH) or normoxia. Plasma-derived exosomes were isolated from moderate-to-severe OSA patients before (V1) and after (V2) adherent CPAP treatment for one year. Exosomes were co-incubated with three3 different melanoma cell lines (CRL 1424; CRL 1619; CRL 1675) that are characterized by genotypes involving different mutations in BRAF, STK11, CDKN2A, and PTEN genes to assess the effect of exosomes on cell proliferation and migration, as well as on pAMK activity in the presence or absence of a chemical activator. Subsequently, CRL-1424 and CRL-1675 cells were exposed to intermittent hypoxia (IH) and normoxia, and exosomal miRNAs were identified followed by GO and KEG pathways and gene networks. The exosomes from these IH-exposed melanoma cells were also administered to THP1 macrophages to examine changes in M1 and M2 polarity markers. Plasma exosomes from V1 increased CRL-1424 melanoma cell proliferation and migration compared to V2, but not the other two cell lines. Exposure to CRL-1424 exosomes reduced pAMPK/tAMPK in V1 compared to V2, and treatment with AMPK activator reversed the effects. Unique exosomal miRNAs profiles were identified for CRL-1424 and CRL-1675 in IH compared to normoxia, with six miRNAs being regulated and several KEGG pathways were identified. Two M1 markers (CXCL10 and IL6) were significantly increased in monocytes when treated with exosomes from IH-exposed CRL-1424 and CRL-1625 cells. Our findings suggest that exosomes from untreated OSA patients increase CRL-1424 melanoma malignant properties, an effect that is not observed in two other melanoma cell lines. Exosomal cargo from CRL-1424 cells showed a unique miRNA signature compared to CRL-1675 cells after IH exposures, suggesting that melanoma cells are differentially susceptible to IH, even if they retain similar effects on immune cell polarity. It is postulated that mutations in STK-11 gene encoding for the serine/threonine kinase family that acts as a tumor suppressor may underlie susceptibility to IH-induced metabolic dysfunction, as illustrated by CRL-1424 cells.
Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis
Authors: Wang Xueyu , Yung Mingo M. H. , Sharma Rakesh , Chen Fushun , Poon Ying-Tung , Lam Wai-Yip , Li Benjamin , Ngan Hextan Y. S. , Chan Karen K. L. , Chan David W.
Published: September 2021

Peritoneal metastases are frequently found in high-grade serous carcinoma (HGSOC) patients and are commonly associated with a poor prognosis. The tumor microenvironment (TME) is a complex milieu that plays a critical role in epigenetic alterations driving tumor development and metastatic progression. However, the impact of epigenetic alterations on metastatic ovarian cancer cells in the harsh peritoneal microenvironment remains incompletely understood. Here, we identified that miR-33b is frequently silenced by promoter hypermethylation in HGSOC cells derived from metastatic omental tumor tissues. Enforced expression of miR-33b abrogates the oncogenic properties of ovarian cancer cells cocultured in omental conditioned medium (OCM), which mimics the ascites microenvironment, and in vivo tumor growth. Of note, restoration of miR-33b inhibited OCM-upregulated de novo lipogenesis and fatty acid β-oxidation in ovarian cancer cells, indicating that miR-33b may play a novel tumor suppressor role in the lipid-mediated oncogenic properties of metastatic ovarian cancer cells found in the omentum. Mechanistic studies demonstrated that miR-33b directly targets transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing the activities of fatty acid synthase (FASN) and carnitine palmitoyltransferase 1A (CPT1A) in modulating lipid metabolic activities and simultaneously inhibiting the phosphorylation of NF-κB signaling to govern the oncogenic behaviors of ovarian cancer cells. Thus, our data suggest that a lipid-rich microenvironment may cause epigenetic silencing of miR-33b, which negatively modulates ovarian cancer peritoneal metastases, at least in part, by suppressing TAK1/FASN/CPT1A/NF-κB signaling.
The Breast Tumor Microenvironment: A Key Player in Metastatic Spread
Authors: Terceiro Lucas E. L. , Edechi Chidalu A. , Ikeogu Nnamdi M. , Nickel Barbara E. , Hombach-Klonisch Sabine , Sharif Tanveer , Leygue Etienne , Myal Yvonne
Published: September 2021

The tumor microenvironment plays a pivotal role in the tumorigenesis, progression, and metastatic spread of many cancers including breast. There is now increasing evidence to support the observations that a bidirectional interplay between breast cancer cells and stromal cells exists within the tumor and the tumor microenvironment both at the primary tumor site and at the metastatic site. This interaction occurs through direct cell to cell contact, or by the release of autocrine or paracrine factors which can activate pro-tumor signaling pathways and modulate tumor behavior. In this review, we will highlight recent advances in our current knowledge about the multiple interactions between breast cancer cells and neighboring cells (fibroblasts, endothelial cells, adipocytes, innate and adaptive immune cells) in the tumor microenvironment that coordinate to regulate metastasis. We also highlight the role of exosomes and circulating tumor cells in facilitating breast cancer metastasis. We discuss some key markers associated with stromal cells in the breast tumor environment and their potential to predict patient survival and guide treatment. Finally, we will provide some brief perspectives on how current technologies may lead to the development of more effective therapies for the clinical management of breast cancer patients.
Mammographic Density Changes over Time and Breast Cancer Risk: A Systematic Review and Meta-Analysis
Authors: Mokhtary Arezo , Karakatsanis Andreas , Valachis Antonis
Published: September 2021

The aim of this meta-analysis was to evaluate the association between mammographic density changes over time and the risk of breast cancer. We performed a systematic literature review based on the PubMed and ISI Web of Knowledge databases. A meta-analysis was conducted by computing extracted hazard ratios (HRs) and 95% confidence intervals (CIs) for cohort studies or odds ratios (ORs) and 95% confidence interval using inverse variance method. Of the nine studies included, five were cohort studies that used HR as a measurement type for their statistical analysis and four were case–control or cohort studies that used OR as a measurement type. Increased breast density over time in cohort studies was associated with higher breast cancer risk (HR: 1.61; 95% CI: 1.33–1.96) whereas decreased breast density over time was associated with lower breast cancer risk (HR: 0.78; 95% CI: 0.71–0.87). Similarly, increased breast density over time was associated with higher breast cancer risk in studies presented ORs (pooled OR: 1.85; 95% CI: 1.29–2.65). Our findings imply that an increase in breast density over time seems to be linked to an increased risk of breast cancer, whereas a decrease in breast density over time seems to be linked to a lower risk of breast cancer.
Organoid Models for Cancer Research—From Bed to Bench Side and Back
Authors: Kastner Carolin , Hendricks Anne , Deinlein Hanna , Hankir Mohammed , Germer Christoph-Thomas , Schmidt Stefanie , Wiegering Armin
Published: September 2021

Organoids are a new 3D ex vivo culture system that have been applied in various fields of biomedical research. First isolated from the murine small intestine, they have since been established from a wide range of organs and tissues, both in healthy and diseased states. Organoids genetically, functionally and phenotypically retain the characteristics of their tissue of origin even after multiple passages, making them a valuable tool in studying various physiologic and pathophysiologic processes. The finding that organoids can also be established from tumor tissue or can be engineered to recapitulate tumor tissue has dramatically increased their use in cancer research. In this review, we discuss the potential of organoids to close the gap between preclinical in vitro and in vivo models as well as clinical trials in cancer research focusing on drug investigation and development.
Vitamin D and the Risk of Non-Melanoma Skin Cancer: A Systematic Literature Review and Meta-Analysis on Behalf of the Italian Melanoma Intergroup
Authors: Caini Saverio , Gnagnarella Patrizia , Stanganelli Ignazio , Bellerba Federica , Cocorocchio Emilia , Queirolo Paola , Bendinelli Benedetta , Saieva Calogero , Raimondi Sara , Gandini Sara
Published: September 2021

We aimed to provide a comprehensive overview of the link between vitamin D and non-melanoma skin cancer (NMSC). For this purpose, we conducted a systematic literature review (updated to 3 February 2021) and meta-analysis of the studies reporting on the association between vitamin D intake (from diet and supplements) and blood concentration, polymorphisms of the vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genes, and the risk of NMSC. Random effects meta-analysis models were fitted to merge study-specific risk estimates into summary relative risk (SRR) and corresponding 95% confidence intervals (CI). Twenty-four studies altogether were included. There was a suggestive association between increasing serum/plasma vitamin D concentration and NMSC risk (SRR for highest vs. lowest concentration 1.67, 95%CI 0.61–4.56), although with large heterogeneity across studies (I2 = 91%). NMSC risk was associated with highest vitamin D intake in observational studies but not in clinical trials. Finally, there was no significant association between any polymorphism of the VDR and VDBP genes and NMSC risk. In conclusion, no strong relationship between vitamin D metabolism and NMSC risk appears to exist according to our systematic review and meta-analysis, although some findings are worthy of further investigation.
Genomic Landscape of Angiosarcoma: A Targeted and Immunotherapy Biomarker Analysis
Authors: Espejo-Freire Andrea , Elliott Andrew , Rosenberg Andrew , Costa Philippos , Barreto-Coelho Priscila , Jonczak Emily , D’Amato Gina , Subhawong Ty , Arshad Junaid , Diaz-Perez Julio , Korn Wolfgang , Oberley Matthew , Magee Daniel , Dizon Don , von Mehren Margaret , Khushman Moh’d , Hussein Atif , Leu Kirsten , Trent Jonathan
Published: September 2021

We performed a retrospective analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin in a cohort of 143 cases. Primary sites were head and neck (31%), breast (22%), extremity (11%), viscera (20%), skin at other locations (8%), and unknown (9%). All cases had Next Generation Sequencing (NGS) data with a 592 gene panel, and 53 cases had Whole Exome Sequencing (WES) data, which we used to study the microenvironment phenotype. The immunotherapy (IO) response biomarkers Tumor Mutation Burden (TMB), Microsatellite Instability (MSI), and PD-L1 status were the most frequently encountered alteration, present in 36.4% of the cohort and 65% of head and neck AS (H/N-AS) (p < 0.0001). In H/N-AS, TMB-High was seen in 63.4% of cases (p < 0.0001) and PDL-1 positivity in 33% of cases. The most common genetic alterations were TP53 (29%), MYC amplification (23%), ARID1A (17%), POT1 (16%), and ATRX (13%). H/N-AS cases had predominantly mutations in TP53 (50.0%, p = 0.0004), POT1 (40.5%, p < 0.0001), and ARID1A (33.3%, p = 0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p < 0.0001), HRAS (16.1%, p = 0.0377), and PIK3CA (16.1%, p = 0.2352). At other sites, conclusions are difficult to generate due to the small number of cases. A microenvironment with a high immune signature, previously associated with IO response, was evenly distributed in 13% of the cases at different primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS.
Impact of KMT2A Rearrangement and CSPG4 Expression in Pediatric Acute Myeloid Leukemia
Authors: Hoffmeister Lina Marie , Orhan Eser , Walter Christiane , Niktoreh Naghmeh , Hanenberg Helmut , von Neuhoff Nils , Reinhardt Dirk , Schneider Markus
Published: September 2021

KMT2A rearrangements (KMT2A-r) are among the most common structural aberrations in pediatric acute myeloid leukemia (AML) and are very important for the risk group stratification of patients. Here, we report the outcome of 967 pediatric AML patients with a known KMT2A-r status. The large cohort was characterized by morphology, multicolor flow cytometry, classical cytogenetics and mutation analysis via panel sequencing. In total, the blasts of 241 patients (24.9%) showed KMT2A-r. KMT2A-r is associated with FAB M5, a high white blood cell count and younger age at diagnosis. When subgroups were combined, KMT2A-r had no impact on event-free survival (EFS) and overall survival (OS); however, various subgroups showed a different prognosis, ranging from a <50% OS for KMT2A/AFDN (n = 11) to a 100% chance of survival for patients harboring the rare translocation KMT2A/SEPTIN9 (n = 3, follow up of 3.7 to 9.6 years). A positive correlation of KMT2A-r with KRAS mutations (p < 0.001) existed, albeit without any prognostic impact. In addition, FLT3-ITDs were detected less frequently in AML with KMT2A-r (p < 0.001). Furthermore, KMT2A-r were mutually exclusive, with mutations in NPM1 (p = 0.002), KIT (p = 0.036), WT1 (p < 0.001) and CEBPA (p = 0.006), and translocations NUP98/NSD1 (p = 0.009), RUNX1/RUNX1T1 (p = 0.003) and CBFB/MYH11 (p = 0.006). In the 346 patients tested for CSPG4 expression, a correlation between CSPG4 expression and KMT2A-r was confirmed. However, CSPG4 expression also occurred in patients without KMT2A-r and had no significant prognostic impact on EFS and OS.
Secreted Factors by Anaplastic Thyroid Cancer Cells Induce Tumor-Promoting M2-like Macrophage Polarization through a TIM3-Dependent Mechanism
Authors: Stempin Cinthia Carolina , Geysels Romina Celeste , Park Sunmi , Palacios Luz Maria , Volpini Ximena , Motran Claudia Cristina , Acosta Rodríguez Eva Virginia , Nicola Juan Pablo , Cheng Sheue-yann , Pellizas Claudia Gabriela , Fozzatti Laura
Published: September 2021

Anaplastic thyroid cancer (ATC) is a highly aggressive type of thyroid cancer (TC). Currently, no effective target treatments are available that can improve overall survival, with ATC representing a major clinical challenge because of its remarkable lethality. Tumor-associated macrophages (TAMs) are the most evident cells in ATCs, and their high density is correlated with a poor prognosis. However, the mechanisms of how TAMs promote ATC progression remain poorly characterized. Here, we demonstrated that the treatment of human monocytes (THP-1 cells) with ATC cell-derived conditioned media (CM) promoted macrophage polarization, showing high levels of M2 markers. Furthermore, we found that STAT3 was activated, and this was correlated with an increased expression and secretion of the inflammatory cytokine interleukin-6. Remarkably, the M2-like macrophages obtained revealed tumor-promoting activity. A cytokine array analysis demonstrated that M2-like macrophage-derived CM contained high levels of TIM3, which is an important immune regulatory molecule. Consistently, TIM3 expression was up-regulated in THP-1 cells cultured with ATC cell-derived CM. Moreover, TIM3 blockade significantly reversed the polarization of THP-1 cells induced by ATC cell-secreted soluble factors. We validated the clinical significance of the TIM3 in human TC by analyzing public datasets and found that the expression of TIM3 and its ligand galectin 9 was significantly higher in human TC tissue samples than in normal thyroid tissues. Taken together, our findings identified a new mechanism by which TIM3 induces tumor-promoting M2-like macrophage polarization in TC. Furthermore, TIM3 interference might be a potential tool for treatment of patients with ATC.
Investigation of the Characteristics of Catalysis Synergy during Co-Combustion for Coal Gasification Fine Slag with Bituminous Coal and Bamboo Residue
Authors: Zhang Yixin , Jia Wenke , Wang Rumeng , Guo Yang , Guo Fanhui , Wu Jianjun , Dai Baiqian
Published: September 2021

As a kind of solid waste from coal chemical production, the disposal of coal gasification fine slag poses a certain threat to the environment and the human body. It is essential for gasification slag (GS) to realize rational utilization. GS contains fewer combustible materials, and the high heating value is only 9.31 MJ/Kg, which is difficult to burn in combustion devices solely. The co-combustion behavior of the tri-fuel blends, including bituminous coal (BC), gasification slag (GS), and bamboo residue (BR), was observed by a thermogravimetric analyzer. The TGA results showed that the combustibility increased owing to the addition of BC and BR, and the ignition and burnout temperatures were lower than those of GS alone. The combustion characteristics of the blended samples became worse with the increase in the proportion of GS. The co-combustion process was divided into two main steps with obvious interactions (synergistic and antagonistic). The synergistic effect was mainly attributed to the catalysis of the ash-forming metals reserved with the three raw fuels and the diffusion of oxygen in the rich pore channels of GS. The combustion reaction of blending samples was dominated by O1 and D3 models. The activation energy of the blending combustion decreased compared to the individual combustion of GS. The analysis of the results in this paper can provide some theoretical guidance for the resource utilization of fine slag.