bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Higher Resolution on Precipitation over China in CMIP6 HighResMIP Models
Authors: Xin Xiaoge , Wu Tongwen , Jie Weihua , Zhang Jie
Published: June 2021

Climate models participated in the High Resolution Model Intercomparison Project (HighResMIP) of Coupled Model Intercomparison Project 6 (CMIP6) are evaluated to reveal the impact of enhanced resolution in simulating the climatological distribution of precipitation over China. The multi-model mean (MME) of five models with 30–50 km horizontal resolution in the atmosphere (MME-50) had a better performance in reproducing the observed spatial patterns of precipitation over Northwest China and Southwest China than the MME of their lower-resolution (70–140 km) models (MME-100). Such an improvement is mainly attributed to the topographical rainfall reproduced by the higher-resolution models, which have the superiority of reproducing the local vertical circulation over the complex terrain. The MME-50 also improves the skill score of the 850-hPa southwesterly of the Indian-Burma trough relative to the MME-100, which may contribute to better simulation skill of precipitation over Southwest China. The MME-50 (0.92) has a close skill score to the MME-100 (0.91) in the simulation of East Asian summer monsoon, which explains why the MME-50 cannot improve the simulation skill of the precipitation over Southeast China and Northern China. The skill score of the precipitation over the Tibetan Plateau (TP) simulated by the MME-50 is even lower than the MME-100, revealing that simulating the climate over the high plateau is still a challenge for the high-resolution models.
Numerical Modeling of Coseismic Tropospheric Disturbances Arising from the Unstable Acoustic Gravity Wave Energetics
Authors: Kherani Esfhan A. , Sanchez Saul A. , de Paula Eurico R.
Published: June 2021

Numerous recent studies report the Coseismic Tropospheric Disturbances (CTDs) during large earthquakes. Their presence suggests the importance of atmospheric seismology in a possible earthquake forecasting scenario. The origin mechanism and associated energetics of CTDs are not well understood though the observations associate them with the atmospheric waves. We present the numerical modeling of coupled dynamics of Gravity waves (GWs) and convective instability (CI) in the dry troposphere that produces the CTDs, in the form of pressure disturbances, of observed magnitudes. The study reveals the altitude and epicentral distribution of CTDs and elaborates the relative role of GWs and CI in the generation and intensification of CTDs. The study finds that mega and strong earthquakes disturb the troposphere to a similar level as the severe meteorological weather.
Occurrence of Volatile and Semi-Volatile Organic Pollutants in the Russian Arctic Atmosphere: The International Siberian Shelf Study Expedition (ISSS-2020)
Authors: Kosyakov Dmitry S. , Shavrina Irina S. , Ul’yanovskii Nikolay V. , Lakhmanov Dmitry E. , Lebedev Albert T.
Published: June 2021

Environmental issues in the Arctic region are of primary importance due to the fragility of the Arctic ecosystem. Mainly persistent organic compounds are monitored in the region by nine stationary laboratories. Information on the volatile (VOC) and semi volatile (SVOC) organic priority pollutants is very limited, especially for the Russian Arctic. Air samples from 16 sites along the Russian Arctic coast from the White Sea to the East Siberian Sea were collected on sorption tubes packed with Tenax, Carbograph, and Carboxen sorbents with different selectivity for a wide range of VOCs and SVOCs in 2020 within the framework of the International Siberian Shelf Study Expedition on the research vessel Akademik Keldysh. Thermal desorption gas chromatography–high-resolution mass spectrometry with Orbitrap was used for the analysis. Eighty-six VOCs and SVOCs were detected in the air samples at ng/m3 levels. The number of quantified compounds varied from 26 to 66 per sample. Benzoic acid was the major constituent, followed by BTEX, phenol, chloroform, bis(2-ethylhexyl) phthalate, and carbon tetrachloride. The study allowed for obtaining the first ever data on the presence of 138 priority pollutants in the air of Russian Arctic, whereas the thorough assessment of their possible sources will be the aim of a next investigation.
A Finitely Axiomatized Non-Classical First-Order Theory Incorporating Category Theory and Axiomatic Set Theory
Authors: Cabbolet Marcoen J. T. F.
Published: June 2021

It is well known that Zermelo-Fraenkel Set Theory (ZF), despite its usefulness as a foundational theory for mathematics, has two unwanted features: it cannot be written down explicitly due to its infinitely many axioms, and it has a countable model due to the Löwenheim–Skolem theorem. This paper presents the axioms one has to accept to get rid of these two features. For that matter, some twenty axioms are formulated in a non-classical first-order language with countably many constants: to this collection of axioms is associated a universe of discourse consisting of a class of objects, each of which is a set, and a class of arrows, each of which is a function. The axioms of ZF are derived from this finite axiom schema, and it is shown that it does not have a countable model—if it has a model at all, that is. Furthermore, the axioms of category theory are proven to hold: the present universe may therefore serve as an ontological basis for category theory. However, it has not been investigated whether any of the soundness and completeness properties hold for the present theory: the inevitable conclusion is therefore that only further research can establish whether the present results indeed constitute an advancement in the foundations of mathematics.
Specific Bioelectrical Impedance Vector Analysis Identifies Body Fat Reduction after a Lifestyle Intervention in Former Elite Athletes
Authors: Campa Francesco , Matias Catarina Nunes , Nunes Catarina L. , Monteiro Cristina P. , Francisco Rubén , Jesus Filipe , Marini Elisabetta , Sardinha Luís B. , Martins Paulo , Minderico Cláudia , Silva Analiza M.
Published: June 2021

Background: specific bioelectrical impedance vector analysis (BIVA) has been proposed as an alternative bioimpedance method for evaluating body composition. This investigation aimed to verify the ability of specific BIVA in identifying changes in fat mass after a 16-week lifestyle program in former athletes. Methods: The 94 participants included in the Champ4life project (clinicaltrials.gov: NCT03031951) were randomized into intervention (n = 49) and control (n = 45) groups, from which 82 athletes completed the intervention (age 43.9 ± 9.2 y; body mass index 31.1 ± 4.6 kg/m2). Fat mass was estimated by dual-energy X-ray absorptiometry. Bioelectric resistance, reactance, phase angle, and vector length were assessed by bioelectric impedance spectroscopy, and the BIVA procedure was applied. Results: A significant (p < 0.05) group x time interaction for fat mass, specific resistance, reactance, and vector length was found. Fat mass and vector length significantly (p < 0.05) decreased in the intervention group, while no change was measured in the control group. Considering the participants as a whole group, changes in vector length were associated with changes in fat mass percentage (r2 = 0.246; β = 0.33; p < 0.001) even after adjusting for age, sex, and group (R2 = 0.373; β = 0.23; p = 0.002). Conclusions: The specific BIVA approach is suitable to track fat mass changes during an intervention program aimed to reduce body fat in former athletes.
A Procedure for Oxytocin Measurement in Hair of Pig: Analytical Validation and a Pilot Application
Authors: López-Arjona Marina , Tecles Fernando , Mateo Sandra V. , Contreras-Aguilar María Dolores , Martínez-Miró Silvia , Cerón José Joaquín , Martínez-Subiela Silvia
Published: June 2021

There is growing interest in oxytocin as a biomarker of stress and welfare. The objective of this study was to develop and validate a procedure based on a highly sensitive immunoassay to measure oxytocin in the hair of pigs. In addition, a pilot study to apply this procedure to evaluate possible changes in concentrations of oxytocin in hair during the reproductive cycle of pigs at different periods of the year was conducted. This procedure used methanol for sample extraction, since it offered better recoveries than acetonitrile, and the immunoassay developed was precise and accurate for the quantification of the oxytocin in the hair. When this procedure was applied to hair collected at different times of the reproductive cycle and season, higher values were found at days 23 and 59 after farrowing in the winter–spring period. In addition, higher oxytocin values in the spring–summer period were found in hair collected 5 days before farrowing compared to winter–spring. Oxytocin in hair showed moderate and low correlations with cortisone and cortisol in hair, respectively. This study represents the first report in which oxytocin was measured in hair and could open new lines for future research about the measurement of oxytocin in pigs and other biological species as a biomarker of stress.
Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19—The Role of RAGE-RAS Crosstalk
Authors: Chiappalupi Sara , Salvadori Laura , Donato Rosario , Riuzzi Francesca , Sorci Guglielmo
Published: June 2021

The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential to the deleterious effects of the renin–angiotensin system (RAS), which participates in infection and multiorgan injury in COVID-19 patients. Thus, RAGE might be a major player in severe COVID-19, and appears to be a useful therapeutic molecular target in infections by SARS-CoV-2. The role of RAGE gene polymorphisms in predisposing patients to severe COVID-19 is discussed.
Welcome to the Family: Identification of the NAD+ Transporter of Animal Mitochondria as Member of the Solute Carrier Family SLC25
Authors: Ziegler Mathias , Monné Magnus , Nikiforov Andrey , Agrimi Gennaro , Heiland Ines , Palmieri Ferdinando
Published: June 2021

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD+ had long remained obscure. Only just recently, the existence of a human mitochondrial NAD+ carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD+ carrier in mammals, a long-standing mystery in NAD+ biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery.
Clinical Value of Virtual Reality versus 3D Printing in Congenital Heart Disease
Authors: Lau Ivan , Gupta Ashu , Sun Zhonghua
Published: June 2021

Both three-dimensional (3D) printing and virtual reality (VR) are reported as being superior to the current visualization techniques in conveying more comprehensive visualization of congenital heart disease (CHD). However, little is known in terms of their clinical value in diagnostic assessment, medical education, and preoperative planning of CHD. This cross-sectional study aims to address these by involving 35 medical practitioners to subjectively evaluate VR visualization of four selected CHD cases in comparison with the corresponding 3D printed heart models (3DPHM). Six questionnaires were excluded due to incomplete sections, hence a total of 29 records were included for the analysis. The results showed both VR and 3D printed heart models were comparable in terms of the degree of realism. VR was perceived as more useful in medical education and preoperative planning compared to 3D printed heart models, although there was no significant difference in the ratings (p = 0.54 and 0.35, respectively). Twenty-one participants (72%) indicated both the VR and 3DPHM provided additional benefits compared to the conventional medical imaging visualizations. This study concludes the similar clinical value of both VR and 3DPHM in CHD, although further research is needed to involve more cardiac specialists for their views on the usefulness of these tools.
Closing the Wearable Gap—Part VIII: A Validation Study for a Smart Knee Brace to Capture Knee Joint Kinematics
Authors: Turner Alana J. , Carroll Will , Kodithuwakku Arachchige Sachini N. K. , Saucier David , Burch V Reuben F. , Ball John E. , Smith Brian K. , Freeman Charles E. , Knight Adam C. , Chander Harish
Published: June 2021

Background: Wearable technology is used by clinicians and researchers and play a critical role in biomechanical assessments and rehabilitation. Objective: The purpose of this research is to validate a soft robotic stretch (SRS) sensor embedded in a compression knee brace (smart knee brace) against a motion capture system focusing on knee joint kinematics. Methods: Sixteen participants donned the smart knee brace and completed three separate tasks: non-weight bearing knee flexion/extension, bodyweight air squats, and gait trials. Adjusted R2 for goodness of fit (R2), root mean square error (RMSE), and mean absolute error (MAE) between the SRS sensor and motion capture kinematic data for all three tasks were assessed. Results: For knee flexion/extension: R2 = 0.799, RMSE = 5.470, MAE = 4.560; for bodyweight air squats: R2 = 0.957, RMSE = 8.127, MAE = 6.870; and for gait trials: R2 = 0.565, RMSE = 9.190, MAE = 7.530 were observed. Conclusions: The smart knee brace demonstrated a higher goodness of fit and accuracy during weight-bearing air squats followed by non-weight bearing knee flexion/extension and a lower goodness of fit and accuracy during gait, which can be attributed to the SRS sensor position and orientation, rather than range of motion achieved in each task.
Acid Precipitation and the Prevalence of Parkinson’s Disease: An Ecologic Study in U.S. States
Authors: Schwartz Gary G. , Williamson Mark R.
Published: June 2021

Although the etiology of Parkinson’s disease (PD) is unknown, potentially informative clues lie in its geographic distribution. PD prevalence rates within the U.S. are significantly higher in the Midwest and Northeast, a pattern that resembles the geographic distribution of acid precipitation (“acid rain”). Using linear and multivariable regression, we examined state-wide data on PD prevalence in relation to environmental factors including total precipitation, the acidity of precipitation, the use of well water, and industrial releases of sulfuric acid. In multivariate analyses, age-, race-, and gender-adjusted prevalence rates for PD were inversely correlated with well water use and positively correlated with industrial releases of sulfuric acid and with the quantity of acid precipitation (p < 0.0001). To our knowledge, this is the first report of an association between PD and acid rain. Because acid rain is known to leach metals from soils and pipes into drinking water, acid rain’s association with PD prevalence adds support for a role for metals in the etiology of PD.
Developmental Dyslexia: Environment Matters
Authors: Theodoridou Daniela , Christodoulides Pavlos , Zakopoulou Victoria , Syrrou Maria
Published: June 2021

Developmental dyslexia (DD) is a multifactorial, specific learning disorder. Susceptibility genes have been identified, but there is growing evidence that environmental factors, and especially stress, may act as triggering factors that determine an individual’s risk of developing DD. In DD, as in most complex phenotypes, the presence of a genetic mutation fails to explain the broad phenotypic spectrum observed. Early life stress has been repeatedly associated with the risk of multifactorial disorders, due to its effects on chromatin regulation, gene expression, HPA axis function and its long-term effects on the systemic stress response. Based on recent evidence, we discuss the potential role of stress on DD occurrence, its putative epigenetic effects on the HPA axis of affected individuals, as well as the necessity of early and appropriate intervention, based on the individual stress-associated (endo)phenotype.
Using Brain-Breaks® as a Technology Tool to Increase Attitude towards Physical Activity among Students in Singapore
Authors: Balasekaran Govindasamy , Ibrahim Ahmad Arif Bin , Cheo Ng Yew , Wang Phua Kia , Kuan Garry , Popeska Biljana , Chin Ming-Kai , Mok Magdalena Mo Ching , Edginton Christopher R. , Culpan Ian , Durstine J. Larry
Published: June 2021

The purpose of this study was to investigate the effects of classroom-based Brain Breaks® Physical Activity Solution in Southeast Asia Singaporean primary school students and their attitude towards physical activity (PA) over a ten-week intervention. A total of 113 participants (8–11 years old) were randomly assigned to either an experimental (EG) or a control group (CG), with six classes to each group; the Brain Breaks® group (EG: six classes) and the Control group (CG: six classes). All EG members participated in a Brain Breaks® video intervention (three–five min) during academic classes and the CG continued their lessons as per normal. The student’s attitudes towards PA in both research conditions were evaluated using the self–reported Attitudes toward Physical Activity Scale (APAS), applied before and after intervention. The effects of the intervention on APAS scores were analysed using a mixed model analysis of variance with Time as within-subject and Group as between-subject factors. The analysis revealed evidence in support of the positive effect of classroom video interventions such as Brain Breaks® on student’s attitudes toward benefits, importance, learning, self-efficacy, fun, fitness, and trying to do their personal best in PA. The Brain Breaks® intervention provided a positive significant impact on students in Singapore. This study also revealed that interactive technology tools implemented into the school curriculum benefit students in terms of health and education.
Is Depression or Apathy Playing a Key Role in Predicting Financial Capacity in Parkinson’s Disease with Dementia and Frontotemporal Dementia?
Authors: Giannouli Vaitsa , Tsolaki Magda
Published: June 2021

(1) Background: Depression and apathy both affect cognitive abilities, such as thinking, concentration and making decisions in young and old individuals. Although apathy is claimed to be a “core” feature of Parkinson’s disease (PD) and frontotemporal dementia (FTD), it may occur in the absence of depression and vice versa. Thus, the aim of this study is to explore whether depression or apathy better predict financial capacity performance in PD and FTD as well as in nondemented participants. (2) Methods: Eighty-eight participants divided into three groups (PD, FTD and non-demented participants) were examined with the Mini-Mental State Examination (MMSE) and the Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS)—Full and short form. The Geriatric Depression Scale informant version (GDS-15) and the Irritability-Apathy Scale (IAS) we completed by caregivers. (3) Results: The results indicated that both PD and FTD patients’ general cognitive functioning and financial capacity performance is negatively influenced by apathy and not by depression. (4) Conclusions: Differences in financial capacity performance indicate that apathy should not be disregarded in clinical assessments. Further studies on larger PD and FTD populations are necessary in order to investigate the decisive role of mood factors on financial capacity impairment.
Impact of High-Dose Methotrexate on the Outcome of Patients with Diffuse Large B-Cell Lymphoma and Skeletal Involvement
Authors: Mercier Mélanie , Orvain Corentin , Drieu La Rochelle Laurianne , Marchand Tony , Nunes Gomes Christopher , Giltat Aurélien , Paillassa Jérôme , Clavert Aline , Farhi Jonathan , Rousselet Marie-Christine , Gyan Emmanuel , Houot Roch , Moles-Moreau Marie-Pierre , Hunault-Berger Mathilde
Published: June 2021

Diffuse large B-cell lymphoma (DLBCL) with extra nodal skeletal involvement is rare. It is currently unclear whether these lymphomas should be treated in the same manner as those without skeletal involvement. We retrospectively analyzed the impact of combining high-dose methotrexate (HD-MTX) with an anthracycline-based regimen and rituximab as first-line treatment in a cohort of 93 patients with DLBCL and skeletal involvement with long follow-up. Fifty patients (54%) received upfront HD-MTX for prophylaxis of CNS recurrence (high IPI score and/or epidural involvement) or because of skeletal involvement. After adjusting for age, ECOG, high LDH levels, and type of skeletal involvement, HD-MTX was associated with an improved PFS and OS (HR: 0.2, 95% CI: 0.1–0.3, p < 0.001 and HR: 0.1, 95% CI: 0.04–0.3, p < 0.001, respectively). Patients who received HD-MTX had significantly better 5-year PFS and OS (77% vs. 39%, p <0.001 and 83 vs. 58%, p < 0.001). Radiotherapy was associated with an improved 5-year PFS (74 vs. 48%, p = 0.02), whereas 5-year OS was not significantly different (79% vs. 66%, p = 0.09). A landmark analysis showed that autologous stem cell transplantation was not associated with improved PFS or OS. The combination of high-dose methotrexate and an anthracycline-based immunochemotherapy is associated with an improved outcome in patients with DLBCL and skeletal involvement and should be confirmed in prospective trials.
Combination of Epithelial Growth Factor Receptor Blockers and CDK4/6 Inhibitor for Nasopharyngeal Carcinoma Treatment
Authors: Li Hsin-Pai , Huang Chen-Yang , Lui Kar-Wai , Chao Yin-Kai , Yeh Chun-Nan , Lee Li-Yu , Huang Yenlin , Lin Tung-Liang , Kuo Yung-Chia , Huang Mei-Yuan , Lai Yi-Ru , Yeh Yuan-Ming , Fan Hsien-Chi , Lin An-Chi , Hsieh Jason Chia-Hsun , Chang Kai-Ping , Lin Chien-Yu , Wang Hung-Ming , Chang Yu-Sun , Hsu Cheng-Lung
Published: June 2021

Background: Nasopharyngeal carcinoma (NPC) involves host genetics, environmental and viral factors. In clinical observations, patients of young and old ages were found to have higher recurrence and metastatic rates. Methods: Cytokine array was employed to screen druggable target(s). The candidate target(s) were confirmed through patient-derived xenografts (PDXs) and a new EBV-positive cell line, NPC-B13. Results: Overexpression of epithelial growth factor (EGF) and EGF receptor (EGFR) was detected in young patients than in older patients. The growth of NPC PDX tumors and cell lines was inhibited by EGFR inhibitors (EGFRi) cetuximab and afatinib when used separately or in combination with the cell cycle blocker palbociclib. Western blot analysis of these drug-treated PDXs demonstrated that the blockade of the EGF signaling pathway was associated with a decrease in the p-EGFR level and reduction in PDX tumor size. RNA sequencing results of PDX tumors elucidated that cell cycle-related pathways were suppressed in response to drug treatments. High EGFR expression (IHC score ≥ grade 3) was correlated with poor survival in metastatic patients (p = 0.008). Conclusions: Our results provide encouraging preliminary data related to the combination treatment of EGFRi and palbociclib in patients with NPC.
Constitutive PSGL-1 Correlates with CD30 and TCR Pathways and Represents a Potential Target for Immunotherapy in Anaplastic Large T-Cell Lymphoma
Authors: Belmonte Beatrice , Cancila Valeria , Gulino Alessandro , Navari Mohsen , Arancio Walter , Macor Paolo , Balduit Andrea , Capolla Sara , Morello Gaia , Vacca Davide , Ferrara Ines , Bertolazzi Giorgio , Balistreri Carmela , Amico Paolo , Ferrante Federica , Maiorana Antonino , Salviato Tiziana , Piccaluga Pier , Mangogna Alessandro
Published: June 2021

Due to the high expression of P-selectin glycoprotein ligand-1 (PSGL-1) in lymphoproliferative disorders and in multiple myeloma, it has been considered as a potential target for humoral immunotherapy, as well as an immune checkpoint inhibitor in T-cells. By investigating the expression of SELPLG in 678 T- and B-cell samples by gene expression profiling (GEP), further supported by tissue microarray and immunohistochemical analysis, we identified anaplastic large T-cell lymphoma (ALCL) as constitutively expressing SELPLG at high levels. Moreover, GEP analysis in CD30+ ALCLs highlighted a positive correlation of SELPLG with TNFRSF8 (CD30-coding gene) and T-cell receptor (TCR)-signaling genes (LCK, LAT, SYK and JUN), suggesting that the common dysregulation of TCR expression in ALCLs may be bypassed by the involvement of PSGL-1 in T-cell activation and survival. Finally, we evaluated the effects elicited by in vitro treatment with two anti-PSGL-1 antibodies (KPL-1 and TB5) on the activation of the complement system and induction of apoptosis in human ALCL cell lines. In conclusion, our data demonstrated that PSGL-1 is specifically enriched in ALCLs, altering cell motility and viability due to its involvement in CD30 and TCR signaling, and it might be considered as a promising candidate for novel immunotherapeutic approaches in ALCLs.
New Heparanase-Inhibiting Triazolo-Thiadiazoles Attenuate Primary Tumor Growth and Metastasis
Authors: Barash Uri , Rangappa Shobith , Mohan Chakrabhavi Dhananjaya , Vishwanath Divakar , Boyango Ilanit , Basappa Basappa , Vlodavsky Israel , Rangappa Kanchugarakoppal S.
Published: June 2021

Compelling evidence ties heparanase, an endoglycosidase that cleaves heparan sulfate side (HS) chains of proteoglycans, with all steps of tumor development, including tumor initiation, angiogenesis, growth, metastasis, and chemoresistance. Moreover, heparanase levels correlate with shorter postoperative survival of cancer patients, encouraging the development of heparanase inhibitors as anti-cancer drugs. Heparanase-inhibiting heparin/heparan sulfate-mimicking compounds and neutralizing antibodies are highly effective in animal models of cancer progression, yet none of the compounds reached the stage of approval for clinical use. The present study focused on newly synthesized triazolo–thiadiazoles, of which compound 4-iodo-2-(3-(p-tolyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)phenol (4-MMI) was identified as a potent inhibitor of heparanase enzymatic activity, cell invasion, experimental metastasis, and tumor growth in mouse models. To the best of our knowledge, this is the first report showing a marked decrease in primary tumor growth in mice treated with small molecules that inhibit heparanase enzymatic activity. This result encourages the optimization of 4-MMI for preclinical and clinical studies primarily in cancer but also other indications (i.e., colitis, pancreatitis, diabetic nephropathy, tissue fibrosis) involving heparanase, including viral infection and COVID-19.
The Hypoxic Microenvironment Induces Stearoyl-CoA Desaturase-1 Overexpression and Lipidomic Profile Changes in Clear Cell Renal Cell Carcinoma
Authors: Melana Juan Pablo , Mignolli Francesco , Stoyanoff Tania , Aguirre María V. , Balboa María A. , Balsinde Jesús , Rodríguez Juan Pablo
Published: June 2021

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). It is characterized by a high cell proliferation and the ability to store lipids. Previous studies have demonstrated the overexpression of enzymes associated with lipid metabolism, including stearoyl-CoA desaturase-1 (SCD-1), which increases the concentration of unsaturated fatty acids in tumor cells. In this work, we studied the expression of SCD-1 in primary ccRCC tumors, as well as in cell lines, to determine its influence on the tumor lipid composition and its role in cell proliferation. The lipidomic analyses of patient tumors showed that oleic acid (18:1n-9) is one of the major fatty acids, and it is particularly abundant in the neutral lipid fraction of the tumor core. Using a ccRCC cell line model and in vitro-generated chemical hypoxia, we show that SCD-1 is highly upregulated (up to 200-fold), and this causes an increase in the cellular level of 18:1n-9, which, in turn, accumulates in the neutral lipid fraction. The pharmacological inhibition of SCD-1 blocks 18:1n-9 synthesis and compromises the proliferation. The addition of exogenous 18:1n-9 to the cells reverses the effects of SCD-1 inhibition on cell proliferation. These data reinforce the role of SCD-1 as a possible therapeutic target.
Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance
Authors: Antognelli Cinzia , Mandarano Martina , Prosperi Enrico , Sidoni Angelo , Talesa Vincenzo Nicola
Published: June 2021

Metastatic prostate cancer (mPCa) is a disease for which to date there is not curative therapy. Even the recent and attractive immunotherapeutic approaches targeting PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance, have proved ineffective. A better understanding of the molecular mechanisms contributing to keep an immunosuppressive microenvironment associated with tumor progression and refractoriness to PD-L1 inhibitors is urgently needed. In the present study, by using gene silencing and specific activators or scavengers, we demonstrated, in mPCa cell models, that methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs), especially 5-hydro-5-methylimidazolone (MG-H1), and its metabolizing enzyme, glyoxalase 1 (Glo1), contribute to maintain an immunosuppressive microenvironment through MG-H1-mediated PD-L1 up-regulation and to promote cancer progression. Moreover, our findings suggest that this novel mechanism might be responsible, at least in part, of mPCa resistance to PD-L1 inhibitors, such as atezolizumab, and that targeting it may sensitize cells to this PD-L1 inhibitor. These findings provide novel insights into the mechanisms of mPCa immunosurveillance escape and help in providing the basis to foster in vivo research toward novel therapeutic strategies for immunotherapy of mPCa.
FGFR Inhibitors in Oncology: Insight on the Management of Toxicities in Clinical Practice
Authors: Kommalapati Anuhya , Tella Sri Harsha , Borad Mitesh , Javle Milind , Mahipal Amit
Published: June 2021

Fibroblast Growth Factor receptor (FGFR) pathway aberrations have been implicated in approximately 7% of the malignancies. As our knowledge of FGFR aberrations in cancer continues to evolve, FGFR inhibitors emerged as potential targeted therapeutic agents. The promising results of pemigatinib and infigratinib in advanced unresectable cholangiocarcinoma harboring FGFR2 fusions or rearrangement, and erdafitinib in metastatic urothelial carcinoma with FGFR2 and FGFR3 genetic aberrations, lead to their accelerated approval by the United States (USA) FDA. Along with these agents, many phase II/III clinical trials are currently evaluating the use of derazantinib, infigratinib, and futibatinib either alone or in combination with immunotherapy. Despite the encouraging results seen with FGFR inhibitors, resistance mechanisms and side effect profile may limit their clinical utility. A better understanding of the unique FGFR-inhibitor-related toxicities would invariably help us in the prevention and effective management of FGFR-inhibitor-induced adverse events thereby enhancing their clinical benefit. Herein, we summarized the physiology of FGF/FGFR signaling and briefly discussed the possible mechanisms that could lead to FGFR inhibitor resistance and side effects. In addition, we proposed treatment guidelines for the management of FGFR-inhibitor-associated toxicities. This work would invariably help practicing oncologists to effectively manage the unique toxicities of FGFR inhibitors.
Paracrine Signaling from a Three-Dimensional Model of Bladder Carcinoma and from Normal Bladder Switch the Phenotype of Stromal Fibroblasts
Authors: Camargo Sandra , Gofrit Ofer N. , Assis Assaf , Mitrani Eduardo
Published: June 2021

We present a three-dimensional model based on acellular scaffolds to recreate bladder carcinoma in vitro that closely describes the in vivo behavior of carcinoma cells. The integrity of the basement membrane and protein composition of the bladder scaffolds were examined by Laminin immunostaining and LC–MS/MS. Human primary bladder carcinoma cells were then grown on standard monolayer cultures and also seeded on the bladder scaffolds. Apparently, carcinoma cells adhered to the scaffold basement membrane and created a contiguous one-layer epithelium (engineered micro-carcinomas (EMCs)). Surprisingly, the gene expression pattern displayed by EMCs was similar to the profile expressed by the carcinoma cells cultured on plastic. However, the pattern of secreted growth factors was significantly different, as VEGF, FGF, and PIGF were secreted at higher levels by EMCs. We found that only the combination of factors secreted by EMCs, but not the carcinoma cells grown on plastic dishes, was able to induce either the pro-inflammatory phenotype or the myofibroblast phenotype depending on the concentration of the secreted factors. We found that the pro-inflammatory phenotype could be reversed. We propose a unique platform that allows one to decipher the paracrine signaling of bladder carcinoma and how this molecular signaling can switch the phenotypes of fibroblasts.
Quality Assessment of Gallbladder Cancer Pathology Reports: A Dutch Nationwide Study
Authors: de Bitter Tessa J. J. , de Savornin-Lohman Elise A. J. , de Reuver Philip R. , Versteeg Valerie Sophie , Vink-Börger Elisa , Verheij Joanne , Nagtegaal Iris D. , van der Post Rachel S.
Published: June 2021

Adequate reporting of pathological findings is essential for optimal patient management and to perform high-quality research. The aim of this study was to assess the completeness of pathology reports of gallbladder cancer (GBC) at the nationwide level to assess guideline adherence and make recommendations for improvement. A retrospective population-based cohort of GBC patients diagnosed in the Netherlands from 2000 to 2019 was collected using data from the Dutch Cancer Registry and the nationwide network and registry of histology. Pathology reports were scored on the presence and content of essential and optional items according to the Dutch consensus-based guideline on biliary tract cancer. By histopathological review of cases, we compared findings with the conclusion of the corresponding pathology report. All pathology reports (n = 849) had a narrative, nonstructured format. Overall completeness was low. Information on key prognostic factors, such as tumor side (hepatic vs. serosal), status of cystic duct and liver surgical margins and venous and perineural invasion, was frequently lacking (80%, 23%, 59%, 74% and 74% missing, respectively). Whereas certain items were often missing from the report, they could be retrospectively detected in a substantial proportion of cases during pathology review (n = 738). In conclusion, significant improvements could be made in the reporting of GBC in the Netherlands. Synoptic reporting could greatly enhance the completeness of reports, as already demonstrated for tumor types.
Synthesis and Laccase-Mediated Oxidation of New Condensed 1,4-Dihydropyridine Derivatives
Authors: Milovanovic Jelena , Gündüz Miyase Gözde , Zerva Anastasia , Petkovic Milos , Beskoski Vladimir , Thomaidis Nikolaos S. , Topakas Evangelos , Nikodinovic-Runic Jasmina
Published: June 2021

We describe herein the synthesis and laccase mediated oxidation of six novel 1,4-dihydropyridine (DHP)-based hexahydroquinolines (DHP1-DHP3) and decahydroacridines (DHP4-DHP6). We employed different laccase enzymes with varying redox potential to convert DHP1-DHP3 and DHP4-DHP6 to the corresponding pyridine-containing tetrahydroquinoline and octahydroacridine derivatives, respectively. Intensively coloured products were detected in all biocatalytic reactions using laccase from Trametes versicolor (TvLacc), possibly due to the presence of conjugated chromophores formed in products after oxidation. The NMR assessment confirmed that the oxidation product of DHP1 was its corresponding pyridine-bearing tetrahydroquinoline derivative. Laccase from Bacillus subtillis (BacillusLacc) was the most efficient enzyme for this group of substrates using HPLC assessment. Overall, it could be concluded that DHP2 and DHP5, bearing catecholic structures, were easily oxidized by all tested laccases, while DHP3 and DHP6 containing electron-withdrawing nitro-groups are not readily oxidized by laccases. DHP4 with decahydroacridine moiety consisting of three condensed six-membered rings that contribute not only to the volume but also to the higher redox potential of the substrate rendered this compound not to be biotransformed with any of the mentioned enzymes. Overall, we showed that multiple analytical approaches are needed in order to assess biocatalytical reactions.
Synthesis and Advanced Characterization of Polymer–Protein Core–Shell Nanoparticles
Authors: Sarnello Erik , Li Tao
Published: June 2021

Enzyme immobilization techniques are widely researched due to their wide range of applications. Polymer–protein core–shell nanoparticles (CSNPs) have emerged as a promising technique for enzyme/protein immobilization via a self-assembly process. Based on the desired application, different sizes and distribution of the polymer–protein CSNPs may be required. This work systematically studies the assembly process of poly(4-vinyl pyridine) and bovine serum albumin CSNPs. Average particle size was controlled by varying the concentrations of each reagent. Particle size and size distributions were monitored by dynamic light scattering, ultra-small-angle X-ray scattering, small-angle X-ray scattering and transmission electron microscopy. Results showed a wide range of CSNPs could be assembled ranging from an average radius as small as 52.3 nm, to particles above 1 µm by adjusting reagent concentrations. In situ X-ray scattering techniques monitored particle assembly as a function of time showing the initial particle growth followed by a decrease in particle size as they reach equilibrium. The results outline a general strategy that can be applied to other CSNP systems to better control particle size and distribution for various applications.
Hydrogen Sulfide Metabolism and Pulmonary Hypertension
Authors: Roubenne Lukas , Marthan Roger , Le Grand Bruno , Guibert Christelle
Published: June 2021

Pulmonary hypertension (PH) is a severe and multifactorial disease characterized by a progressive elevation of pulmonary arterial resistance and pressure due to remodeling, inflammation, oxidative stress, and vasoreactive alterations of pulmonary arteries (PAs). Currently, the etiology of these pathological features is not clearly understood and, therefore, no curative treatment is available. Since the 1990s, hydrogen sulfide (H2S) has been described as the third gasotransmitter with plethoric regulatory functions in cardiovascular tissues, especially in pulmonary circulation. Alteration in H2S biogenesis has been associated with the hallmarks of PH. H2S is also involved in pulmonary vascular cell homeostasis via the regulation of hypoxia response and mitochondrial bioenergetics, which are critical phenomena affected during the development of PH. In addition, H2S modulates ATP-sensitive K+ channel (KATP) activity, and is associated with PA relaxation. In vitro or in vivo H2S supplementation exerts antioxidative and anti-inflammatory properties, and reduces PA remodeling. Altogether, current findings suggest that H2S promotes protective effects against PH, and could be a relevant target for a new therapeutic strategy, using attractive H2S-releasing molecules. Thus, the present review discusses the involvement and dysregulation of H2S metabolism in pulmonary circulation pathophysiology.
In Silico Identification of miRNA–lncRNA Interactions in Male Reproductive Disorder Associated with COVID-19 Infection
Authors: Sabetian Soudabeh , Castiglioni Isabella , Jahromi Bahia Namavar , Mousavi Pegah , Cava Claudia
Published: June 2021

Coronavirus disease 2019 (COVID-19), a global pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin-converting enzyme 2 (ACE2) is the receptor for SARS-CoV-2 and transmembrane serine protease 2 (TMPRSS2) facilitates ACE2-mediated virus entry. Moreover, the expression of ACE2 in the testes of infertile men is higher than normal, which indicates that infertile men may be susceptible to be infected and SARS-CoV-2 may cause reproductive disorder through the pathway induced by ACE2 and TMPRSS2. Little is known about the pathway regulation of ACE2 and TMPRSS2 expression in male reproductive disorder. Since the regulation of gene expression is mediated by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) at the post-transcriptional level, the aim of this study was to analyze the dysregulated miRNA–lncRNA interactions of ACE2 and TMPRSS2 in male reproductive disorder. Using bioinformatics analysis, we speculate that the predicted miRNAs including miR-125a-5p, miR-125b-5p, miR-574-5p, and miR-936 as regulators of ACE2 and miR-204-5p as a modulator of TMPRSS2 are associated with male infertility. The lncRNAs with a tissue-specific expression for testis including GRM7-AS3, ARHGAP26-AS1, BSN-AS1, KRBOX1-AS1, CACNA1C-IT3, AC012361.1, FGF14-IT1, AC012494.1, and GS1-24F4.2 were predicted. The identified miRNAs and lncRNAs are proposed as potential biomarkers to study the possible association between COVID-19 and male infertility. This study encourages further studies of miRNA–lncRNA interactions to explain the molecular mechanisms of male infertility in COVID-19 patients.
Xanthohumol Impairs the PMA-Driven Invasive Behaviour of Lung Cancer Cell Line A549 and Exerts Anti-EMT Action
Authors: Sławińska-Brych Adrianna , Mizerska-Kowalska Magdalena , Król Sylwia Katarzyna , Stepulak Andrzej , Zdzisińska Barbara
Published: June 2021

Xanthohumol (XN), the main prenylated flavonoid from hop cones, has been recently reported to exert significant proapoptotic, anti-proliferative, and growth inhibitory effects against lung cancer in both in vitro and in vivo studies. However, its anti-metastatic potential towards this malignancy is still unrevealed. Previously, we indicated that the human lung adenocarcinoma A549 cell line was sensitive to XN treatment. Therefore, using the same tumour cell model, we have studied the influence of XN on the phorbol-12-myristate-13-acetate (PMA)-induced cell migration and invasion. The effects of XN on the expression/activity of pro-invasive MMP-9 and MMP-2 and the expression of MMP inhibitors, i.e., TIMP-1 and TIMP-2 (anti-angiogenic factors), were evaluated. Additionally, the influence of XN on the production of the key pro-angiogenic cytokine, i.e., VEGF, and the release of TGF-β, which is both a pro-angiogenic cytokine and an epithelial-mesenchymal transition (EMT) stimulator, was studied. Furthermore, the influence of XN on the expression of EMT-associated proteins such as E-cadherin and α-E-catenin (epithelial markers), vimentin and N-cadherin (mesenchymal markers), and Snail-1 (transcriptional repressor of E-cadherin) was studied. To elucidate the molecular mechanism underpinning the XN-mediated inhibition of metastatic progression in PMA-activated cells, the phosphorylation levels of AKT, FAK, and ERK1/2 kinases, which are signalling molecules involved in EMT program activation, were assayed. The results showed that XN in non-cytotoxic concentrations impaired the PMA-driven migratory and invasive capacity of A549 cells by decreasing the level of expression of MMP-9 and concomitantly increasing the expression of the TIMP-1 protein, i.e., a specific blocker of pro-MMP-9 activation. Moreover, XN decreased the PMA-induced production of VEGF and TGF-β. Furthermore, the XN-treatment counteracted the PMA-induced EMT of the A549 cells by the upregulation of E-cadherin and α-E-catenin and the downregulation of N-cadherin, vimentin, and Snail-1 expression. The proposed mechanism underlying the anti-invasive XN activity involved the inhibition of the ERK/MAPK pathway and suppression of FAK and PI3/AKT signalling. Our results suggesting migrastatic properties of XN against lung cancer cells require further verification in in vivo assays.
Lymph-Derived Neutrophils Primarily Locate to the Subcapsular and Medullary Sinuses in Resting and Inflamed Lymph Nodes
Authors: de Castro Pinho Jenny , Förster Reinhold
Published: June 2021

Neutrophils are the first immune cells to be recruited from the blood to the tissue site of an infection or inflammation. It has been suggested that neutrophils are capable of migrating from the infected tissue via lymphatic vessels to the draining lymph nodes. However, it remains elusive as to which areas within the lymph nodes can be reached by such reversely migrating cells. To address this question, we applied a model for adoptive neutrophil transfer into the afferent lymphatic vessel that drains towards the popliteal lymph node in mice. We showed that resting and in vitro-activated neutrophils did not enter the lymph node parenchyma but localized primarily in the subcapsular and medullary sinuses. Within the medulla, neutrophils show random migration and are able to sense laser-induced sterile tissue injury by massively swarming to the damaged tissue site. Co-injected dendritic cells supported the entry of resting neutrophils into the lymph node parenchyma via the subcapsular sinus. In contrast, in vivo-activated adoptively transferred neutrophils were capable of migrating into the interfollicular areas of the lymph node. Collectively, the data presented here give further insights into the functional behavior of neutrophils within the lymph nodes.
The Role of Prostaglandins in Different Types of Cancer
Authors: Jara-Gutiérrez Álvaro , Baladrón Victoriano
Published: June 2021

The prostaglandins constitute a family of lipids of 20 carbon atoms that derive from polyunsaturated fatty acids such as arachidonic acid. Traditionally, prostaglandins have been linked to inflammation, female reproductive cycle, vasodilation, or bronchodilator/bronchoconstriction. Recent studies have highlighted the involvement of these lipids in cancer. In this review, existing information on the prostaglandins associated with different types of cancer and the advances related to the potential use of them in neoplasm therapies have been analyzed. We can conclude that the effect of prostaglandins depends on multiple factors, such as the target tissue, their plasma concentration, and the prostaglandin subtype, among others. Prostaglandin D2 (PGD2) seems to hinder tumor progression, while prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2α) seem to provide greater tumor progression and aggressiveness. However, more studies are needed to determine the role of prostaglandin I2 (PGI2) and prostaglandin J2 (PGJ2) in cancer due to the conflicting data obtained. On the other hand, the use of different NSAIDs (non-steroidal anti-inflammatory drugs), especially those selective of COX-2 (cyclooxygenase 2), could have a crucial role in the fight against different neoplasms, either as prophylaxis or as an adjuvant treatment. In addition, multiple targets, related to the action of prostaglandins on the intracellular signaling pathways that are involved in cancer, have been discovered. Thus, in depth research about the prostaglandins involved in different cancer and the different targets modulated by them, as well as their role in the tumor microenvironment and the immune response, is necessary to obtain better therapeutic tools to fight cancer.