bluuebunny/crossref_metadata_2025 huggingface dataset:
Elastic Simulation of Joints with Particle-Based Fluid
Authors: Sung Su-Kyung , Han Sang-Won , Shin Byeong-Seok
Published: July 2021

Skinning, which is used in skeletal simulations to express the human body, has been weighted between bones to enable muscle-like motions. Weighting is not a form of calculating the pressure and density of muscle fibers in the human body. Therefore, it is not possible to express physical changes when external forces are applied. To express a similar behavior, an animator arbitrarily customizes the weight values. In this study, we apply the kernel and pressure-dependent density variations used in particle-based fluid simulations to skinning simulations. As a result, surface tension and elasticity between particles are applied to muscles, indicating realistic human motion. We also propose a tension yield condition that reflects Tresca’s yield condition, which can be easily approximated using the difference between the maximum and minimum values of the principal stress to simulate the tension limit of the muscle fiber. The density received by particles in the kernel is assumed to be the principal stress. The difference is calculated by approximating the moment of greatest force to the maximum principal stress and the moment of least force to the minimum principal stress. When the density of a particle increases beyond the yield condition, the object is no longer subjected to force. As a result, one can express realistic muscles.
Detection of Carrageenan in Cheese Using Lectin Histochemistry
Authors: Bartlová Marie , Pospiech Matej , Javůrková Zdeňka , Tremlová Bohuslava
Published: July 2021

Carrageenan is a substance widely used as an additive in the food industry. Among other things, it is often added to processed cheese, where it has a positive effect on texture. Processing of such cheese involves grinding, melting and emulsifying the cheese. There is currently no official method by which carrageenan can be detected in foodstuffs, but there are several studies describing its negative health impact on consumers. Lectin histochemistry is a method that is used mainly in medical fields, but it has great potential to be used in food analysis as well. It has been demonstrated that lectin histochemistry can be used to detect carrageenan in processed cheese by Human Inspection and Computer-Assisted Analysis (CIE L*a*b*). The limit of detection (LoD) was established at 100 mg kg−1 for Human Inspection and 43.64 for CIE L*a*b*. The CIE L*a*b* results indicate that Computer-Assisted Analysis may be an appropriate alternative to Human Inspection. The most suitable parameter for Computer-Assisted Analysis was the b* parameter in the CIE L*a*b* color space.
Respite for SMEs: A Systematic Review of Socio-Technical Cybersecurity Metrics
Authors: van Haastrecht Max , Yigit Ozkan Bilge , Brinkhuis Matthieu , Spruit Marco
Published: July 2021

Cybersecurity threats are on the rise, and small- and medium-sized enterprises (SMEs) struggle to cope with these developments. To combat threats, SMEs must first be willing and able to assess their cybersecurity posture. Cybersecurity risk assessment, generally performed with the help of metrics, provides the basis for an adequate defense. Significant challenges remain, however, especially in the complex socio-technical setting of SMEs. Seemingly basic questions, such as how to aggregate metrics and ensure solution adaptability, are still open to debate. Aggregation and adaptability are vital topics to SMEs, as they require the assimilation of metrics into an actionable advice adapted to their situation and needs. To address these issues, we systematically review socio-technical cybersecurity metric research in this paper. We analyse aggregation and adaptability considerations and investigate how current findings apply to the SME situation. To ensure that we provide valuable insights to researchers and practitioners, we integrate our results in a novel socio-technical cybersecurity framework geared towards the needs of SMEs. Our framework allowed us to determine a glaring need for intuitive, threat-based cybersecurity risk assessment approaches for the least digitally mature SMEs. In the future, we hope our framework will help to offer SMEs some deserved respite by guiding the design of suitable cybersecurity assessment solutions.
Research on Kinematic Parameters of Multiple Gait Pattern Transitions
Authors: Guo Chaoyue , Liu Yali , Song Qiuzhi , Liu Shuting
Published: July 2021

Gait recognition technology is the key technology in the field of exoskeletons. In the current research of gait recognition technology, there is less focus on the recognition of the transition between gait patterns. This study aims to determine which kinematic parameters have significant differences in the transitions (between level and stair walking and between level and ramp walking) of different gait patterns, to determine whether these parameters change differently in different gait pattern transitions, and the order the significant differences occur through a comparative analysis of various kinematic parameters between the transition stride and the before stride in the former pattern. We analyzed 18 parameters concerning both lower limbs and trunk. We compared each time point of the transition strides to the corresponding time points of the before stride using a series of two-sample t-tests, and we then evaluated the difference between the transition stride and the before stride based upon the number of time points within the gait cycle that were statistically different. We found that the sagittal plane angular velocity and the angular acceleration of all joints and the resultant velocity of the thigh and shank of the leading limb had significant differences in the process of transition; the sagittal plane angular velocity of all joints of the trailing limb and the velocity of the trunk in the coronary axis direction also showed a significant difference. The angular acceleration of all joints, the sagittal plane angular velocity of the ankle joint of the leading limb, and the acceleration of the trunk in the coronal axis direction showed a difference in the early stage of the transition. In general, the leading limb had a significant difference earlier than the trailing limb, and the acceleration parameters changed earlier than the velocity parameters. These parameters showed different combinations of changes in the transition of different gait patterns, and the changes in these parameters reflected different gait pattern transitions. Therefore, we believe that the results of this study can provide a reference for the gait pattern transition recognition of wearable exoskeletons.
The Administration of Probiotics against Hypercholesterolemia: A Systematic Review
Authors: Sivamaruthi Bhagavathi Sundaram , Bharathi Muruganantham , Kesika Periyanaina , Suganthy Natarajan , Chaiyasut Chaiyavat
Published: July 2021

Hypercholesterolemia is a key factor in the progression of atherosclerosis and cardiovascular disease (CVD). CVD is a significant public health concern with a high death rate. Some of the main factors linked to CVD include genetics and lifestyle. Dyslipidemia has been one of the factors related to the onset of several CVD-related diseases. Several clinicopathological studies have shown a correlation between high cholesterol levels, particularly low-density lipoprotein cholesterol (LDL-c), and CVD development. Probiotics have received a lot of attention for various beneficial effects, especially their ability to reduce blood cholesterol in humans. Probiotics were shown in several investigations to affect hypercholesterolemia by influencing cholesterol biosynthesis. The current review focuses on the human dietary interventions with probiotics and their effects on CVD risk factors and hypercholesterolemia. The outcomes are debatable and consider various parameters such as probiotic strain, dosing frequency, therapeutic response, dietary changes, and so forth. As a result, probiotics have the propensity to become dietary supplements in moderate/severe hypercholesterolemic patients, which significantly reduces the CVD risk.
Why COVID-19 Will Not Change the Global Art Market
Authors: Tuszko Feliks
Published: July 2021

This article investigates the valuation of artworks during the COVID-19 pandemic. It examines how art market participants employ fictional expectations of the future to stabilize valuations during uncertain times. A total of 86 forecasts originating from both the center and periphery of the global art market were analyzed. Taking a meta-analytic approach, focus was placed on what each analysis predicts, how it constructs the future it purports to know, and how the expected value of artworks and methods for their purchase are justified. This uncovered the paradoxical reality of art market forecasts—their authors are convinced that the power of crisis could reformulate the art market, but their conclusions do not assume the possibility of real change. Further, the argument is made that speculation about the future is at the core of today’s art economy. Therefore, in a crisis, market participants conservatively orient themselves toward artworks that already have established value.
Adaptive 3D Visual Servoing of a Scara Robot Manipulator with Unknown Dynamic and Vision System Parameters
Authors: Sarapura Jorge Antonio , Roberti Flavio , Carelli Ricardo
Published: July 2021

In the present work, we develop an adaptive dynamic controller based on monocular vision for the tracking of objects with a three-degrees of freedom (DOF) Scara robot manipulator. The main characteristic of the proposed control scheme is that it considers the robot dynamics, the depth of the moving object, and the mounting of the fixed camera to be unknown. The design of the control algorithm is based on an adaptive kinematic visual servo controller whose objective is the tracking of moving objects even with uncertainties in the parameters of the camera and its mounting. The design also includes a dynamic controller in cascade with the former one whose objective is to compensate the dynamics of the manipulator by generating the final control actions to the robot even with uncertainties in the parameters of its dynamic model. Using Lyapunov’s theory, we analyze the two proposed adaptive controllers for stability properties, and, through simulations, the performance of the complete control scheme is shown.
The Treasury Chest of Text Mining: Piling Available Resources for Powerful Biomedical Text Mining
Authors: Rosário-Ferreira Nícia , Marques-Pereira Catarina , Pires Manuel , Ramalhão Daniel , Pereira Nádia , Guimarães Victor , Santos Costa Vítor , Moreira Irina Sousa
Published: July 2021

Text mining (TM) is a semi-automatized, multi-step process, able to turn unstructured into structured data. TM relevance has increased upon machine learning (ML) and deep learning (DL) algorithms’ application in its various steps. When applied to biomedical literature, text mining is named biomedical text mining and its specificity lies in both the type of analyzed documents and the language and concepts retrieved. The array of documents that can be used ranges from scientific literature to patents or clinical data, and the biomedical concepts often include, despite not being limited to genes, proteins, drugs, and diseases. This review aims to gather the leading tools for biomedical TM, summarily describing and systematizing them. We also surveyed several resources to compile the most valuable ones for each category.
Delivery of Bioactive Compounds to Improve Skin Cell Responses on Microfabricated Electrospun Microenvironments
Authors: Ramos-Rodriguez David H. , MacNeil Sheila , Claeyssens Frederik , Ortega Asencio Ilida
Published: July 2021

The introduction of microtopographies within biomaterial devices is a promising approach that allows one to replicate to a degree the complex native environment in which human cells reside. Previously, our group showed that by combining electrospun fibers and additive manufacturing it is possible to replicate to an extent the stem cell microenvironment (rete ridges) located between the epidermal and dermal layers. Our group has also explored the use of novel proangiogenic compounds to improve the vascularization of skin constructs. Here, we combine our previous approaches to fabricate innovative polycaprolactone fibrous microtopographical scaffolds loaded with bioactive compounds (2-deoxy-D-ribose, 17β-estradiol, and aloe vera). Metabolic activity assay showed that microstructured scaffolds can be used to deliver bioactive agents and that the chemical relation between the working compound and the electrospinning solution is critical to replicate as much as possible the targeted morphologies. We also reported that human skin cell lines have a dose-dependent response to the bioactive compounds and that their inclusion has the potential to improve cell activity, induce blood vessel formation and alter the expression of relevant epithelial markers (collagen IV and integrin β1). In summary, we have developed fibrous matrixes containing synthetic rete-ridge-like structures that can deliver key bioactive compounds that can enhance skin regeneration and ultimately aid in the development of a complex wound healing device.
Tissue-Nonspecific Alkaline Phosphatase (TNAP) as the Enzyme Involved in the Degradation of Nucleotide Analogues in the Ligand Docking and Molecular Dynamics Approaches
Authors: Madaj Rafal , Gostynski Bartlomiej , Pawlowska Roza , Chworos Arkadiusz
Published: July 2021

Tissue-nonspecific alkaline phosphatase (TNAP) is known to be involved in the degradation of extracellular ATP via the hydrolysis of pyrophosphate (PPi). We investigated, using three different computational methods, namely molecular docking, thermodynamic integration (TI) and conventional molecular dynamics (MD), whether TNAP may also be involved in the utilization of β,γ-modified ATP analogues. For that, we analyzed the interaction of bisphosphonates with this enzyme and evaluated the obtained structures using in silico studies. Complexes formed between pyrophosphate, hypophosphate, imidodiphosphate, methylenediphosphonic acid monothiopyrophosphate, alendronate, pamidronate and zoledronate with TNAP were generated and analyzed based on ligand docking, molecular dynamics and thermodynamic integration. The obtained results indicate that all selected ligands show high affinity toward this enzyme. The forming complexes are stabilized through hydrogen bonds, electrostatic interactions and van der Waals forces. Short- and middle-term molecular dynamics simulations yielded very similar affinity results and confirmed the stability of the protein and its complexes. The results suggest that certain effectors may have a significant impact on the enzyme, changing its properties.
TGF-β Increases MFGE8 Production in Myeloid-Derived Suppressor Cells to Promote B16F10 Melanoma Metastasis
Authors: Lim Heejin , Yang Taewoo , Lee Wongeun , Park Sung-Gyoo
Published: July 2021

There is growing evidence that myeloid-derived suppressor cells (MDSCs) are directly involved in all stages leading to metastasis. Many mechanisms for this effect have been proposed, but mechanisms of coregulation between tumor cells and MDSCs remain poorly understood. In this study, we demonstrate that MDSCs are a source of milk fat globule-epidermal growth factor (EGF) factor 8 (MFGE8), which is known to be involved in tumor metastasis. Interestingly, TGF-β, an abundant cytokine in the tumor microenvironment (TME), increased MFGE8 production by MDSCs. In addition, co-culturing MDSCs with B16F10 melanoma cells increased B16F10 cell migration, while MFGE8 neutralization decreased their migration. Taken together, these findings suggest that MFGE8 is an important effector molecule through which MDSCs promote tumor metastasis, and the TME positively regulates MFGE8 production by MDSCs through TGF-β.
Cognitive Reserve, Executive Function, and Memory in Parkinson’s Disease
Authors: Loftus Andrea M. , Gasson Natalie , Lopez Nicole , Sellner Michelle , Reid Carly , Cocks Naomi , Lawrence Blake J.
Published: July 2021

Cognitive impairment is acknowledged as a feature of Parkinson’s disease (PD), and the most common cognitive declines are in executive function (EF) and memory. Cognitive reserve (CR) may offer some protection against cognitive dysfunction in PD. The present study used two proxies of CR (years of education, premorbid IQ) to examine the relationship between CR and (i) EF (ii) memory in a large PD sample (n = 334). Two aspects of EF were examined, including verbal fluency and planning skills. Two aspects of verbal memory were examined, including immediate recall and delayed recall. For EF, both CR proxies significantly predicted verbal fluency, but only years of education predicted planning skills. Years of education significantly predicted immediate recall, but premorbid IQ did not. Neither CR proxy predicted delayed recall. These findings suggest that CR, in particular years of education, may contribute to EF and memory function in those with PD. A key finding of this study is the varying contribution of CR proxies to different aspects of the same cognitive domain. The findings indicate that using only one proxy has the potential to be misleading and suggest that when testing the relationship between CR and cognition, studies should include tasks that measure different aspects of the cognitive domain(s) of interest.
Cytoplasmic Localization of RXRα Determines Outcome in Breast Cancer
Authors: Zati zehni Alaleh , Batz Falk , Cavaillès Vincent , Sixou Sophie , Kaltofen Till , Keckstein Simon , Heidegger Helene Hildegard , Ditsch Nina , Mahner Sven , Jeschke Udo , Vilsmaier Theresa
Published: July 2021

The aim of this retrospective study was to assess the prognostic value of cytoplasmic versus nuclear RXRα expression in breast cancer (BC) tissue samples and to correlate the results with clinicopathological parameters. In 319 BC patients, the expression of RXRα was evaluated via immunohistochemistry. Prognosis-determining aspects were calculated through uni- and multivariate analyses. Correlation analysis revealed a trend association with nuclear RXRα expression regarding an improved overall survival (OS) (p = 0.078), whereas cytoplasmic RXRα expression was significantly correlated with a poor outcomes in terms of both OS (p = 0.038) and disease-free survival (DFS) (p = 0.037). Strengthening these results, cytoplasmic RXRα was found to be an independent marker for DFS (p = 0.023), when adjusted to clinicopathological parameters, whereas nuclear RXRα expression was positively associated with lower TNM-staging, i.e., pT (p = 0.01), pN (p = 0.029) and pM (p = 0.001). Additionally, cytoplasmic RXRα expression was positively associated with a higher histopathological tumor grading (p = 0.02). Cytoplasmic RXRα was also found to be a negative prognosticator for Her-2neu-negative and triple-negative patients. Altogether, these findings support the hypothesis that the subcellular localization of RXRα plays an important role in carcinogenesis and the prognosis of BC. The expression of cytoplasmic RXRα is correlated with a more aggressive course of the disease, whereas nuclear RXRα expression appears to be a protective factor. These data may help to identify high-risk BC subgroups in order to find possible specific options in targeted tumor therapy.
On-Treatment Albumin-Bilirubin Grade: Predictor of Response and Outcome of Sorafenib-Regorafenib Sequential Therapy in Patients with Unresectable Hepatocellular Carcinoma
Authors: Wang Hung-Wei , Chuang Po-Heng , Su Wen-Pang , Kao Jung-Ta , Hsu Wei-Fan , Lin Chun-Che , Huang Guan-Tarn , Lin Jaw-Town , Lai Hsueh-Chou , Peng Cheng-Yuan
Published: July 2021

In the RESORCE study, regorafenib after sorafenib therapy improved survival in patients with advanced hepatocellular carcinoma (HCC). In total, 88 patients with unresectable HCC who received sorafenib–regorafenib sequential therapy were enrolled. The objective response rate and disease control rate were 19.3% and 48.9%, respectively, for regorafenib therapy (median duration: 8.1 months). Median progression-free survival (PFS) after regorafenib therapy was 4.2 months (95% CI: 3.2–5.1). The median overall survival (OS; from initiation of either sorafenib or regorafenib) was not reached in this cohort. According to multivariate Cox regression analyses, albumin-bilirubin (ALBI) grade at the initiation of regorafenib therapy is an independent predictor of disease control, PFS, and OS. Moreover, the combination of ALBI grade 2 and an alpha-fetoprotein (AFP) level of ≥20 ng/mL was an independent predictor of PFS (hazard ratio (HR): 3.088, 95% CI: 1.704–5.595; p < 0.001) for regorafenib therapy, and OS for both regorafenib (HR: 3.783, 95% CI: 1.316–10.88; p = 0.014) and sorafenib–regorafenib sequential (HR: 4.603, 95% CI: 1.386–15.29; p = 0.013) therapy. A combination of ALBI grade and AFP level can be used to stratify patients with unresectable HCC by PFS and OS probability for sorafenib–regorafenib sequential therapy.
From Distress Screening to Uptake: An Italian Multicenter Study of Cancer Patients
Authors: Meggiolaro Elena , De Padova Silvia , Ruffilli Federica , Bertelli Tatiana , Bragagni Marina , Prati Sabrina , Pisotti Lidia , Massa Ilaria , Foca Flavia , Tamberi Stefano , De Giorgi Ugo , Zerbinati Luigi , Tiberto Elisa , Grassi Luigi
Published: July 2021

Introduction: Little consideration is given to the referral and uptake of available supportive services after distress screening. However, identifying the reasons for accepting or refusing help is mandatory for implementing a screening policy. The present study explored the practical usefulness of and potential barriers to the application of distress management. Methods: 406 cancer patients were consecutively selected and asked to complete the Distress Thermometer (DT) and Problem Check List (PL). All patients with a DT score ≥6 were invited for a post-DT telephone interview with a trained psychologist. Results: The 112 patients who refused to take part were more often older, retired, at a more advanced stage of illness, and with no previous experience of psychological intervention with respect to those who accepted. Of the 78 patients with a score ≥6 who were referred to the Psycho-Oncology Service, 65.4% accepted the telephone interview. Twenty-two patients rejected the initial invitation immediately for various reasons including logistic difficulties, physical problems, and feeling embarrassed about opening up to a psychologist. Conclusions: Our study confirms that screening per sé is insufficient to deal with the problem of distress and that more emphasis should be placed on implementing referral and treatment.
Glioblastomas within the Subventricular Zone Are Region-Specific Enriched for Mesenchymal Transition Markers: An Intratumoral Gene Expression Analysis
Authors: Dalemans Diana J. Z. , Berendsen Sharon , Draaisma Kaspar , Robe Pierre A. , Snijders Tom J.
Published: July 2021

Background: Involvement of the subventricular zone (SVZ) in glioblastoma is associated with poor prognosis and is associated with specific tumor-biological characteristics. The SVZ microenvironment can influence gene expression in glioblastoma cells in preclinical models. We aimed to investigate whether the SVZ microenvironment has any influence on intratumoral gene expression patterns in glioblastoma patients. Methods: The publicly available Ivy Glioblastoma database contains clinical, radiological and whole exome sequencing data from multiple regions from resected glioblastomas. SVZ involvement of the various tissue samples was evaluated on MRI scans. In tumors that contacted the SVZ, we performed gene expression analyses and gene set enrichment analyses to compare gene (set) expression in tumor regions within the SVZ to tumor regions outside the SVZ. We also compared these samples to glioblastomas that did not contact the SVZ. Results: Within glioblastomas that contacted the SVZ, tissue samples within the SVZ showed enrichment of gene sets involved in (epithelial-)mesenchymal transition, NF-κB and STAT3 signaling, angiogenesis and hypoxia, compared to the samples outside of the SVZ region from the same tumors (p < 0.05, FDR < 0.25). Comparison of glioblastoma samples within the SVZ region to samples from tumors that did not contact the SVZ yielded similar results. In contrast, we observed no differences when comparing the samples outside of the SVZ from SVZ-contacting glioblastomas with samples from glioblastomas that did not contact the SVZ at all. Conclusion: Glioblastoma samples in the SVZ region are enriched for increased (epithelial-)mesenchymal transition and angiogenesis/hypoxia signaling, possibly mediated by the SVZ microenvironment.
Relevance of Polymorphic KIR and HLA Class I Genes in NK-Cell-Based Immunotherapies for Adult Leukemic Patients
Authors: Dubreuil Léa , Chevallier Patrice , Retière Christelle , Gagne Katia
Published: July 2021

Since the mid-1990s, the biology and functions of natural killer (NK) cells have been deeply investigated in healthy individuals and in people with diseases. These effector cells play a particularly crucial role after allogeneic hematopoietic stem-cell transplantation (HSCT) through their graft-versus-leukemia (GvL) effect, which is mainly mediated through polymorphic killer-cell immunoglobulin-like receptors (KIRs) and their cognates, HLA class I ligands. In this review, we present how KIRs and HLA class I ligands modulate the structural formation and the functional education of NK cells. In particular, we decipher the current knowledge about the extent of KIR and HLA class I gene polymorphisms, as well as their expression, interaction, and functional impact on the KIR+ NK cell repertoire in a physiological context and in a leukemic context. In addition, we present the impact of NK cell alloreactivity on the outcomes of HSCT in adult patients with acute leukemia, as well as a description of genetic models of KIRs and NK cell reconstitution, with a focus on emergent T-cell-repleted haplo-identical HSCT using cyclosphosphamide post-grafting (haplo-PTCy). Then, we document how the immunogenetics of KIR/HLA and the immunobiology of NK cells could improve the relapse incidence after haplo-PTCy. Ultimately, we review the emerging NK-cell-based immunotherapies for leukemic patients in addition to HSCT.
Reactive Oxygen Species: A Promising Therapeutic Target for SDHx-Mutated Pheochromocytoma and Paraganglioma
Authors: Hadrava Vanova Katerina , Yang Chunzhang , Meuter Leah , Neuzil Jiri , Pacak Karel
Published: July 2021

Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors derived from neural crest cells. Germline variants in approximately 20 PHEO/PGL susceptibility genes are found in about 40% of patients, half of which are found in the genes that encode succinate dehydrogenase (SDH). Patients with SDH subunit B (SDHB)-mutated PHEO/PGL exhibit a higher likelihood of developing metastatic disease, which can be partially explained by the metabolic cell reprogramming and redox imbalance caused by the mutation. Reactive oxygen species (ROS) are highly reactive molecules involved in a multitude of important signaling pathways. A moderate level of ROS production can help regulate cellular physiology; however, an excessive level of oxidative stress can lead to tumorigenic processes including stimulation of growth factor-dependent pathways and the induction of genetic instability. Tumor cells effectively exploit antioxidant enzymes in order to protect themselves against harmful intracellular ROS accumulation, which highlights the essential balance between ROS production and scavenging. Exploiting ROS accumulation can be used as a possible therapeutic strategy in ROS-scavenging tumor cells. Here, we focus on the role of ROS production in PHEO and PGL, predominantly in SDHB-mutated cases. We discuss potential strategies and approaches to anticancer therapies by enhancing ROS production in these difficult-to-treat tumors.
How about Levetiracetam in Glioblastoma? An Institutional Experience and Meta-Analysis
Authors: Jabbarli Ramazan , Ahmadipour Yahya , Rauschenbach Laurèl , Santos Alejandro N. , Darkwah Oppong Marvin , Pierscianek Daniela , Quesada Carlos M. , Kebir Sied , Dammann Philipp , Guberina Nika , Scheffler Björn , Kaier Klaus , Stuschke Martin , Sure Ulrich , Wrede Karsten H.
Published: July 2021

Despite multimodal treatment, the prognosis of patients with glioblastoma (GBM) remains poor. Previous studies showed conflicting results on the effect of antiepileptic drugs (AED) on GBM survival. We investigated the associations of different AED with overall survival (OS) and progression-free survival (PFS) in a large institutional GBM cohort (n = 872) treated January 2006 and December 2018. In addition, we performed a meta-analysis of previously published studies, including this study, to summarize the evidence on the value of AED for GBM prognosis. Of all perioperatively administered AED, only the use of levetiracetam (LEV) was associated with longer OS (median: 12.8 vs. 8.77 months, p < 0.0001) and PFS (7 vs. 4.5 months, p = 0.001). In the multivariable analysis, LEV was independently associated with longer OS (aHR = 0.74, p = 0.017) and PFS (aHR = 0.68, p = 0.008). In the meta-analysis with 5614 patients from the present and seven previously published studies, outcome benefit for OS (HR = 0.83, p = 0.02) and PFS (HR = 0.77, p = 0.02) in GBM individuals with LEV was confirmed. Perioperative treatment with LEV might improve the prognosis of GBM patients. We recommend a prospective randomized controlled trial addressing the efficacy of LEV in GBM treatment.
Shorter Leukocyte Telomere Length Is Associated with Worse Survival of Patients with Bladder Cancer and Renal Cell Carcinoma
Authors: Zheng Xi , Wezel Felix , Azoitei Anca , Meessen Sabine , Wang Wenya , Najjar Gregoire , Wang Xue , Kraus Johann M. , Kestler Hans A. , John Axel , Zengerling Friedemann , Bolenz Christian , Günes Cagatay
Published: July 2021

Background: Telomeres are protein–DNA complexes at the tips of linear chromosomes. They protect the DNA from end-to-end fusion and exonucleolytic degradation. Shortening of telomeric DNA during aging can generate dysfunctional telomeres, promoting tumorigenesis. More recent data indicate that both short and long telomeres of peripheral blood leukocyte (PBL) cells can serve as prognostic biomarkers for cancer risk and may be associated with survival of patients with solid cancers. Telomere length in PBL cells could also be a potential prognostic biomarker for survival in bladder cancer (BC) or renal cell carcinoma (RCC). Methods: The relative telomere length (RTL) of PBL cells was assessed in patients with BC (n = 144) and RCC (n = 144) by using qPCR. A control population of patients without malignant disease (NC, n = 73) was included for comparison. The correlation and association of RTL with histopathological parameters and overall survival (OS) were evaluated. Results: Patients with BC and RCC had significantly shorter telomeres compared to patients without malignant disease. Within the cancer cohorts, multivariate analysis revealed that short RTL is an independent predictor of worse survival in BC (p = 0.039) and RCC (p = 0.041). Conclusion: Patients with BC and RCC had significantly shorter telomeres compared to the normal population. Shorter RTL in BC and RCC was an independent predictor of reduced survival.
The Microbiome as a Potential Target for Therapeutic Manipulation in Pancreatic Cancer
Authors: Abdul Rahman Rozana , Lamarca Angela , Hubner Richard A. , Valle Juan W. , McNamara Mairéad G.
Published: July 2021

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is projected to be the second most common cause of cancer-related death by 2030, with an overall 5-year survival rate between 7% and 9%. Despite recent advances in surgical, chemotherapy, and radiotherapy techniques, the outcome for patients with PDAC remains poor. Poor prognosis is multifactorial, including the likelihood of sub-clinical metastatic disease at presentation, late-stage at presentation, absence of early and reliable diagnostic biomarkers, and complex biology surrounding the extensive desmoplastic PDAC tumour micro-environment. Microbiota refers to all the microorganisms found in an environment, whereas microbiome is the collection of microbiota and their genome within an environment. These organisms reside on body surfaces and within mucosal layers, but are most abundantly found within the gut. The commensal microbiome resides in symbiosis in healthy individuals and contributes to nutritive, metabolic and immune-modulation to maintain normal health. Dysbiosis is the perturbation of the microbiome that can lead to a diseased state, including inflammatory bowel conditions and aetiology of cancer, such as colorectal and PDAC. Microbes have been linked to approximately 10% to 20% of human cancers, and they can induce carcinogenesis by affecting a number of the cancer hallmarks, such as promoting inflammation, avoiding immune destruction, and microbial metabolites can deregulate host genome stability preceding cancer development. Significant advances have been made in cancer treatment since the advent of immunotherapy. The microbiome signature has been linked to response to immunotherapy and survival in many solid tumours. However, progress with immunotherapy in PDAC has been challenging. Therefore, this review will focus on the available published evidence of the microbiome association with PDAC and explore its potential as a target for therapeutic manipulation.
Epigenetic Reprogramming of Tumor-Associated Fibroblasts in Lung Cancer: Therapeutic Opportunities
Authors: Alcaraz Jordi , Ikemori Rafael , Llorente Alejandro , Díaz-Valdivia Natalia , Reguart Noemí , Vizoso Miguel
Published: July 2021

Lung cancer is the leading cause of cancer-related death worldwide. The desmoplastic stroma of lung cancer and other solid tumors is rich in tumor-associated fibroblasts (TAFs) exhibiting an activated/myofibroblast-like phenotype. There is growing awareness that TAFs support key steps of tumor progression and are epigenetically reprogrammed compared to healthy fibroblasts. Although the mechanisms underlying such epigenetic reprogramming are incompletely understood, there is increasing evidence that they involve interactions with either cancer cells, pro-fibrotic cytokines such as TGF-β, the stiffening of the surrounding extracellular matrix, smoking cigarette particles and other environmental cues. These aberrant interactions elicit a global DNA hypomethylation and a selective transcriptional repression through hypermethylation of the TGF-β transcription factor SMAD3 in lung TAFs. Likewise, similar DNA methylation changes have been reported in TAFs from other cancer types, as well as histone core modifications and altered microRNA expression. In this review we summarize the evidence of the epigenetic reprogramming of TAFs, how this reprogramming contributes to the acquisition and maintenance of a tumor-promoting phenotype, and how it provides novel venues for therapeutic intervention, with a special focus on lung TAFs.
Significance of RAS Mutations in Thyroid Benign Nodules and Non-Medullary Thyroid Cancer
Authors: Marotta Vincenzo , Bifulco Maurizio , Vitale Mario
Published: July 2021

Thyroid nodules are detected in up to 60% of people by ultrasound examination. Most of them are benign nodules requiring only follow up, while about 4% are carcinomas and require surgery. Malignant nodules can be diagnosed by the fine-needle aspiration cytology (FNAC), which however yields an indeterminate result in about 30% of the cases. Testing for RAS mutations has been proposed to refine indeterminate cytology. However, the new entity of non-invasive follicular thyroid neoplasm, considered as having a benign evolution and frequently carrying RAS mutations, is expected to lower the specificity of this mutation. The aggressive behavior of thyroid cancer with RAS mutations, initially reported, has been overturned by the recent finding of the cooperative role of TERT mutations. Although some animal models support the carcinogenic role of RAS mutations in the thyroid, evidence that adenomas harboring these mutations evolve in carcinomas is lacking. Their poor specificity and sensitivity make the clinical impact of RAS mutations on the management of thyroid nodules with indeterminate cytology unsatisfactory. Evidence suggests that RAS mutation-positive benign nodules demand a conservative treatment. To have a clinical impact, RAS mutations in thyroid malignancies need not to be considered alone but rather together with other genetic abnormalities in a more general context.
Pathophysiological Implications of Urinary Peptides in Hepatocellular Carcinoma
Authors: Bannaga Ayman , Metzger Jochen , Voigtländer Torsten , Pejchinovski Martin , Frantzi Maria , Book Thorsten , James Sean , Gopalakrishnan Kishore , Mischak Harald , Manns Michael P. , Arasaradnam Ramesh P.
Published: July 2021

Hepatocellular carcinoma (HCC) is known to be associated with protein alterations and extracellular fibrous deposition. We investigated the urinary proteomic profiles of HCC patients in this prospective cross sectional multicentre study. 195 patients were recruited from the UK (Coventry) and Germany (Hannover) between 1 January 2013 and 30 June 2019. Out of these, 57 were HCC patients with a background of liver cirrhosis (LC) and 138 were non-HCC controls; 72 patients with LC, 57 with non-cirrhotic liver disease and 9 with normal liver function. Analysis of the urine samples was performed by capillary electrophoresis (CE) coupled to mass spectrometry (MS). Peptide sequences were obtained and 31 specific peptide markers for HCC were identified and further integrated into a multivariate classification model. The peptide model demonstrated 79.5% sensitivity and 85.1% specificity (95% CI: 0.81–0.93, p < 0.0001) for HCC and 4.1-fold increased risk of death (95% CI: 1.7–9.8, p = 0.0005). Proteases potentially involved in HCC progression were mapped to the N- and C-terminal sequence motifs of the CE-MS peptide markers. In silico protease prediction revealed that kallikrein-6 (KLK6) elicits increased activity, whilst Meprin A subunit α (MEP1A) has reduced activity in HCC compared to the controls. Tissue expression of KLK6 and MEP1A was subsequently verified by immunohistochemistry.
Improved Sulfur Resistance of COMMERCIAl V2O5-WO3/TiO2 SCR Catalyst Modified by Ce and Cu
Authors: Li Huirong , Yi Xianfang , Miao Jifa , Chen Yanting , Chen Jinsheng , Wang Jinxiu
Published: July 2021

The accumulation of NH4HSO4 leads to the deactivation of commercial V2O5-WO3/TiO2 catalyst (VWTi) in practical application. The commercial catalyst is modified with 0.3 wt. % Ce and 0.05 wt. % Cu (donated as VWCeCuTi), and its sulfur resistance is noticeably improved. After loading 20 wt. % NH4HSO4, the NOx conversion of VWCeCuTi-S remains 40% at 250 °C, higher than that of VWTi-S (25%). Through a series of characterization analyses, it was found that the damaged surface areas and acid sites are the key factors for the deactivation of S-poisoned samples. However, surface-active oxygen and NO adsorption are increased by NH4HSO4 deposition, and the L–H mechanism is promoted over S-poisoned samples. Due to the interaction between V, Ce and Cu, the surface-active oxygen over VWCeCuTi-S is increased, and then NO adsorption is promoted. In addition, VWCeCuTi-S obtains a higher V5+ ratio and a better redox property than VWTi-S, which in turn accelerates the NH3-SCR reaction. More NO adsorption and encouraged reaction contribute to the better sulfur resistance of VWCeCuTi.
Efficient CO2 Electroreduction on Tin Modified Cuprous Oxide Synthesized via a One-Pot Microwave-Assisted Route
Authors: Zeng Juqin , Fontana Marco , Castellino Micaela , Sacco Adriano , Farkhondehfal M. Amin , Drago Filippo , Pirri Candido Fabrizio
Published: July 2021

Bimetallic copper-tin catalysts are considered cost-effective and suitable for large-scale electrochemical conversion of CO2 to valuable products. In this work, a class of tin (Sn) modified cuprous oxide (Cu2O) is simply synthesized through a one-pot microwave-assisted solvothermal method and thoroughly characterized by various techniques. Sn is uniformly distributed on the Cu2O crystals showing a cube-within-cube structure, and CuSn alloy phase emerges at high Sn contents. The atomic ratio of Cu to Sn is found to be crucially important for the selectivity of the CO2 reduction reaction, and a ratio of 11.6 leads to the optimal selectivity for CO. This electrode shows a high current density of 47.2 mA cm−2 for CO formation at −1.0 V vs. the reversible hydrogen electrode and also displays good CO selectivity of 80–90% in a wide potential range. In particular, considerable CO selectivity of 72–81% is achieved at relatively low overpotentials from 240 mV to 340 mV. During the long-term tests, satisfactory stability is observed for the optimal electrode in terms of both electrode activity and CO selectivity. The relatively low price, the fast and scalable synthesis, and the encouraging performance of the proposed material implies its good potential to be implemented in large-scale CO2 electrolyzers.
Role of NF-κB in Ageing and Age-Related Diseases: Lessons from Genetically Modified Mouse Models
Authors: García-García Verónica A. , Alameda Josefa P. , Page Angustias , Casanova María Llanos
Published: July 2021

Ageing is a complex process, induced by multifaceted interaction of genetic, epigenetic, and environmental factors. It is manifested by a decline in the physiological functions of organisms and associated to the development of age-related chronic diseases and cancer development. It is considered that ageing follows a strictly-regulated program, in which some signaling pathways critically contribute to the establishment and maintenance of the aged state. Chronic inflammation is a major mechanism that promotes the biological ageing process and comorbidity, with the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) as a crucial mediator of inflammatory responses. This, together with the finding that the activation or inhibition of NF-κB can induce or reverse respectively the main features of aged organisms, has brought it under consideration as a key transcription factor that acts as a driver of ageing. In this review, we focused on the data obtained entirely through the generation of knockout and transgenic mouse models of either protein involved in the NF-κB signaling pathway that have provided relevant information about the intricate processes or molecular mechanisms that control ageing. We have reviewed the relationship of NF-κB and premature ageing; the development of cancer associated with ageing and the implication of NF-κB activation in the development of age-related diseases, some of which greatly increase the risk of developing cancer.
Direct and Indirect Pathways of Variation in Length of Exposure to the Majority Language, Cognitive and Language Skills in Preschoolers’ Listening Narrative Comprehension
Authors: Dicataldo Raffaele , Roch Maja
Published: July 2021

Listening narrative comprehension, according to the theoretical framework of the multicomponent model for comprehension, involves numerous skills that interact dynamically between each other and have the potential to give rise to individual differences in comprehension. The purpose of the current work was to define a comprehensive and complete multicomponent model of listening narrative comprehension in preschool age. We investigated how variation in Length of Exposure to majority Language (i.e., how long children have been exposed to the Italian language), lower-order cognitive (WM, inhibitory control, attention shifting), language skills (receptive vocabulary, syntactic knowledge, rapid naming), and higher-order cognitive skills (inferences, TOM, knowledge of story-structure) are related to listening narrative comprehension in Italian of 111 preschool children (Mage = 61 months; SD = 6.8) growing in a monolingual or multilingual context. Structural equation modeling results showed that the model explained 60% variance in listening narrative comprehension in Italian of children aged four to six and predicted the outcome both through direct and mediated paths, coherently with the multicomponent model of comprehension.
Recipient-Specific Risk Factors Impairing Patient and Graft Outcome after Pediatric Liver Transplantation—Analysis of 858 Transplantations in 38 Years
Authors: Leiskau Christoph , Junge Norman , Pfister Eva-Doreen , Goldschmidt Imeke , Mutschler Frauke , Laue Tobias , Ohlendorf Johanna , Nasser Hamoud , Beneke Jan , Richter Nicolas , Vondran Florian , Baumann Ulrich
Published: July 2021

(1) Background and Aim: Despite excellent long-term results in pediatric liver transplantation (pLTx), mortality and graft loss still are to be diminished. We aim to describe time-dependent changes and long-term outcome of a large single-center pLTx cohort and to identify independent recipient-related risk factors impairing patient and graft survival. (2) Methods: This is a retrospective single-center study analyzing all pediatric liver transplants from 1983–2020. Risk factors for mortality and graft loss were identified by univariable and multi-linear regression analysis. (3) Results: We analyzed 858 liver transplantations in 705 pediatric patients. Five-year patient/graft survival increased from 60.9%/48.0% (1983–1992) to 97.5%/86.5% (OR = 12.5; p < 0.0001/OR = 6.5; p < 0.0001) (2014–2020). Indications changed significantly over time, with a higher proportion of patients being transplanted for malignancies and metabolic disease and indications of PFIC and α1AT-deficiency declining. The era of transplantation (log7.378/9.657; p < 0.0001) and indication of acute liver failure (log = 1.944/2.667; HR = 2.015/1.772; p = 0.0114/0.002) impairs patient/graft survival significantly in the multivariate analysis. Furthermore, patient survival is worsened by re-transplantation (log = 1.755; HR = 1.744; p = 0.0176) and prolonged waiting times in high-urgency status (log = 2.588; HR = 1.073; p = 0.0026), whereas the indication of biliary atresia improved outcome (log = 1.502; HR = 0.575; p = 0.0315). Graft survival was additionally impaired by pre-existing portal vein thrombosis (log = 1.482; HR = 2.016; p = 0.0330). (4) Conclusions: Despite more complex indications, patient and graft survival after pLTx continue to improve.. Acute liver failure remains the indication with poorest outcome, and listing for high urgency liver transplantation should be considered carefully and early to keep waiting time on HU list short. Furthermore, pre-transplant portal vein thrombosis should be prevented whenever possible to improve graft survival.
Fluoropyrimidine-Induced Severe Toxicities Associated with Rare DPYD Polymorphisms: Case Series from Saudi Arabia and a Review of the Literature
Authors: Bukhari Nedal , Alshangiti Abdulraheem , Tashkandi Emad , Algarni Mohammed , Al-Shamsi Humaid O. , Al-Khallaf Hamoud
Published: July 2021

Dihydropyrimidine dehydrogenase (DPD) is the major enzyme in the catabolism of 5-Fluorouracil (5-FU) and its prodrug capecitabine. We report cases from our institute with colorectal cancer who experienced severe toxicities to standard dose 5-FU based chemotherapy. DPYD gene sequencing revealed rare different polymorphisms that prompted dose adjustments of administered 5-FU and capecitabine. To our knowledge, this is the first case series looking at DPYD polymorphisms in the Saudi Arabian population.