bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial Concept Query Based on Lattice-Tree
Authors: Xu Aopeng , Zhang Zhiyuan , Ma Xiaqing , Zhang Zixiang , Xu Tao
Published: May 2022

As a basic method of spatial data operation, spatial keyword query can provide meaningful information to meet user demands by searching spatial textual datasets. How to accurately understand users’ intentions and efficiently retrieve results from spatial textual big data are always the focus of research. Spatial textual big data and their complex correlation between textual features not only enrich the connotation of spatial objects but also bring difficulties to the efficient recognition and retrieval of similar spatial objects. Because there are a lot of many-to-many relationships between massive spatial objects and textual features, most of the existing research results that employ tree-like and table-like structures to index spatial data and textual data are inefficient in retrieving similar spatial objects. In this paper, firstly, we define spatial textual concept (STC) as a group of spatial objects with the same textual keywords in a limited spatial region in order to present the many-to-many relationships between spatial objects and textual features. Then we attempt to introduce the concept lattice model to maintain a group of related STCs and propose a hybrid tree-like spatial index structure, the lattice-tree, for spatial textual big data. Lattice-tree employs R-tree to index the spatial location of objects, and it embeds a concept lattice structure into specific tree nodes to organize the STC set from a large number of textual keywords of objects and their relationships. Based on this, we also propose a novel spatial keyword query, named Top-k spatial concept query (TkSCQ), to answer STC and retrieve similar spatial objects with multiple textual features. The empirical study is carried out on two spatial textual big data sets from Yelp and Amap. Experiments on the lattice-tree verify its feasibility and demonstrate that it is efficient to embed the concept lattice structure into tree nodes of 3 to 5 levels. Experiments on TkSCQ evaluate lattice from results, keywords, data volume, and so on, and two baseline index structures based on IR-tree and Fp-tree, named the inverted-tree and Fpindex-tree, are developed to compare with the lattice-tree on data sets from Yelp and Amap. Experimental results demonstrate that the Lattice-tree has the better retrieval efficiency in most cases, especially in the case of large amounts of data queries, where the retrieval performance of the lattice-tree is much better than the inverted-tree and Fpindex-tree.
Sustainable Urban Land-Use Optimization Using GIS-Based Multicriteria Decision-Making (GIS-MCDM) Approach
Authors: Rahman Md. Mostafizur , Szabó György
Published: May 2022

Land-use optimization is an effective technique to produce optimal benefits in urban land-use planning. There are many approaches and methods to optimize land-use allocation. However, the focus on addressing urban sustainability in land-use optimization is very limited. In this study, we presented a GIS-based multicriteria decision-making (GIS-MCDM) approach to optimize the location of a new residential development considering sustainability dimensions (social, economic, and environmental benefits). Rajshahi City in Bangladesh was taken as a case study. Different types of data, including land use, land cover, ecosystem service value, land surface temperature, and carbon storage, were used to define sustainability criteria. Five physical criteria, three sustainability criteria, and two constraints were used to optimize residential land. Fuzzy membership functions were used to standardize the criteria. The ordered weighted averaging (OWA) was used to produce a residential suitability map. Finally, the multiobjective land allocation (MOLA) module of TerrSet v 19.0 was used to generate optimal locations under an alternative decision scenario. The findings suggest that about 9.00% more sustainability benefits can be achieved using our approach. Using our proposed approach, we also generated six alternative decision scenarios. Among the alternative decision strategies, “high risk–no trade-off” proved to be the most optimal decision strategy that generated the highest sustainability benefit in our case.
Potential Chemotherapeutic Effect of Selenium for Improved Canceration of Esophageal Cancer
Authors: Ahsan Anil , Liu Zhiwei , Su Ruibing , Liu Chencai , Liao Xiaoqi , Su Min
Published: May 2022

Esophageal squamous cell carcinoma is the most common type of esophageal cancer and accounts for 5% of malignant tumor deaths. Recent research suggests that chronic inflammation and DNA damage may drive the onset of esophageal squamous cell carcinoma, implying that lowering chronic inflammation and DNA damage compounds may provide chemo-prevention. According to epidemiological and experimental evidence, selenium is linked to a lower risk of several malignancies, including esophageal squamous cell carcinoma. However, its exact mechanism is still unclear. In the present study, we used cell lines and a 4-NQO mice model to explore the anti-cancer mechanism of four types of selenium. Our findings indicated that selenium inhibited the proliferation, colony formation, and ROS level of ESCC cell lines in a time-dependent manner. Intriguingly, selenium treatment impeded 4-NQO-induced high-grade intraepithelial neoplasia and reduced the number of positive inflammatory cells by preserving DNA from oxidative damage. In addition, selenium significantly decreased the expression of Ki-67 and induced apoptosis. This study demonstrates that selenium has a significant chemo-preventive effect on ESCC by reducing high-grade dysplasia to low-grade dysplasia. For the first time, selenium was shown to slow down the progression of esophageal cancer by lowering inflammation and oxidative DNA damage.
Zebrafish Melanoma-Derived Interstitial EVs Are Carriers of ncRNAs That Induce Inflammation
Authors: Biagini Valentina , Busi Federica , Anelli Viviana , Kerschbamer Emanuela , Baghini Marta , Gurrieri Elena , Notarangelo Michela , Pesce Isabella , van Niel Guillaume , D’Agostino Vito G. , Mione Marina
Published: May 2022

Extracellular vesicles (EVs) are membranous particles released by all cell types. Their role as functional carrier of bioactive molecules is boosted by cells that actively secrete them in biological fluids or in the intercellular space (interstitial EVs, iEVs). Here we have optimised a method for the isolation and characterization of zebrafish iEVs from whole melanoma tissues. Zebrafish melanoma iEVs are around 140 nm in diameter, as determined by nanoparticle tracking and transmission electron microscopy (TEM) analysis. Western blot analysis shows enrichment for CD63 and Alix in the iEV fraction, but not in melanoma cell lysates. Super resolution and confocal microscopy reveal that purified zebrafish iEVs are green fluorescent protein positive (GFP+), indicating that they integrate the oncogene GFP-HRASV12G used to induce melanoma in this model within their vesicular membrane or luminal content. Analysis of RNA-Seq data found 118 non-coding (nc)RNAs differentially distributed between zebrafish melanoma and their iEVs, with only 17 of them being selectively enriched in iEVs. Among these, the RNA components of RNAses P and MRP, which process ribosomal RNA precursors, mitochondrial RNAs, and some mRNAs, were enriched in zebrafish and human melanoma EVs, but not in iEVs extracted from brain tumours. We found that melanoma iEVs induce an inflammatory response when injected in larvae, with increased expression of interferon responsive genes, and this effect is reproduced by MRP- or P-RNAs injected into circulation. This suggests that zebrafish melanoma iEVs are a source of MRP- and P-RNAs that can trigger inflammation in cells of the innate immune system.
Adipose Tissue Plasticity in Response to Pathophysiological Cues: A Connecting Link between Obesity and Its Associated Comorbidities
Authors: De Fano Michelatonio , Bartolini Desirèe , Tortoioli Cristina , Vermigli Cristiana , Malara Massimo , Galli Francesco , Murdolo Giuseppe
Published: May 2022

Adipose tissue (AT) is a remarkably plastic and active organ with functional pleiotropism and high remodeling capacity. Although the expansion of fat mass, by definition, represents the hallmark of obesity, the dysregulation of the adipose organ emerges as the forefront of the link between adiposity and its associated metabolic and cardiovascular complications. The dysfunctional fat displays distinct biological signatures, which include enlarged fat cells, low-grade inflammation, impaired redox homeostasis, and cellular senescence. While these events are orchestrated in a cell-type, context-dependent and temporal manner, the failure of the adipose precursor cells to form new adipocytes appears to be the main instigator of the adipose dysregulation, which, ultimately, poses a deleterious milieu either by promoting ectopic lipid overspill in non-adipose targets (i.e., lipotoxicity) or by inducing an altered secretion of different adipose-derived hormones (i.e., adipokines and lipokines). This “adipocentric view” extends the previous “expandability hypothesis”, which implies a reduced plasticity of the adipose organ at the nexus between unhealthy fat expansion and the development of obesity-associated comorbidities. In this review, we will briefly summarize the potential mechanisms by which adaptive changes to variations of energy balance may impair adipose plasticity and promote fat organ dysfunction. We will also highlight the conundrum with the perturbation of the adipose microenvironment and the development of cardio-metabolic complications by focusing on adipose lipoxidation, inflammation and cellular senescence as a novel triad orchestrating the conspiracy to adipose dysfunction. Finally, we discuss the scientific rationale for proposing adipose organ plasticity as a target to curb/prevent adiposity-linked cardio-metabolic complications.
New Evidence on a Distinction between Aβ40 and Aβ42 Amyloids: Thioflavin T Binding Modes, Clustering Tendency, Degradation Resistance, and Cross-Seeding
Authors: Sulatskaya Anna I. , Rychkov Georgy N. , Sulatsky Maksim I. , Mikhailova Ekaterina V. , Melnikova Nadezhda M. , Andozhskaya Veronika S. , Kuznetsova Irina M. , Turoverov Konstantin K.
Published: May 2022

The relative abundance of two main Abeta-peptide types with different lengths, Aβ40 and Aβ42, determines the severity of the Alzheimer’s disease progression. However, the factors responsible for different behavior patterns of these peptides in the amyloidogenesis process remain unknown. In this comprehensive study, new evidence on Aβ40 and Aβ42 amyloid polymorphism was obtained using a wide range of experimental approaches, including custom-designed approaches. We have for the first time determined the number of modes of thioflavin T (ThT) binding to Aβ40 and Aβ42 fibrils and their binding parameters using a specially developed approach based on the use of equilibrium microdialysis, which makes it possible to distinguish between the concentration of the injected dye and the concentration of dye bound to fibrils. The binding sites of one of these modes located at the junction of adjacent fibrillar filaments were predicted by molecular modeling techniques. We assumed that the sites of the additional mode of ThT-Aβ42 amyloid binding observed experimentally (which are not found in the case of Aβ40 fibrils) are localized in amyloid clots, and the number of these sites could be used for estimation of the level of fiber clustering. We have shown the high tendency of Aβ42 fibers to form large clots compared to Aβ40 fibrils. It is probable that this largely determines the high resistance of Aβ42 amyloids to destabilizing effects (denaturants, ionic detergents, ultrasonication) and their explicit cytotoxic effect, which we have shown. Remarkably, cross-seeding of Aβ40 fibrillogenesis using the preformed Aβ42 fibrils changes the morphology and increases the stability and cytotoxicity of Aβ40 fibrils. The differences in the tendency to cluster and resistance to external factors of Aβ40 and Aβ42 fibrils revealed here may be related to the distinct role they play in the deposition of amyloids and, therefore, differences in pathogenicity in Alzheimer’s disease.
Behavioral Evidence for a Tau and HIV-gp120 Interaction
Authors: Vijayan Murali , Yin Linda , Reddy P. Hemachandra , Benamar Khalid
Published: May 2022

Despite successful virologic control with combination antiretroviral therapy (cART), about half of people living with the human immunodeficiency virus-1 (HIV) develop an HIV-associated neurocognitive disorder (HAND). It is estimated that 50% of individuals who are HIV-positive in the United States are aged 50 years or older. Therefore, a new challenge looms as individuals living with HIV increase in age. There is concern that Alzheimer’s disease (AD) may become prevalent with an earlier onset of cognitive decline in people living with HIV (PLWH). Clinical data studies reported the presence of AD biomarkers in PLWH. However, the functional significance of the interaction between HIV or HIV viral proteins and AD biomarkers is still not well studied. The main goal of the present study is to address this knowledge gap by determining if the HIV envelope glycoprotein 120 (HIV-gp120) can affect the cognitive functions in the Tau mouse AD model. Male Tau and age-matched, wild-type (WT) control mice were treated intracerebroventricularly (ICV) with HIV-gp120. The animals were evaluated for cognitive function using a Y-maze. We found that HIV-gp120 altered cognitive function in Tau mice. Notably, HIV-gp120 was able to promote a cognitive decline in transgenic Tau (P301L) mice compared to the control (HIV-gp120 and WT). We provide the first in vivo evidence of a cognitive interaction between an HIV viral protein and Tau mice.
Neurotoxicity Associated with Treatment of Acute Lymphoblastic Leukemia Chemotherapy and Immunotherapy
Authors: Śliwa-Tytko Patrycja , Kaczmarska Agnieszka , Lejman Monika , Zawitkowska Joanna
Published: May 2022

Immunotherapy is a milestone in the treatment of poor-prognosis pediatric acute lymphoblastic leukemia (ALL) and is expected to improve treatment outcomes and reduce doses of conventional chemotherapy without compromising the effectiveness of the therapy. However, both chemotherapy and immunotherapy cause side effects, including neurological ones. Acute neurological complications occur in 3.6–11% of children treated for ALL. The most neurotoxical chemotherapeutics are L-asparaginase (L-ASP), methotrexate (MTX), vincristine (VCR), and nelarabine (Ara-G). Neurotoxicity associated with methotrexate (MTX-NT) occurs in 3–7% of children treated for ALL and is characterized by seizures, stroke-like symptoms, speech disturbances, and encephalopathy. Recent studies indicate that specific polymorphisms in genes related to neurogenesis may have a predisposition to MTX toxicity. One of the most common complications associated with CAR T-cell therapy is immune effector cell-associated neurotoxicity syndrome (ICANS). Mechanisms of neurotoxicity in CAR T-cell therapy are still unknown and may be due to disruption of the blood–brain barrier and the effects of elevated cytokine levels on the central nervous system (CNS). In this review, we present an analysis of the current knowledge on the mechanisms of neurotoxicity of standard chemotherapy and the targeted therapy in children with ALL.
PAI-1: A Major Player in the Vascular Dysfunction in Obstructive Sleep Apnea?
Authors: Badran Mohammad , Gozal David
Published: May 2022

Obstructive sleep apnea is a chronic and prevalent condition that is associated with endothelial dysfunction, atherosclerosis, and imposes excess overall cardiovascular risk and mortality. Despite its high prevalence and the susceptibility of CVD patients to OSA-mediated stressors, OSA is still under-recognized and untreated in cardiovascular practice. Moreover, conventional OSA treatments have yielded either controversial or disappointing results in terms of protection against CVD, prompting the need for the identification of additional mechanisms and associated adjuvant therapies. Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue-type plasminogen activator (tPA) and urinary-type plasminogen activator (uPA), is a key regulator of fibrinolysis and cell migration. Indeed, elevated PAI-1 expression is associated with major cardiovascular adverse events that have been attributed to its antifibrinolytic activity. However, extensive evidence indicates that PAI-1 can induce endothelial dysfunction and atherosclerosis through complex interactions within the vasculature in an antifibrinolytic-independent matter. Elevated PAI-1 levels have been reported in OSA patients. However, the impact of PAI-1 on OSA-induced CVD has not been addressed to date. Here, we provide a comprehensive review on the mechanisms by which OSA and its most detrimental perturbation, intermittent hypoxia (IH), can enhance the transcription of PAI-1. We also propose causal pathways by which PAI-1 can promote atherosclerosis in OSA, thereby identifying PAI-1 as a potential therapeutic target in OSA-induced CVD.
Effects of Exercise Training during Advanced Maternal Age on the Cognitive Function of Offspring
Authors: Kim Tae-Woon , Park Sang-Seo , Park Hye-Sang
Published: May 2022

Advanced maternal age (AMA) denotes an age of ≥35 years during the time of delivery. Maternal metabolism affects the offspring’s physical and neurological development as well as their cognitive function. This study aimed to elucidate the effects of exercise training among old female animals on the cognitive function, hippocampal neuroplasticity, mitochondrial function, and apoptosis in the offspring. We found that the offspring of mothers with AMA without exercise training had decreased spatial learning and memory, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95) protein levels, neurogenesis, and mitochondrial function, as well as hippocampal cell death. Contrastingly, offspring of mothers with AMA with exercise training showed improved spatial learning, memory, hippocampal neuroplasticity, and mitochondrial function. These findings indicate that despite the AMA, increasing fitness through exercise significantly contributes to a positive prenatal environment for fetuses. The maternal exercises augmented the hippocampal levels of BDNF, which prevents decreased cognitive function in the offspring of mothers with AMA.
Overlapping Features of Psoriasis and Atopic Dermatitis: From Genetics to Immunopathogenesis to Phenotypes
Authors: Tsai Ya-Chu , Tsai Tsen-Fang
Published: May 2022

Psoriasis (PSO) and atopic dermatitis (AD) were once considered to be mutually exclusive diseases, but gradually regarded as a spectrum of disease. Shared genetic loci of both diseases were noted in some populations, including Chinese. Shared immunopathogenesis involving Th17, Th1, Th22 cells, or even IL-13 was found in certain stages or phenotypes. This review discusses the overlapping genetic susceptibility, shared cytokines, immune-mediated comorbidities, and clinical presentations. Overlapping conditions could be classified into mainly PSO lesions with AD features or vice versa, concomitant PSO and AD, or disease transformation as a result of biologics treatment.
Inhalative as well as Intravenous Administration of H2S Provides Neuroprotection after Ischemia and Reperfusion Injury in the Rats’ Retina
Authors: Scheid Stefanie , Goeller Max , Baar Wolfgang , Wollborn Jakob , Buerkle Hartmut , Schlunck Günther , Lagrèze Wolf , Goebel Ulrich , Ulbrich Felix
Published: May 2022

Background: Neuronal ischemia-reperfusion injury (IRI), such as it can occur in glaucoma or strokes, is associated with neuronal cell death and irreversible loss of function of the affected tissue. Hydrogen sulfide (H2S) is considered a potentially neuroprotective substance, but the most effective route of application and the underlying mechanism remain to be determined. Methods: Ischemia-reperfusion injury was induced in rats by a temporary increase in intraocular pressure (1 h). H2S was then applied by inhalation (80 ppm at 0, 1.5, and 3 h after reperfusion) or by intravenous administration of the slow-releasing H2S donor GYY 4137. After 24 h, the retinas were harvested for Western blotting, qPCR, and immunohistochemical staining. Retinal ganglion cell survival was evaluated 7 days after ischemia. Results: Both inhalative and intravenously delivered H2S reduced retinal ganglion cell death with a better result from inhalative application. H2S inhalation for 1.5 h, as well as GYY 4137 treatment, increased p38 phosphorylation. Both forms of application enhanced the extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and inhalation showed a significant increase at all three time points. H2S treatment also reduced apoptotic and inflammatory markers, such as caspase-3, intracellular adhesion molecule 1 (ICAM-1), vascular endothelial growth factor (VEGF), and inducible nitric oxide synthase (iNOS). The protective effect of H2S was partly abolished by the ERK1/2 inhibitor PD98059. Inhalative H2S also reduced the heat shock response including heme oxygenase (HO-1) and heat shock protein 70 (HSP-70) and the expression of radical scavengers such as superoxide dismutases (SOD1, SOD2) and catalase. Conclusion: Hydrogen sulfide acts, at least in part, via the mitogen-activated protein kinase (MAPK) ERK1/2 to reduce apoptosis and inflammation. Both inhalative H2S and intravenous GYY 4137 administrations can improve neuronal cell survival.
Expression of Oxidative Stress and Inflammation-Related Genes in Nasal Mucosa and Nasal Polyps from Patients with Chronic Rhinosinusitis
Authors: Mihalj Hrvoje , Butković Josip , Tokić Stana , Štefanić Mario , Kizivat Tomislav , Bujak Maro , Baus Lončar Mirela , Mihalj Martina
Published: May 2022

Chronic rhinosinusitis (CRS) is a prevalent, multifaceted inflammatory condition affecting the nasal cavity and the paranasal sinuses, frequently accompanied by formation of nasal polyps (CRSwNP). This apparently uniform clinical entity is preceded by heterogeneous changes in cellular and molecular patterns, suggesting the presence of multiple CRS endotypes and a diverse etiology. Alterations of the upper airway innate defense mechanisms, including antimicrobial and antioxidant capacity, have been implicated in CRSwNP etiology. The aim of this study was to investigate mRNA expression patterns of antioxidative enzymes, including superoxide dismutase (SOD) and peroxiredoxin-2 (PRDX2), and innate immune system defense players, namely the bactericidal/permeability-increasing fold-containing family A, member 1 (BPIFA1) and PACAP family members, particularly adenylate-cyclase-activating polypeptide receptor 1 (ADCYAP1) in nasal mucosa and nasal polyps from CRSwNP patients. Additional stratification based on age, sex, allergic comorbidity, and disease severity was applied. The results showed that ADCYAP1, BPIFA1, and PRDX2 transcripts are differentially expressed in nasal mucosa and scale with radiologically assessed disease severity in CRSwNP patients. Sinonasal transcriptome is not associated with age, sex, and smoking in CRSwNP. Surgical and postoperative corticosteroid (CS) therapy improves endoscopic appearance of the mucosa, but variably reverses target gene expression patterns in the nasal cavity of CRSwNP patients. Transcriptional cross-correlations analysis revealed an increased level of connectedness among differentially expressed genes under inflammatory conditions and restoration of basic network following CS treatment. Although results of the present study imply a possible engagement of ADCYAP1 and BPIFA1 as biomarkers for CRSwNP, a more profound study taking into account disease severity and CRSwNP endotypes prior to the treatment would provide additional information on their sensitivity.
MicroRNA-29a Manifests Multifaceted Features to Intensify Radiosensitivity, Escalate Apoptosis, and Revoke Cell Migration for Palliating Radioresistance-Enhanced Cervical Cancer Progression
Authors: Chuang Pei-Chin , Chen Ping-Tsung , Wang Chih-Chi , Su Wen-Hong , Chen Yen-Hao , Huang Eng-Yen
Published: May 2022

Radioresistance remains a major clinical challenge in cervical cancer therapy and results in tumor relapse and metastasis. Nevertheless, the detailed mechanisms are still largely enigmatic. This study was conducted to elucidate the prospective impacts of microRNA-29a (miR-29a) on the modulation of radioresistance-associated cervical cancer progression. Herein, we established two pairs of parental wild-type (WT) and radioresistant (RR) cervical cancer cells (CaSki and C33A), and we found that constant suppressed miR-29a, but not miR-29b/c, was exhibited in RR-clones that underwent a dose of 6-Gy radiation treatment. Remarkably, radioresistant clones displayed low radiosensitivity, and the reduced apoptosis rate resulted in augmented surviving fractions, measured by the clonogenic survival curve assay and the Annexin V/Propidium Iodide apoptosis assay, respectively. Overexpression of miR-29a effectively intensified the radiosensitivity and triggered the cell apoptosis in RR-clones. In contrast, suppressed miR-29a modestly abridged the radiosensitivity and abolished the cell apoptosis in WT-clones. Hence, ectopically introduced miR-29a into RR-clones notably attenuated the wound-healing rate and cell migration, whereas reduced miR-29a aggravated cell mobilities of WT-clones estimated via the in vitro wound-healing assay and time-lapse recording assay. Notably, we further established the in vivo short-term lung locomotion metastasis model in BALB/c nude mice, and we found that increased lung localization was shown after tail-vein injection of RR-CaSki cells compared to those of WT-CaSki cells. Amplified miR-29a significantly eliminated the radioresistance-enhanced lung locomotion. Our data provide evidence suggesting that miR-29a is a promising microRNA signature in radioresistance of cervical cancer cells and displays multifaceted innovative roles involved in anti-radioresistance, escalated apoptosis, and anti-cell migration/metastasis. Amalgamation of a nucleoid-based strategy (miR-29a) together with conventional radiotherapy may be an innovative and eminent strategy to intensify the radiosensitivity and further protect against the subsequent radioresistance and the potential metastasis in cervical cancer treatment.
Fasciola hepatica Gastrodermal Cells Selectively Release Extracellular Vesicles via a Novel Atypical Secretory Mechanism
Authors: Bennett Adam , de la Torre-Escudero Eduardo , Dermott Susan , Threadgold Lawrence , Hanna Robert , Robinson Mark
Published: May 2022

The liver fluke, Fasciola hepatica, is an obligate blood-feeder, and the gastrodermal cells of the parasite form the interface with the host’s blood. Despite their importance in the host–parasite interaction, in-depth proteomic analysis of the gastrodermal cells is lacking. Here, we used laser microdissection of F. hepatica tissue sections to generate unique and biologically exclusive tissue fractions of the gastrodermal cells and tegument for analysis by mass spectrometry. A total of 226 gastrodermal cell proteins were identified, with proteases that degrade haemoglobin being the most abundant. Other detected proteins included those such as proton pumps and anticoagulants which maintain a microenvironment that facilitates digestion. By comparing the gastrodermal cell proteome and the 102 proteins identified in the laser microdissected tegument with previously published tegument proteomic datasets, we showed that one-quarter of proteins (removed by freeze–thaw extraction) or one-third of proteins (removed by detergent extraction) previously identified as tegumental were instead derived from the gastrodermal cells. Comparative analysis of the laser microdissected gastrodermal cells, tegument, and F. hepatica secretome revealed that the gastrodermal cells are the principal source of secreted proteins, as well as showed that both the gastrodermal cells and the tegument are likely to release subpopulations of extracellular vesicles (EVs). Microscopical examination of the gut caeca from flukes fixed immediately after their removal from the host bile ducts showed that selected gastrodermal cells underwent a progressive thinning of the apical plasma membrane which ruptured to release secretory vesicles en masse into the gut lumen. Our findings suggest that gut-derived EVs are released via a novel atypical secretory route and highlight the importance of the gastrodermal cells in nutrient acquisition and possible immunomodulation by the parasite.
Modulation of Endocannabinoid System Components in Depression: Pre-Clinical and Clinical Evidence
Authors: Bright Uri , Akirav Irit
Published: May 2022

Depression is characterized by continuous low mood and loss of interest or pleasure in enjoyable activities. First-line medications for mood disorders mostly target the monoaminergic system; however, many patients do not find relief with these medications, and those who do suffer from negative side effects and a discouragingly low rate of remission. Studies suggest that the endocannabinoid system (ECS) may be involved in the etiology of depression and that targeting the ECS has the potential to alleviate depression. ECS components (such as receptors, endocannabinoid ligands, and degrading enzymes) are key neuromodulators in motivation and cognition as well as in the regulation of stress and emotions. Studies in depressed patients and in animal models for depression have reported deficits in ECS components, which is motivating researchers to identify potential diagnostic and therapeutic biomarkers within the ECS. By understanding the effects of cannabinoids on ECS components in depression, we enhance our understanding of which brain targets they hit, what biological processes they alter, and eventually how to use this information to design better therapeutic options. In this article, we discuss the literature on the effects of cannabinoids on ECS components of specific depression-like behaviors and phenotypes in rodents and then describe the findings in depressed patients. A better understanding of the effects of cannabinoids on ECS components in depression may direct future research efforts to enhance diagnosis and treatment.
Risk Factors Associated with Mortality among Patients with COVID-19: Analysis of a Cohort of 1213 Patients in a Tertiary Healthcare Center
Authors: Romero-Gameros Carlos Alfonso , Vargas-Ortega Guadalupe , Rendón-Macias Mario Enrique , Cuevas-García Carlos Fredy , Colín-Martínez Tania , Sánchez-Hurtado Luis Alejandro , Balcázar-Hernández Lourdes Josefina , De la Cruz-Rodríguez Iván Emilio , Pérez-Dionisio Enid Karina , Retana-Torres Perla Michelle , García-Montesinos Elsy Sarahí , López-Moreno Mayra Alejandra , Intriago-Alor Marielle , Waizel-Haiat Salomón , González-Virla Baldomero
Published: May 2022

The presence of cardio-metabolic and respiratory comorbidities, immunosuppression, and chronic kidney disease have been associated with an increase in mortality from COVID-19. The objective of this study is to establish the risk factors associated with 30-day mortality in a cohort of hospitalized patients with COVID-19. This paper conducts a retrospective and analytical study of patients hospitalized for COVID-19 in a tertiary care center. A Cox proportional hazard analysis was performed to estimate the association of comorbidities with 30-day mortality. A total of 1215 patients with a median age of 59 years were included. In the adjusted Cox proportional hazards regression model, hypothyroidism, D-dimer ≥ 0.8 μg/mL, LHD ≥ 430 IU/L, CRP ≥ 4.83 ng/mL, and triglycerides ≥ 214 mg/dL were associated with an increased risk of death. The presence of a history of hypothyroidism and biomarkers (D-dimer, lactic dehydrogenase, CRP, and triglycerides) were associated with an increase in mortality in the studied cohort.
Custom Massive Allograft in a Case of Pelvic Bone Tumour: Simulation of Processing with Computerised Numerical Control vs. Robotic Machining
Authors: Vivarelli Leonardo , Govoni Marco , Attala Dario , Zoccali Carmine , Biagini Roberto , Dallari Dante
Published: May 2022

The use of massive bone allografts after the resection of bone tumours is still a challenging process. However, to overcome some issues related to the processing procedures and guarantee the best three-dimensional matching between donor and recipient, some tissue banks have developed a virtual tissue database based on the scanning of the available allografts for using their 3D shape during virtual surgical planning (VSP) procedures. To promote the use of future VSP bone-shaping protocols useful for machining applications within a cleanroom environment, in our work, we simulate a massive bone allograft machining with two different machines: a four-axes (computer numerical control, CNC) vs. a five-axes (robot) milling machine. The allograft design was based on a real case of allograft reconstruction after pelvic tumour resection and obtained with 3D Slicer and Rhinoceros software. Machining simulations were performed with RhinoCAM and graphically and mathematically analysed with CloudCompare and R, respectively. In this case, the geometrical differences of the allograft design are not clinically relevant; however, the mathematical analysis showed that the robot performed better than the four-axes machine. The proof-of-concept presented here paves the way towards massive bone allograft cleanroom machining. Nevertheless, further studies, such as the simulation of different types of allografts and real machining on massive bone allografts, are needed.
Metronomic Chemotherapy for Advanced Prostate Cancer: A Literature Review
Authors: Parshad Shruti , Sidhu Amanjot K. , Khan Nabeeha , Naoum Andrew , Emmenegger Urban
Published: May 2022

Metastatic castration-resistant prostate cancer (mCRPC) is the ultimately lethal form of prostate cancer. Docetaxel chemotherapy was the first life-prolonging treatment for mCRPC; however, the standard maximally tolerated dose (MTD) docetaxel regimen is often not considered for patients with mCRPC who are older and/or frail due to its toxicity. Low-dose metronomic chemotherapy (LDMC) is the frequent administration of typically oral and off-patent chemotherapeutics at low doses, which is associated with a superior safety profile and higher tolerability than MTD chemotherapy. We conducted a systematic literature review using the PUBMED, EMBASE, and MEDLINE electronic databases to identify clinical studies that examined the impact of LDMC on patients with advanced prostate cancer. The search identified 30 reports that retrospectively or prospectively investigated LDMC, 29 of which focused on mCRPC. Cyclophosphamide was the most commonly used agent integrated into 27/30 (90%) of LDMC regimens. LDMC resulted in a clinical benefit rate of 56.8 ± 24.5% across all studies. Overall, there were only a few non-hematological grade 3 or 4 adverse events reported. As such, LDMC is a well-tolerated treatment option for patients with mCRPC, including those who are older and frail. Furthermore, LDMC is considered more affordable than conventional mCRPC therapies. However, prospective phase III trials are needed to further characterize the efficacy and safety of LDMC in mCRPC before its use in practice.
Cardio Protective Effects of Lipid Emulsion against Ropivacaine-Induced Local Anesthetic Systemic Toxicity—An Experimental Study
Authors: Lazar Alexandra Elena , Gurzu Simona , Kovecsi Attila , Perian Marcel , Cordos Bogdan , Gherghinescu Mircea Constantin , Enache Liviu Sorin
Published: May 2022

Inadvertent intravascular injection of local anesthetics (LA) during regional anesthesia causes Local Anesthetic Systemic Toxicity (LAST). Theories of lipid rescue in the case of LAST proved that the administration of lipids in LAST has beneficial effects. One possible mechanism of action is based on the lipophilic properties of LA which allow plasma-free LA to be bound by the molecules of Lipid Emulsion (LE). The association LA–LE is shuttled towards organs such as liver and the kidneys, and the half-life of LA is shortened. The main objective of this experimental study was to assess the possible cardio-prophylactic effect of LE administration before the induction of LAST by intravenous administration of Ropivacaine. This was an experimental, interventional, prospective, and non-randomized study. The subjects were divided into groups and received, under general anesthesia, LE 20% first 0.3–0.4 mL, followed by 0.1 mL Ropivacaine 2 mg/mL, or Ropivacaine alone. At the end of the experiment, the subjects were sacrificed, and tissue samples of kidney, heart and liver were harvested for histopathological examination. LE, when administered as prophylaxis in Ropivacaine-induced LAST, had protective cardiac effects in rats. The LE known side effects were not produced if the substance was administered in the low doses used for LAST prophylaxis.
Paracrine Interaction of Cholangiocellular Carcinoma with Cancer-Associated Fibroblasts and Schwann Cells Impact Cell Migration
Authors: Gundlach Jan-Paul , Kerber Jannik , Hendricks Alexander , Bernsmeier Alexander , Halske Christine , Röder Christian , Becker Thomas , Röcken Christoph , Braun Felix , Sebens Susanne , Heits Nils
Published: May 2022

Although the Mitogen-activated protein kinase (MAPK) pathway is enriched in cholangiocarcinoma (CCA), treatment with the multityrosine kinase-inhibitor Sorafenib is disappointing. While cancer-associated fibroblasts (CAF) are known to contribute to treatment resistance in CCA, knowledge is lacking for Schwann cells (SC). We investigated the impact of stromal cells on CCA cells and whether this is affected by Sorafenib. Immunohistochemistry revealed elevated expression of CAF and SC markers significantly correlating with reduced tumor-free survival. In co-culture with CAF, CCA cells mostly migrated, which could be diminished by Sorafenib, while in SC co-cultures, SC predominantly migrated towards CCA cells, unaffected by Sorafenib. Moreover, increased secretion of pro-inflammatory cytokines MCP-1, CXCL-1, IL-6 and IL-8 was determined in CAF mono- and co-cultures, which could be reduced by Sorafenib. Corresponding to migration results, an increased expression of phospho-AKT was measured in CAF co-cultured HuCCT-1 cells, although was unaffected by Sorafenib. Intriguingly, CAF co-cultured TFK-1 cells showed increased activation of STAT3, JNK, ERK and AKT pathways, which was partly reduced by Sorafenib. This study indicates that CAF and SC differentially impact CCA cells and Sorafenib partially reverts these stroma-mediated effects. These findings contribute to a better understanding of the paracrine interplay of CAF and SC with CCA cells.
Ferric Carboxymaltose Improves the Quality of Life of Patients with Inflammatory Bowel Disease and Iron Deficiency without Anaemia
Authors: Huguet Jose María , Cortés Xavier , Boscá-Watts Marta Maia , Muñoz Margarita , Maroto Nuria , Iborra Marisa , Hinojosa Esther , Capilla María , Asencio Carmina , Amoros Cirilo , Paredes Jose María
Published: May 2022

Background: Iron deficiency (ID) without anaemia is a common comorbidity associated with inflammatory bowel disease (IBD) that has a negative impact on health-related quality of life (HRQoL). Methods: This multicentre, prospective, observational study examined the response to, safety of and impact on HRQoL of a single 500 mg dose of intravenous ferric carboxymaltose (FCM) in patients with IBD and ID without anaemia. The diagnostic criteria for ID were low serum ferritin (<30 µg/L in the absence of inflammatory activity or <100 µg/L with inflammation) and transferrin saturation index (TSAT) < 16%. The effect on iron levels and HRQoL, according to the health status questionnaires SF-12v2 and EQ-5D, was evaluated 1 month after FCM infusion in an outpatient setting. Results: Of the 105 patients who received FCM, 98 patients completed the study. After 1 month, a single dose of FCM significantly increased serum ferritin, serum iron and TSAT. Importantly, patients reported fewer ID symptoms and problems on all EQ-5D dimensions. They also had higher EQ-5D visual analogue scale and SF-12v2 scores after treatment. FCM had similar clinical effects on men and women and on patients with Crohn’s disease (n = 66) and ulcerative colitis (n = 32). Conclusion: A single dose of FCM rapidly restored iron parameters and significantly improved patients’ symptoms and HRQoL at 1 month after treatment.
Use of the Biocartis Idylla™ Platform for the Detection of Epidermal Growth Factor Receptor, BRAF and KRAS Proto-Oncogene Mutations in Liquid-Based Cytology Specimens from Patients with Non-Small Cell Lung Carcinoma and Pancreatic Adenocarcinoma
Authors: Wheeldon Leonie , Jones Mary , Probyn Ben , Shetty Dushyant , Garvican James
Published: May 2022

The study aimed to demonstrate rapid and effective molecular testing on liquid-based cytology (LBC) samples for EGFR, KRAS and BRAF mutations using the Biocartis Idylla™. Rapid on-site evaluation (ROSE) LBC samples for patients with non-small cell lung carcinoma (NSCLC) or pancreatic ductal adenocarcinoma (PDAC) were tested for EGFR, KRAS and BRAF mutations based on the relevance to tumour subtype. The quantification values (Cq values) and mutation detection status were compared between LBC samples and routine formalin-fixed paraffin-embedded (FFPE) clot samples. ROSE LBC samples (n = 54) showed a higher yield of well-preserved tumour and wild type (WT) DNA, demonstrated by lower quantification cycles, no false positives or false negatives, and a higher sensitivity for low allele frequency mutations when compared with FFPE clot samples. The Biocartis Idylla™ provides highly sensitive, reliable and rapid testing for LBC samples for the detection of EFGR and KRAS mutations. BRAF mutations were not detected in the participant cohort; however, all LBC WT BRAF results correlated with the results from the FFPE clot samples. Access to rapid molecular testing using LBC samples can detect the most frequent driver mutations closer to the time of diagnosis, enabling the selection of the most effective first-line targeted therapy sooner, reducing delays or side effects from suboptimal treatments, patient anxiety and costs to healthcare systems, whilst improving patient outcomes.
A Study of Arca noae (Linnaeus, 1758) in Elounda Bay, Crete, Eastern Mediterranean
Authors: Skouradakis Grigorios , Dounas Costas , Androulakis Dimitrios N. , Papadaki Maria , Koulouri Panayota , Pavlidis Michail
Published: May 2022

There is growing interest about marine bivalve aquaculture globally, not only for the market value of the goods produced, but also for the socio-economic and environmental services that this activity can provide. Arca noae is an endemic Mediterranean bivalve of commercial value, whose previously undescribed population in Elounda Bay we studied in terms of its structure and reproduction, while constructing a timeseries of the basic environmental parameters of the bay, thus, gaining fundamental knowledge for the potential future exploitation of the species in the area. We found a variable spatial distribution of arks in the study area, with local high peaks in the population density, consisting of smaller size individuals, in comparison to other areas. Because of protandry of the species, human pressure on this population could have a strong negative effect, by targeting the limited numbers of large females in the study area. The reproduction pattern was similar to the reports from other Mediterranean locations. The abiotic conditions in Elounda Bay differed from those in the adjacent coastal zone, confirming that the Bay is a unique semi-enclosed marine area in the island of Crete.
The Entomopathogenic Fungus Metarhizium anisopliae Affects Feeding Preference of Sogatella furcifera and Its Potential Targets’ Identification
Authors: Wang Yirong , Han Lijuan , Xia Yuxian , Xie Jiaqin
Published: May 2022

The rice planthopper Sogatella furcifera is a unique vector of the southern rice black-streaked dwarf virus (SRBSDV). The feeding behavior of S. furcifera should directly affect the diffusion of this virus. In this study, we noted that the infection of Metarhizium anisopliae CQMa421 on S. furcifera disturbed the feeding behavior of this pest to SRBSDV-infected rice, from preference to non-preference. Then, we further investigated the potential targets of M. anisopliae CQMa421 on the feeding behavior of S. furcifera after 0 h, 24 h and 48 h of infection by transcriptomic analysis via Illumina deep sequencing. A total of 93.27 GB of data was collected after sequencing, from which 91,125 unigenes were annotated, including 75 newly annotated genes. There were 1380 vs. 2187 and 137 vs. 106 upregulated and downregulated differentially expressed genes (DEGs) detected at 24 h and 48 h, respectively. The biological functions and associated metabolic processes of these genes were determined with the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The results suggested that major of DEGs are involved in energy metabolism, biosynthesis, immune response, the FoxO signaling pathway, the MAPK signaling pathway and apoptosis in response to the fungal infection. Noteworthily, several olfactory-related genes, including odorant receptors and odorant binding proteins, were screened from these differentially expressed genes, which played critical roles in regulating the olfactory behavior of insects. Taken together, these results provide new insights for understanding the molecular mechanisms underlying fungus and host insect interaction, especially for olfactory behavior regulated by fungus.
Can Lung Imaging Scores and Clinical Variables Predict Severe Course and Fatal Outcome in COVID-19 Pneumonia Patients? A Single-Center Observational Study
Authors: Skopljanac Ivan , Pavicic Ivelja Mirela , Budimir Mrsic Danijela , Barcot Ognjen , Jelicic Irena , Domjanovic Josipa , Dolic Kresimir
Published: May 2022

COVID-19 prediction models mostly consist of combined clinical features, laboratory parameters, and, less often, chest X-ray (CXR) findings. Our main goal was to propose a prediction model involving imaging methods, specifically ultrasound. This was a single-center, retrospective cohort observational study of patients admitted to the University Hospital Split from November 2020 to May 2021. Imaging protocols were based on the assessment of 14 lung zones for both lung ultrasound (LUS) and computed tomography (CT), correlated to a CXR score assessing 6 lung zones. Prediction models for the necessity of mechanical ventilation (MV) or a lethal outcome were developed by combining imaging, biometric, and biochemical parameters. A total of 255 patients with COVID-19 pneumonia were included in the study. Four independent predictors were added to the regression model for the necessity of MV: LUS score, day of the illness, leukocyte count, and cardiovascular disease (χ2 = 29.16, p < 0.001). The model accurately classified 89.9% of cases. For the lethal outcome, only two independent predictors contributed to the regression model: LUS score and patient’s age (χ2 = 48.56, p < 0.001, 93.2% correctly classified). The predictive model identified four key parameters at patient admission which could predict an adverse outcome.