bluuebunny/crossref_metadata_2025 huggingface dataset:
Monitoring the Hydration Process in Carbon Nanotube Reinforced Cement-Based Composites Using Nonlinear Elastic Waves
Authors: Tragazikis Ilias K. , Kordatou Theodoti Z. , Exarchos Dimitrios A. , Dalla Panagiota T. , Matikas Theodore E.
Published: February 2021

There is currently an increased need for associating construction material properties and behavior with the nature of their microstructure. One of the major issues in this context is the need for understanding the curing process in freshly poured cement-based materials. This is particularly important when nanoreinforcement materials, such as carbon nanotubes, are used to enhance the mechanical behavior and multifunctionality of the final structure. The solidification point, at which the state of liquid suspension transmutes to the solid state, is of particular interest since it greatly influences the load-bearing capacity of the cement-based material and its structural behavior at the long term. The main purpose of the present work is to develop a reliable method for monitoring the hydration process during the early stages of freshly poured cementitious composites enhanced with carbon nanotubes. This methodology is based on the use of nonlinear elastic waves. To achieve this goal, a combination of contact ultrasonics with noncontact optical detection was used. The detection method for evaluating the setting process is based on the assessment of higher-harmonic amplitudes of an ultrasonic wave, with a given frequency, propagating through the cementitious material. It was observed that the material nonlinearity changes significantly during the hardening process, compared to velocity or attenuation measurements which are based on linear acoustics. These changes were more noticeable as the concentration of carbon nanotubes in the cement matrix increases, indicating that higher harmonics are more susceptible to minute microstructural changes.
The Kinetics of Pollutant Removal through Biofiltration from Stormwater Containing Airport De-Icing Agents
Authors: Mielcarek Artur , Rodziewicz Joanna , Janczukowicz Wojciech , Ostrowska Kamila
Published: February 2021

The present study aimed to determine the kinetics of pollutant removal in biofilters with LECA filling (used as a buffer to prevent de-icing agents from being released into the environment with stormwater runoff). It demonstrated a significant effect of temperature and a C/N ratio on the rate of nitrification, denitrification, and organic compound removal. The nitrification rate was the highest (0.32 mg N/L·h) at 25 °C and C/N = 0.5, whereas the lowest (0.18 mg N/L·h) at 0 °C and C/N = 2.5 and 5.0. Though denitrification rate is mainly affected by the available quantity of organic substrate, it actually decreased as the C/N increased and was positively correlated with the temperature levels. Its value was found to be the highest (0.31 mg N/L·h) at 25 °C and C/N = 0.5, and the lowest (0.18 mg N/L·h) at 0 °C and C/N = 5.0. As the C/N increased, so did the content of organic compounds in the treated effluent. The lowest organic removal rates were noted for C/N = 0.5, ranging between 11.20 and 18.42 mg COD/L·h at 0 and 25 °C, respectively. The highest rates, ranging between 27.83 and 59.43 mg COD/L·h, were recorded for C/N = 0.5 at 0 and 25 °C, respectively.
Diurnal Variability of Surface Temperature over Lakes: Case Study for Lake Huron
Authors: Chen Wen , Pinker Rachel T. , Rivera Gerardo , Hook Simon
Published: February 2021

The significance of the diurnal variability of Lake Surface Temperature (LST) has been recognized; yet, its magnitude in terms of spatial and temporal variability is not well known. Attempts have been made to derive such information from satellites at a high spatial resolution; however, most have been made from polar orbiting satellites that sample only twice per day. We have developed an approach to derive such information from geostationary satellites at an hourly time scale and at a spatial resolution of about 5 km. The approach to derive LST uses the Radiative Transfer for TIROS Operational Vertical Sounder (TOVS) (RTTOV) model driven by the Modern-Era Retrospective analysis for Research and Applications (MERRA)-2 information. The methodology has been implemented over Lake Huron for about six years. We present the results of the evaluation against various independent satellite products and demonstrate that there is a strong diurnal variability in the skin temperature over the lake and that the lowest and highest values, as derived twice per day from polar orbiting satellites, may not represent the magnitude of the Diurnal Temperature Range (DTR).
Areal Probability of Precipitation in Moist Tropical Air Masses for the United States
Authors: Reesman Cade , Miller Paul , D’Antonio Rebecca , Gilmore Kevin , Schott Ben , Bannan Chris
Published: February 2021

Moist tropical (MT) air masses routinely host convective precipitation, including weakly forced thunderstorms (WFTs). These short-lived, isolated events present recurring forecasting challenges due to their spatially small footprints and seemingly erratic behavior in quiescent warm-season environments worldwide. In particular, their activity is difficult to accurately characterize via probability of precipitation (POP), a common forecast product for the general public. This study builds an empirical climatological POP distribution for MT days over the continental United States using Stage IV precipitation estimates. Stage IV estimates within MT air masses between May–September (i.e., the boreal warm season) 2002–2019 are masked into precipitation (≥0.25 mm) and nonprecipitation (<0.25 mm) areas and standardized by the number of MT days. POPs are higher when MT air masses are present. For the Southeast U.S., POP generally increases ~15% compared to the overall warm-season value. At 1800 UTC (1–2 PM LT) daily, POPs are confined to coastal areas and east-facing ridges, and advance inland by 2100 UTC (4–5 PM LT). Climatologically, ~50% of the warm-season precipitation in the Southern U.S. occurred in MT environments. This study emphasizes the need for better forecasting tools and climatological analyses of weakly forced environments.
Time-Dependent Pathological Changes in Hypoperfusion-Induced Abdominal Aortic Aneurysm
Authors: Kugo Hirona , Sukketsiri Wanida , Tanaka Hiroki , Fujishima Rena , Moriyama Tatsuya , Zaima Nobuhiro
Published: February 2021

Hypoperfusion due to vasa vasorum stenosis can cause wall hypoxia and abdominal aortic aneurysm (AAA) development. Even though hypoperfusion is an important contributor toward pathological changes in AAA, the correlation between hypoperfusion and AAA is not fully understood. In this study, a time-dependent semi-quantitative pathological analysis of hypoperfusion-induced aortic wall changes was performed to understand the mechanisms underlying the gradual degradation of the aortic wall leading to AAA formation. AAA-related factors evaluated in this study were grouped according to the timing of dynamic change, and five groups were formed as follows: first group: angiotensin II type 1 receptor, endothelin-1 (ET-1), and malondialdehyde (MDA); second group: matrix metalloproteinase (MMP)-2, -9, -12, M1 macrophages (Mac387+ cells), and monocyte chemotactic protein-1; third group: synthetic smooth muscle cells (SMCs); fourth group: neutrophil elastase, contractile SMCs, and angiotensinogen; and the fifth group: M2 macrophages (CD163+ cells). Hypoxia-inducible factor-1α, ET-1, MDA, and MMP-9 were colocalized with alpha-smooth muscle actin cells in 3 h, suggesting that hypoperfusion-induced hypoxia directly affects the activities of contractile SMCs in the initial stage of AAA. Time-dependent pathological analysis clarified the cascade of AAA-related factors. These findings provide clues for understanding complicated multistage pathologies in AAA.
Low Expression of miR-375 and miR-190b Differentiates Grade 3 Patients with Endometrial Cancer
Authors: Pietrus Miłosz , Seweryn Michał , Kapusta Przemysław , Wołkow Paweł , Pityński Kazimierz , Wątor Gracjan
Published: February 2021

Endometrial cancer (EC) is treated according to the stage and prognostic risk factors. Most EC patients are in the early stages and they are treated surgically. However some of them, including those with high grade (grade 3) are in the intermediate and high intermediate prognostic risk groups and may require adjuvant therapy. The goal of the study was to find differences between grades based on an miRNA gene expression profile. Tumor samples from 24 patients with grade 1 (n = 10), 2 (n = 7), and 3 (n = 7) EC were subjected to miRNA profiling using next generation sequencing. The results obtained were validated using the miRNA profile of 407 EC tumors from the external Cancer Genome Atlas (TCGA) cohort. We obtained sets of differentially expressed (DE) miRNAs with the largest amount between G2 to G1 (50 transcripts) and G3 to G1 (40 transcripts) patients. Validation of our results with external data (TCGA) gave us a reasonable gene overlap of which we selected two miRNAs (miR-375 and miR190b) that distinguish the high grade best from the low grade EC. Unsupervised clustering showed a high degree of heterogeneity within grade 2 samples. MiR-375 as well as 190b might be useful to create grading verification test for high grade EC. One of the possible mechanisms that is responsible for the high grade is modulation by virus of host morphology or physiology.
α-Ketoheterocycles Able to Inhibit the Generation of Prostaglandin E2 (PGE2) in Rat Mesangial Cells
Authors: Psarra Anastasia , Theodoropoulou Maria A. , Erhardt Martin , Mertiri Marina , Mantzourani Christiana , Vasilakaki Sofia , Magrioti Victoria , Huwiler Andrea , Kokotos George
Published: February 2021

Prostaglandin E2 (PGE2) is a key mediator of inflammation, and consequently huge efforts have been devoted to the development of novel agents able to regulate its formation. In this work, we present the synthesis of various α-ketoheterocycles and a study of their ability to inhibit the formation of PGE2 at a cellular level. A series of α-ketobenzothiazoles, α-ketobenzoxazoles, α-ketobenzimidazoles, and α-keto-1,2,4-oxadiazoles were synthesized and chemically characterized. Evaluation of their ability to suppress the generation of PGE2 in interleukin-1β plus forskolin-stimulated mesangial cells led to the identification of one α-ketobenzothiazole (GK181) and one α-ketobenzoxazole (GK491), which are able to suppress the PGE2 generation at a nanomolar level.
Protective Role of Sphingomyelin in Eye Lens Cell Membrane Model against Oxidative Stress
Authors: Ravandeh Mehdi , Coliva Giulia , Kahlert Heike , Azinfar Amir , Helm Christiane A. , Fedorova Maria , Wende Kristian
Published: February 2021

In the eye lens cell membrane, the lipid composition changes during the aging process: the proportion of sphingomyelins (SM) increases, that of phosphatidylcholines decreases. To investigate the protective role of the SMs in the lens cell membrane against oxidative damage, analytical techniques such as electrochemistry, high-resolution mass spectrometry (HR-MS), and atomic force microscopy (AFM) were applied. Supported lipid bilayers (SLB) were prepared to mimic the lens cell membrane with different fractions of PLPC/SM (PLPC: 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine). The SLBs were treated with cold physical plasma. A protective effect of 30% and 44% in the presence of 25%, and 75% SM in the bilayer was observed, respectively. PLPC and SM oxidation products were determined via HR-MS for SLBs after plasma treatment. The yield of fragments gradually decreased as the SM ratio increased. Topographic images obtained by AFM of PLPC-bilayers showed SLB degradation and pore formation after plasma treatment, no degradation was observed in PLPC/SM bilayers. The results of all techniques confirm the protective role of SM in the membrane against oxidative damage and support the idea that the SM content in lens cell membrane is increased during aging in the absence of effective antioxidant systems to protect the eye from oxidative damage and to prolong lens transparency.
Methyl Caffeate Isolated from the Flowers of Prunus persica (L.) Batsch Enhances Glucose-Stimulated Insulin Secretion
Authors: Lee Dahae , Qi Yutong , Kim Ranhee , Song Jungbin , Kim Hocheol , Kim Hyun Young , Jang Dae Sik , Kang Ki Sung
Published: February 2021

Phenolic compounds from natural products are considered effective enhancers of insulin secretion to prevent and treat type 2 diabetes (T2DM). The flowers of Prunus persica (L.) Batsch also contain many phenolic compounds. In this study, the extract of flowers of P. persica (PRPE) exhibited an insulin secretion effect in a glucose-stimulated insulin secretion (GSIS) assay, which led us to isolate and identify the bioactive compound(s) responsible for these effects. Compounds isolated from PRPE were screened for their efficacy in INS-1 rat pancreatic β-cells. Among them, caffeic acid (5), methyl caffeate (6), ferulic acid (7), chlorogenic acid (8), naringenin (11), nicotiflorin (12), and astragalin (13) isolated from PRPE increased GSIS without inducing cytotoxicity. Interestingly, the GSIS effect of methyl caffeate (6) as a phenolic compound was similar to gliclazide, an antidiabetic sulfonylurea drug. Western blot assay showed that methyl caffeate (6) enhanced the related signaling proteins of the activated pancreatic and duodenal homeobox-1 (PDX-1) and peroxisome proliferator-activated receptor-γ (PPAR-γ), but also the phosphorylation of the total insulin receptor substrate-2 (IRS-2), phosphatidylinositol 3-kinase (PI3K), and Akt, which influence β-cell function and insulin secretion. This study provides evidence that methyl caffeate (6) isolated from PRPE may aid in the management of T2DM.
The Interrelationships between Intestinal Permeability and Phlegm Syndrome and Therapeutic Potential of Some Medicinal Herbs
Authors: Park Junghyun , Choi Tae Joon , Kang Ki Sung , Choi Seo-Hyung
Published: February 2021

The gastrointestinal (GI) tract has an intriguing and critical role beyond digestion in both modern and complementary and alternative medicine (CAM), as demonstrated by its link with the immune system. In this review, we attempted to explore the interrelationships between increased GI permeability and phlegm, an important pathological factor in CAM, syndrome, and therapeutic herbs for two disorders. The leaky gut and phlegm syndromes look considerably similar with respect to related symptoms, diseases, and suitable herbal treatment agents, including phytochemicals even though limitations to compare exist. Phlegm may be spread throughout the body along with other pathogens via the disruption of the GI barrier to cause several diseases sharing some parts of symptoms, diseases, and mechanisms with leaky gut syndrome. Both syndromes are related to inflammation and gut microbiota compositions. Well-designed future research should be conducted to verify the interrelationships for evidence based integrative medicine to contribute to the promotion of public health. In addition, systems biology approaches should be adopted to explore the complex synergistic effects of herbal medicine and phytochemicals on conditions associated with phlegm and leaky gut syndromes.
Impact of SAfinamide on Depressive Symptoms in Parkinson’s Disease Patients (SADness-PD Study): A Multicenter Retrospective Study
Authors: Peña Esteban , Borrué Carmen , Mata Marina , Martínez-Castrillo Juan , Alonso-Canovas Araceli , Chico Juan , López-Manzanares Lydia , Llanero Marcos , Herreros-Rodríguez Jaime , Esquivel Alberto , Maycas-Cepeda Teresa , Ruíz-Huete Cristina
Published: February 2021

Background: We aimed to assess the effects of safinamide on depression, motor symptoms, and the serotonin syndrome related to its co-administration with antidepressants in patients with Parkinson’s disease (PD). Methods: We retrospectively analyzed the data of patients at 1 and 3 months of follow-up compared to baseline. Results: n = 82 (safinamide 50 mg = 22, 100 mg = 60, with antidepressants = 44). First, we found improvement in depression (Hamilton Depression Rating Scale: −6 ± 5.10 at 1 month and −7.27 ± 5.10 at 3 months, p < 0.0001; Patient Global Impression of Improvement Scale: 60.3% and 69.5% of patients at 1 and 3 months reported some improvement). Second, safinamide improved the daily life activities and motor symptoms/motor complications (Unified Parkinson’s Disease Rating Scale (UPDRS-II): −2.51 ± 6.30 and −2.47 ± 6.11 at 1 and 3 months, p < 0.0001; III: −3.58 ± 8.68 and −4.03 ± 8.95 at 1 and 3 months, p < 0.0001; IV: −0.61 ± 2.61 and −0.8 ± 2.53 at 1 and 3 months, p < 0.0001). Third, 7.31% and 8.53% of patients developed non-severe adverse events related to safinamide at 1 and 3 months. Serotonin syndrome was not observed in the patients treated with antidepressants; some isolated serotonin syndrome symptoms were reported. Conclusions: Safinamide could be useful for treating depression in PD; it was effective for motor symptoms and motor complications and safe even when co-administered with antidepressants.
Pain-Related Brain Connectivity Changes in Migraine: A Narrative Review and Proof of Concept about Possible Novel Treatments Interference
Authors: de Tommaso Marina , Vecchio Eleonora , Quitadamo Silvia Giovanna , Coppola Gianluca , Di Renzo Antonio , Parisi Vincenzo , Silvestro Marcello , Russo Antonio , Tedeschi Gioacchino
Published: February 2021

A neuronal dysfunction based on the imbalance between excitatory and inhibitory cortical-subcortical neurotransmission seems at the basis of migraine. Intercritical neuronal abnormal excitability can culminate in the bioelectrical phenomenon of Cortical Spreading Depression (CSD) with secondary involvement of the vascular system and release of inflammatory mediators, modulating in turn neuronal activity. Neuronal dysfunction encompasses the altered connectivity between the brain areas implicated in the genesis, maintenance and chronic evolution of migraine. Advanced neuroimaging techniques allow to identify changes in functional connectivity (FC) between brain areas involved in pain processes. Through a narrative review, we re-searched case-control studies on FC in migraine, between 2015 and 2020, by inserting the words migraine, fMRI, EEG, MEG, connectivity, pain in Pubmed. Studies on FC have shown that cortical processes, in the neurolimbic pain network, are likely to be prevalent for triggering attacks, in response to predisposing factors, and that these lead to a demodulation of the subcortical areas, at the basis of migraine maintenance. The link between brain dysfunction and peripheral interactions through the inhibition of CGRP, the main mediator of sterile migraine inflammation needs to be further investigated. Preliminary evidence could suggest that peripheral nerves inference at somatic and trigeminal levels, appears to change brain FC.
Occipital Nerve Stimulation for Pain Modulation in Drug-Resistant Chronic Cluster Headache
Authors: Díaz-de-Terán Javier , Membrilla Javier A. , Paz-Solís José , de Lorenzo Iñigo , Roa Javier , Lara-Lara Manuel , Gil-Martínez Alfonso , Díez-Tejedor Exuperio
Published: February 2021

Occipital nerve stimulation (ONS) is a surgical treatment proposed for drug-resistant chronic cluster headache (drCCH). Long-term series assessing its efficacy are scarce. We designed a retrospective observational study with consecutive sampling, evaluating the follow-up of 17 drCCH patients who underwent ONS. Our main endpoint was the reduction the rate of attacks per week. We also evaluated the pain intensity through the Visual Analogue Scale (VAS), patient overall perceived improvement and decrease in oral medication intake. After a median follow-up of 6.0 years (4.5–9.0), patients decreased from a median of 30 weekly attacks to 22.5 (5.6–37.5, p = 0.012), 7.5 at 1 year (p = 0.006) and 15.0 at the end of follow-up (p = 0.041). The VAS decreased from a median of 10.0 to 8.0 (p = 0.011) at three months, to 7.0 (p = 0.008) at twelve months and 7.0 (p = 0.003) at the end of the follow-up. A total of 23.5% had an overall perceived improvement of ≥70% at 3 months, 41.2% at 1 year and 27.8% at the end of follow-up. Reducing prophylactic oral medication was possible in 76.5% and it was stopped in 17.7%. Triptan use decreased in all the responder patients and 17.7% stopped its intake. A total of 41.2% presented mild adverse events. In conclusion, our long-term experience suggests that ONS could be an interesting option for drCCH-selected patients, as it is a beneficial and minimally invasive procedure with no serious adverse events.
Elevated Neurofilament Light Chain in Cerebrospinal Fluid and Plasma Reflect Inflammatory MRI Activity in Neurosarcoidosis
Authors: Byg Keld-Erik , Nielsen Helle , Sejbaek Tobias , Madsen Jonna , Olsen Dorte , Nguyen Nina , Kindt Astrid , Grauslund Jakob , Illes Zsolt , Ellingsen Torkell
Published: February 2021

Background: Damage to axonal cells releases neurofilament light chain (NFL) into the cerebrospinal fluid and plasma. The objective of this study was to investigate NFL as a potential biomarker of disease activity in neurosarcoidosis. MRIs were graded according to enhancing lesions at different central nervous system (CNS) sites. Results: In cerebrospinal fluid, levels of NFL were higher in neurosarcoidosis patients (n = 20) median 2304 pg/mL (interquartile range (IQR) 630–19,612) compared to 426 pg/mL (IQR 261-571) in extra-neurologic sarcoidosis patients (n = 20) and 336 pg/mL (IQR 194–402) in healthy controls (n = 11) (p = 0.0002). In plasma, levels of NFL were higher in neurosarcoidosis patients median 28.2 pg/mL (IQR 11.5–49.3) compared to 6.2 pg/mL (IQR 4.3–8.2) in extra-neurologic sarcoidosis patients and 7.1 pg/mL (IQR 6.2–9.0) in healthy controls (p = 0.0001). Levels in both cerebrospinal fluid and plasma were higher in neurosarcoidosis patients with moderate/severe enhancement than patients with mild enhancement on MRI (p = 0.009 and p = 0.005, respectively). To distinguish neurosarcoidosis patients from extra-neurologic patients and healthy controls, a cut-off level of 630 pg/mL in cerebrospinal fluid had 94% specificity and 79% sensitivity, while a cut-off level of 11.4 pg/mL in plasma had 97% specificity and 75% sensitivity. Conclusions: NFL levels in cerebrospinal fluid and plasma are significantly higher in neurosarcoidosis patients compared to extra-neurologic patients and healthy controls, and the levels correlate to the extent of inflammation on MRI.
Heart Rate Variability and Decision-Making: Autonomic Responses in Making Decisions
Authors: Forte Giuseppe , Morelli Matteo , Casagrande Maria
Published: February 2021

Decision-making is one of the most crucial cognitive processes in daily life. An adaptable, rapid, and flexible decision requires integration between brain and body. Heart rate variability (HRV) indexes this brain–body connection and appears to be related to cognitive performance. However, its relationship with decision-making is poorly analyzed. This study investigates the relationship between HRV and the decision-making process, assessed through the Iowa Gambling Task (IGT). One hundred and thirty healthy university students (mean age = 23.35 ± 2.50) participated in the study. According to IGT performance, they were divided into high decision-makers (n = 79) and low decision-makers (n = 51). Heart rate variability was measured in the resting, reactivity (i.e., during IGT), and recovery phases. Higher vagally mediated HRV (vmHRV; indexed in frequency domain measures) was evidenced in good decision-makers in the resting, reactivity, and recovery phases. During the task, a higher vagal modulation after a first evaluation was highlighted in good decision-makers. In conclusion, HRV proves to be a valid index of inhibitory circuit functioning in the prefrontal cortex. The relationship with cognitive functions was also confirmed, considering the ability to inhibit disadvantageous responses and make better decisions.
Structural Optimization in Civil Engineering: A Literature Review
Authors: Mei Linfeng , Wang Qian
Published: February 2021

Since tremendous resources are consumed in the architecture, engineering, and construction (AEC) industry, the sustainability and efficiency in this field have received increasing concern in the past few decades. With the advent and development of computational tools and information technologies, structural optimization based on mathematical computation has become one of the most commonly used methods for the sustainable and efficient design in the field of civil engineering. However, despite the wide attention of researchers, there has not been a critical review of the recent research progresses on structural optimization yet. Therefore, the main objective of this paper is to comprehensively review the previous research on structural optimization, provide a thorough analysis on the optimization objectives and their temporal and spatial trends, optimization process, and summarize the current research limitations and recommendations of future work. The paper first introduces the significance of sustainability and efficiency in the AEC industry as well as the background of this review work. Then, relevant articles are retrieved and selected, followed by a statistical analysis of the selected articles. Thereafter, the selected articles are analyzed regarding the optimization objectives and their temporal and spatial trends. The four major steps in the structural optimization process, including structural analysis and modelling, formulation of optimization problems, optimization techniques, and computational tools and design platforms, are also reviewed and discussed in detail based on the collected articles. Finally, research gaps of the current works and potential directions of future works are proposed. This paper critically reviews the achievements and limitations of the current research on structural optimization, which provide guidelines for future research on structural optimization in the field of civil engineering.
Exploring the Potential Role of the Gut Microbiome in Chemotherapy-Induced Neurocognitive Disorders and Cardiovascular Toxicity
Authors: Ciernikova Sona , Mego Michal , Chovanec Michal
Published: February 2021

Chemotherapy, targeting not only malignant but also healthy cells, causes many undesirable side effects in cancer patients. Due to this fact, long-term cancer survivors often suffer from late effects, including cognitive impairment and cardiovascular toxicity. Chemotherapy damages the intestinal mucosa and heavily disrupts the gut ecosystem, leading to gastrointestinal toxicity. Animal models and clinical studies have revealed the associations between intestinal dysbiosis and depression, anxiety, pain, impaired cognitive functions, and cardiovascular diseases. Recently, a possible link between chemotherapy-induced gut microbiota disruption and late effects in cancer survivors has been proposed. In this review, we summarize the current understanding of preclinical and clinical findings regarding the emerging role of the microbiome and the microbiota–gut–brain axis in chemotherapy-related late effects affecting the central nervous system (CNS) and heart functions. Importantly, we provide an overview of clinical trials evaluating the relationship between the gut microbiome and cancer survivorship. Moreover, the beneficial effects of probiotics in experimental models and non-cancer patients with neurocognitive disorders and cardiovascular diseases as well as several studies on microbiota modulations via probiotics or fecal microbiota transplantation in cancer patients are discussed.
Cross-Reactivity and Functionality of Approved Human Immune Checkpoint Blockers in Dogs
Authors: Pantelyushin Stanislav , Ranninger Elisabeth , Guerrera Diego , Hutter Gregor , Maake Caroline , Markkanen Enni , Bettschart-Wolfensberger Regula , Rohrer Bley Carla , Läubli Heinz , vom Berg Johannes
Published: February 2021

Background: Rodent cancer models have limitations in predicting efficacy, tolerability and accompanying biomarkers of ICIs in humans. Companion dogs suffering from neoplastic diseases have gained attention as a highly relevant translational disease model. Despite successful reports of PD-1/PD-L1 blockade in dogs, no compounds are available for veterinary medicine. Methods: Here, we assessed suitability of seven FDA-approved human ICIs to target CTLA-4 or PD-1/PD-L1 in dogs. Cross-reactivity and blocking potential was assessed using ELISA and flow cytometry. Functional responses were assessed on peripheral blood mononuclear cells (PBMCs) derived from healthy donors (n = 12) and cancer patient dogs (n = 27) as cytokine production after stimulation. Immune composition and target expression of healthy donors and cancer patients was assessed via flow cytometry. Results: Four candidates showed cross-reactivity and two blocked the interaction of canine PD-1 and PD-L1. Of those, only atezolizumab significantly increased cytokine production of healthy and patient derived PBMCs in vitro. Especially lymphoma patient PBMCs responded with increased cytokine production. In other types of cancer, response to atezolizumab appeared to correlate with a lower frequency of CD8 T cells. Conclusions: Cross-functionality of atezolizumab encourages reverse translational efforts using (combination) immunotherapies in companion dog tumor patients to benefit both veterinary and human medicine.
Epithelial–Mesenchymal Transition in Liver Fluke-Induced Cholangiocarcinoma
Authors: Sawanyawisuth Kanlayanee , Sashida Goro , Sheng Guojun
Published: February 2021

Cholangiocarcinoma (CCA) is the second most common type of hepatic cancer. In east and southeast Asia, intrahepatic CCA is caused predominantly by infection of Opisthorchis viverrini and Clonorchis sinensis, two species of parasitic liver flukes. In this review, we present molecular evidence that liver fluke-associated CCAs have enhanced features of epithelial–mesenchymal transition (EMT) in bile duct epithelial cells (cholangiocytes) and that some of those features are associated with mis-regulation at the epigenetic level. We hypothesize that both direct and indirect mechanisms underlie parasitic infection-induced EMT in CCA.
A Growth Modulation Index-Based GEISTRA Score as a New Prognostic Tool for Trabectedin Efficacy in Patients with Advanced Soft Tissue Sarcomas: A Spanish Group for Sarcoma Research (GEIS) Retrospective Study
Authors: Martínez-Trufero Javier , De Sande-González Luis Miguel , Luna Pablo , Martin-Broto Javier , Álvarez Rosa , Marquina Gloria , Diaz-Beveridge Roberto , Poveda Andrés , Cano Juana María , Cruz-Jurado Josefina , López Pousa Antonio , Vaz Salgado María Angeles , Valverde-Morales Claudia M. , Sevilla Isabel , Martínez-García Jerónimo , Rubio-Casadevall Jordi , De Juan Ana , Carrasco Juan Antonio , Moura David S , Gurruchaga-Sotes Ibon , Gutiérrez Antonio
Published: February 2021

The aim of this study was to identify an easily reliable prognostic score that selects the subset of advanced soft tissue sarcoma (ASTS) patients with a higher benefit with trabectedin in terms of time to progression and overall survival. A retrospective series of 357 patients with ASTS treated with trabectedin as second- or further-line in 19 centers across Spain was analyzed. First, it was confirmed that patients with high growth modulation index (GMI > 1.33) were associated with the better clinical outcome. Univariate and multivariate analyses were performed to identify factors associated with a GMI > 1.33. Thus, GEISTRA score was based on metastasis free-interval (MFI ≤ 9.7 months), Karnofsky < 80%, Non L-sarcomas and better response in the previous systemic line. The median GMI was 0.82 (0–69), with 198 patients (55%) with a GMI < 1, 41 (11.5%) with a GMI 1–1.33 and 118 (33.1%) with a GMI > 1.33. The lowest GEISTRA score showed a median of time-to-progression (TTP) and overall survival (OS) of 5.7 and 19.5 months, respectively, whereas it was 1.8 and 3.1 months for TTP and OS, respectively, for the GEISTRA 4 score. This prognostic tool can contribute to better selecting candidates for trabectedin treatment in ASTS.
Proteomic Analysis of Low-Grade, Early-Stage Endometrial Carcinoma Reveals New Dysregulated Pathways Associated with Cell Death and Cell Signaling
Authors: López-Janeiro Álvaro , Ruz-Caracuel Ignacio , Ramón-Patino Jorge L. , De Los Ríos Vivian , Villalba Esparza María , Berjón Alberto , Yébenes Laura , Hernández Alicia , Masetto Ivan , Kadioglu Ece , Goubert Virginie , Heredia-Soto Victoria , Barderas Rodrigo , Casal José Ignacio , de Andrea Carlos E. , Redondo Andrés , Mendiola Marta , Peláez-García Alberto , Hardisson David
Published: February 2021

Low-grade, early-stage endometrial carcinoma (EC) is the most frequent malignant tumor of the uterine corpus. However, the molecular alterations that underlie these tumors are far from being fully understood. The purpose of this study is to describe dysregulated molecular pathways from EC patients. Sixteen samples of tumor tissue and paired healthy controls were collected and both were subjected to mass spectrometry (MS)/MS proteomic analysis. Gene ontology and pathway analysis was performed to discover dysregulated pathways and/or proteins using different databases and bioinformatic tools. Dysregulated pathways were cross-validated in an independent external cohort. Cell signaling, immune response, and cell death-associated pathways were robustly identified. The SLIT/ROBO signaling pathway demonstrated dysregulation at the proteomic and transcriptomic level. Necroptosis and ferroptosis were cell death-associated processes aberrantly regulated, in addition to apoptosis. Immune response-associated pathways showed a dominance of innate immune responses. Tumor immune infiltrates measured by immunofluorescence demonstrated diverse lymphoid and myeloid populations. Our results suggest a role of SLIT/ROBO, necroptosis, and ferroptosis, as well as a prominent role of innate immune response in low-grade, early-stage EC. These results could guide future research in this group of tumors.
Impact of FAPI-PET/CT on Target Volume Definition in Radiation Therapy of Locally Recurrent Pancreatic Cancer
Authors: Liermann Jakob , Syed Mustafa , Ben-Josef Edgar , Schubert Kai , Schlampp Ingmar , Sprengel Simon David , Ristau Jonas , Weykamp Fabian , Röhrich Manuel , Koerber Stefan A. , Haberkorn Uwe , Debus Juergen , Herfarth Klaus , Giesel Frederik L. , Naumann Patrick
Published: February 2021

(1) Background: A new radioactive positron emission tomography (PET) tracer uses inhibitors of fibroblast activation protein (FAPI) to visualize FAP-expressing cancer associated fibroblasts. Significant FAPI-uptake has recently been demonstrated in pancreatic cancer patients. Target volume delineation for radiation therapy still relies on often less precise conventional computed tomography (CT) imaging, especially in locally recurrent pancreatic cancer patients. The need for improvement in precise tumor detection and delineation led us to innovatively use the novel FAPI-PET/CT for radiation treatment planning. (2) Methods: Gross tumor volumes (GTVs) of seven locally recurrent pancreatic cancer cases were contoured by six radiation oncologists. In addition, FAPI-PET/CT was used to automatically delineate tumors. The interobserver variability in target definition was analyzed and FAPI-based automatic GTVs were compared to the manually defined GTVs. (3) Results: Target definition differed significantly between different radiation oncologists with mean dice similarity coefficients (DSCs) between 0.55 and 0.65. There was no significant difference between the volumes of automatic FAPI-GTVs based on the threshold of 2.0 and most of the manually contoured GTVs by radiation oncologists. (4) Conclusion: Due to its high tumor to background contrast, FAPI-PET/CT seems to be a superior imaging modality compared to the current gold standard contrast-enhanced CT in pancreatic cancer. For the first time, we demonstrate how FAPI-PET/CT could facilitate target definition and increases consistency in radiation oncology in pancreatic cancer.
Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology
Authors: Leroux Cédric , Konstantinidou Georgia
Published: February 2021

Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies. In this review, we provide an overview of the current and emerging treatment strategies in pancreatic cancer. By highlighting new paradigms in pancreatic ductal adenocarcinoma treatment, we hope to stimulate new thoughts for clinical trials aimed at improving patient outcomes.
Janus Kinases in Leukemia
Authors: Raivola Juuli , Haikarainen Teemu , Abraham Bobin George , Silvennoinen Olli
Published: February 2021

Janus kinases (JAKs) transduce signals from dozens of extracellular cytokines and function as critical regulators of cell growth, differentiation, gene expression, and immune responses. Deregulation of JAK/STAT signaling is a central component in several human diseases including various types of leukemia and other malignancies and autoimmune diseases. Different types of leukemia harbor genomic aberrations in all four JAKs (JAK1, JAK2, JAK3, and TYK2), most of which are activating somatic mutations and less frequently translocations resulting in constitutively active JAK fusion proteins. JAKs have become important therapeutic targets and currently, six JAK inhibitors have been approved by the FDA for the treatment of both autoimmune diseases and hematological malignancies. However, the efficacy of the current drugs is not optimal and the full potential of JAK modulators in leukemia is yet to be harnessed. This review discusses the deregulation of JAK-STAT signaling that underlie the pathogenesis of leukemia, i.e., mutations and other mechanisms causing hyperactive cytokine signaling, as well as JAK inhibitors used in clinic and under clinical development.
AKT3 Expression in Mesenchymal Colorectal Cancer Cells Drives Growth and Is Associated with Epithelial-Mesenchymal Transition
Authors: Buikhuisen Joyce Y. , Gomez Barila Patricia M. , Torang Arezo , Dekker Daniëlle , de Jong Joan H. , Cameron Kate , Vitale Sara , Stassi Giorgio , van Hooff Sander R. , Castro Mauro A. A. , Vermeulen Louis , Medema Jan Paul
Published: February 2021

Colorectal cancer (CRC) is a heterogeneous disease that can currently be subdivided into four distinct consensus molecular subtypes (CMS) based on gene expression profiling. The CMS4 subtype is marked by high expression of mesenchymal genes and is associated with a worse overall prognosis compared to other CMSs. Importantly, this subtype responds poorly to the standard therapies currently used to treat CRC. We set out to explore what regulatory signalling networks underlie the CMS4 phenotype of cancer cells, specifically, by analysing which kinases were more highly expressed in this subtype compared to others. We found AKT3 to be expressed in the cancer cell epithelium of CRC specimens, patient derived xenograft (PDX) models and in (primary) cell cultures representing CMS4. Importantly, chemical inhibition or knockout of this gene hampers outgrowth of this subtype, as AKT3 controls expression of the cell cycle regulator p27KIP1. Furthermore, high AKT3 expression was associated with high expression of epithelial-mesenchymal transition (EMT) genes, and this observation could be expanded to cell lines representing other carcinoma types. More importantly, this association allowed for the identification of CRC patients with a high propensity to metastasise and an associated poor prognosis. High AKT3 expression in the tumour epithelial compartment may thus be used as a surrogate marker for EMT and may allow for a selection of CRC patients that could benefit from AKT3-targeted therapy.
Modulation of the Vascular-Immune Environment in Metastatic Cancer
Authors: He Bo , Ganss Ruth
Published: February 2021

Advanced metastatic cancer is rarely curable. While immunotherapy has changed the oncological landscape profoundly, cure in metastatic disease remains the exception. Tumor blood vessels are crucial regulators of tumor perfusion, immune cell influx and metastatic dissemination. Indeed, vascular hyperpermeability is a key feature of primary tumors, the pre-metastatic niche in host tissue and overt metastases at secondary sites. Combining anti-angiogenesis and immune therapies may therefore unlock synergistic effects by inducing a stabilized vascular network permissive for effector T cell trafficking and function. However, anti-angiogenesis therapies, as currently applied, are hampered by intrinsic or adaptive resistance mechanisms at primary and distant tumor sites. In particular, heterogeneous vascular and immune environments which can arise in metastatic lesions of the same individual pose significant challenges for currently approved drugs. Thus, more consideration needs to be given to tailoring new combinations of vascular and immunotherapies, including dosage and timing regimens to specific disease microenvironments.
Comparison of Trans-Arterial Chemoembolization and Bland Embolization for the Treatment of Hepatocellular Carcinoma: A Propensity Score Analysis
Authors: Roth Gaël S. , Benhamou Maxime , Teyssier Yann , Seigneurin Arnaud , Abousalihac Mélodie , Sengel Christian , Seror Olivier , Ghelfi Julien , Ganne-Carrié Nathalie , Blaise Lorraine , Sutter Olivier , Decaens Thomas , Nault Jean-Charles
Published: February 2021

No definitive conclusion could be reached about the role of chemotherapy in adjunction of embolization in the treatment of hepatocellular carcinoma (HCC). We aim to compare radiological response, toxicity and long-term outcomes of patients with hepatocellular carcinoma (HCC) treated by trans-arterial bland embolization (TAE) versus trans-arterial chemoembolization (TACE). We retrospectively included 265 patients with HCC treated by a first session of TACE or TAE in two centers. Clinical and biological features were recorded before the treatment and radiological response was assessed after the first treatment using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Correlation between the treatment and overall, progression-free and transplantation-free survival was performed after adjustment using a propensity score matching: 86 patients were treated by bland embolization and 179 patients by TACE, including 44 patients with drug-eluting beads and 135 with lipiodol TACE, 89.8% of patients were male with a median age of 65 years old. Cirrhosis was present in 90.9% of patients with a Child Pugh score A in 84% of cases. After adjustment, no difference in the rate of AE, including liver failure, was observed between the two treatments. TACE was associated with a significant increase in complete radiological response (odds ratio (OR) = 8.5 (95% confidence interval (CI): 2.8–25.4)) but not in the overall response rate (OR = 2.2 (95% CI = 0.8–5.8)). No difference in terms of overall survival (p = 0.3905), progression-free survival (p = 0.4478) and transplantation-free survival (p = 0.9020) was observed between TACE and TAE. TACE was associated with a higher rate of complete radiological response but without any impact on overall radiological response, progression-free survival and overall survival compared to TAE.
Preparation of Granulated Biomass Carbon Catalysts—Structure Tailoring, Characterization, and Use in Catalytic Wet Air Oxidation of Bisphenol A
Authors: Juhola Riikka , Heponiemi Anne , Tuomikoski Sari , Hu Tao , Huuhtanen Mika , Bergna Davide , Lassi Ulla
Published: February 2021

New carbonized biomass–metakaolin (PSD/MK_Fe) granular composite catalyst materials were manufactured for the catalytic wet air oxidation (CWAO) of bisphenol A (BPA). These catalysts were characterized using different analytical and spectroscopic techniques, and results showed that the catalysts’ final properties were influenced by the addition of metakaolin (MK), polyvinyl alcohol, boric acid, and iron. Under the optimal CWAO experimental conditions (p: 20 bar, T: 160 °C, initial pH: 5–6, c[catalyst]: 1.0 g/L), nearly complete BPA conversion (>98%) and total organic carbon (TOC) conversion of 70% were reached. A key factor behind the enhanced catalytic activity was high specific surface area, although catalytic activity was also affected by surface acidity. These results confirmed the high efficiency of the current BPA conversion process involving the use of the easily separable and reusable PSD/MK_Fe catalyst. Therefore, biomass composite catalysts can be regarded as efficient catalysts for the oxidation of BPA during the CWAO process.
Towards the Large-Scale Electrochemical Reduction of Carbon Dioxide
Authors: Park Subin , Wijaya Devina Thasia , Na Jonggeol , Lee Chan Woo
Published: February 2021

The severe increase in the CO2 concentration is a causative factor of global warming, which accelerates the destruction of ecosystems. The massive utilization of CO2 for value-added chemical production is a key to commercialization to guarantee both economic feasibility and negative carbon emission. Although the electrochemical reduction of CO2 is one of the most promising technologies, there are remaining challenges for large-scale production. Herein, an overview of these limitations is provided in terms of devices, processes, and catalysts. Further, the economic feasibility of the technology is described in terms of individual processes such as reactions and separation. Additionally, for the practical implementation of the electrochemical CO2 conversion technology, stable electrocatalytic performances need to be addressed in terms of current density, Faradaic efficiency, and overpotential. Hence, the present review also covers the known degradation behaviors and mechanisms of electrocatalysts and electrodes during electrolysis. Furthermore, strategic approaches for overcoming the stability issues are introduced based on recent reports from various research areas involved in the electrocatalytic conversion.
Characterization of a Novel Thermophilic Mannanase and Synergistic Hydrolysis of Galactomannan Combined with Swollenin
Authors: Gu Xinxi , Lu Haiqiang , Chen Wei , Meng Xiangchen
Published: February 2021

Aspergillus fumigatus HBFH5 is a thermophilic fungus which can efficiently degrade lignocellulose and which produces a variety of glycoside hydrolase. In the present study, a novel β-mannanase gene (AfMan5A) was expressed in Pichia pastoris and characterized. AfMan5A is composed of 373 amino acids residues, and has a calculated molecular weight of 40 kDa. It has been observed that the amino acid sequence of AfMan5A showed 74.4% homology with the ManBK from Aspergillus niger. In addition, the recombined AfMan5A exhibited optimal hydrolytic activity at 60 °C and pH 6.0. It had no activity loss after incubation for 1h at 60 °C, while 65% of the initial activity was observed after 1 h at 70 °C. Additionally, it maintained about 80% of its activity in the pH range from 3.0 to 9.0. When carob bean gum was used as the substrate, the Km and Vmax values of AfMan5A were 0.21 ± 0.05 mg·mL−1 and 15.22 ± 0.33 U mg−1·min−1, respectively. AfMan5A and AfSwol showed a strong synergistic interaction on galactomannan degradation, increasing the reduction of the sugars by up to 31%. Therefore, these findings contribute to new strategies for improving the hydrolysis of galactomannan using the enzyme cocktail.