bluuebunny/crossref_metadata_2025 huggingface dataset:
Right-Hand Side Expanding Algorithm for Maximal Frequent Itemset Mining
Authors: Zhang Yalong , Yu Wei , Zhu Qiuqin , Ma Xuan , Ogura Hisakazu
Published: November 2021

When it comes to association rule mining, all frequent itemsets are first found, and then the confidence level of association rules is calculated through the support degree of frequent itemsets. As all non-empty subsets in frequent itemsets are still frequent itemsets, all frequent itemsets can be acquired only by finding all maximal frequent itemsets (MFIs), whose supersets are not frequent itemsets. In this study, an algorithm, named right-hand side expanding (RHSE), which can accurately find all MFIs, was proposed. First, an Expanding Operation was designed, which, starting from any given frequent itemset, could add items using certain rules and form some supersets of given frequent itemsets. In addition, these supersets were all MFIs. Next, this operator was used to add items by taking all frequent 1-itemsets as the starting point alternately, and all MFIs were found in the end. Due to the special design of the Expanding Operation, each MFI could be found. Moreover, the path found was unique, which avoided the algorithm redundancy in temporal and spatial complexity. This algorithm, which has a high operating rate, is applicable to the big data of high-dimensional mass transactions as it is capable of avoiding the computing redundancy and finding all MFIs. In the end, a detailed experimental report on 10 open standard transaction sets was given in this study, including the big data calculation results of million-class transactions.
Transverse Cracking of Concrete Base Plate in CRTS III Ballastless Track Structure: Effects of Environmental Boundary Conditions
Authors: Guo Weiqiang , Huang Xin , Zhao Lijun , Wei Ya
Published: November 2021

The cast-in-place concrete base plate is a main member of the China Railway Track System (CRTS) III ballastless track structure that is prone to generating early transverse cracking. Such cracks can dramatically affect the performance and service life of the railway track structure. This study investigated the influence of temperature and moisture boundary conditions on early cracking behavior of the CRTS III base plate by using approaches of both in situ measurements and numerical modelling. In-site measurements of strain and temperature were made in four test series of CRTS III base plates under the same natural environmental condition but cured with different regimes, and a total of 96 measuring positions were monitored for up to 150 days. The results showed that the strain magnitude and distribution in the field base plate, the initial time at cracking, and the observed cracking pattern varied significantly between the different test series. In order to understand the mechanisms that create these transverse cracks and to provide guidelines for the current curing strategy during construction, the characteristics of temperature-induced and moisture-induced stresses were analyzed by using 3D numerical modelling and by considering early-age concrete creep properties, meteorological factors, and the influence from environmental boundary conditions. The calculated results revealed that early-age transverse cracking in CRTS III base plate depends more on drying shrinkage stress than temperature stress. By conducting this study, we expect to provide guidance for reducing or eliminating early cracks of CRTS III concrete base plate.
A Combined Anomaly and Trend Detection System for Industrial Robot Gear Condition Monitoring
Authors: Nentwich Corbinian , Reinhart Gunther
Published: November 2021

Conditions monitoring of industrial robot gears has the potential to increase the productivity of highly automated production systems. The huge amount of health indicators needed to monitor multiple gears of multiple robots requires an automated system for anomaly and trend detection. In this publication, such a system is presented and suitable anomaly detection and trend detection methods for the system are selected based on synthetic and real world industrial application data. A statistical test, namely the Cox-Stuart test, appears to be the most suitable approach for trend detection and the local outlier factor algorithm or the long short-term neural network performs best for anomaly detection in the application of industrial robot gear condition monitoring in the presented experiments.
A Polymer Inclusion Membrane for Sensing Metal Complexation in Natural Waters
Authors: Alcalde Berta , Anticó Enriqueta , Fontàs Clàudia
Published: November 2021

Metal speciation studies are of great importance in assessing metal bioavailability in aquatic environments. Functionalized membranes are a simple tool to perform metal chemical speciation. In this study, we have prepared and tested a polymer inclusion membrane (PIM) made of the polymer cellulose triacetate (CTA), the extractant di-(2-ethylhexyl) phosphoric acid (D2EHPA), and the plasticizer 2-nitrophenyloctyl ether (NPOE) as a sensor for Zn and Cu complexation studies. This PIM, incorporated in a device with an 0.01 M HNO3 receiving solution, is shown to effectively transport free metal ions, and it is demonstrated that the presence of ligands that form stable complexes with divalent metallic ions, such as ethylenediaminetetraacetic acid (EDTA) and humic acid (HA), greatly influences the accumulation of the metals in the receiving phase due to the increasing metal fraction complexed in the feed phase. Moreover, the effect of major ions found in natural waters has been investigated, and it is found that the presence of calcium did not decrease the accumulation of either Zn or Cu. Finally, the PIM sensor has been used successfully to evaluate metal complexation in a river water affected by Zn pollution.
Efficient Moment-Independent Sensitivity Analysis of Uncertainties in Seismic Demand of Bridges Based on a Novel Four-Point-Estimate Method
Authors: Li Xingyu , Lei Ying , Liu Lijun
Published: November 2021

Moment-independent importance (MII) analysis is known as a global sensitivity measurement in qualifying the influence of uncertainties, which is taken as a crucial step towards seismic performance analysis. Most MII analysis is based on Monte Carlo simulation, which leads to a high computational cost since a large number of nonlinear time history analyses are required to obtain the probability density function. To address this limitation, this study presents a computational efficient MII analysis to investigate the uncertain parameters in the seismic demands of bridges. A modified four-point-estimate method is derived from Rosenblueth’s two-point-estimate method. Thus, the statistical moments of a bridge’s seismic demands can be obtained by several sampling points and their weights. Then, the shifted generalized lognormal distribution method is adopted to estimate the unconditional and conditional probability density functions of seismic demands, which are used for the MII analysis. The analysis of seismic demands based on piers and bearings in a finite element model of a continuous girder bridge is taken as a validation example. The MII measures of the uncertain parameters are estimated by just several nonlinear time history analyses at the point-estimate sampling points, and the results by the proposed method are compared with those found by Monte Carlo simulation.
Optimization Design of the Lower Rocker Arm of a Vertical Roller Mill Based on ANSYS Workbench
Authors: Wei Weihua , Shen Jicheng , Yu Haipeng , Chen Bingrui , Wei Yu
Published: November 2021

The lower rocker arm is an important part of the vertical roller mill and its lightweight design is of great significance for reducing the mass and production cost of the roller mill. Firstly, the strength and deformation distribution of the lower rocker arm under working load were analyzed by ANSYS Workbench to determine the maximum stress and maximum deformation. The parts with large strength margin were used as the basis for the optimal design. During the analysis, firstly, the arm body of the lower rocker arm was determined part of the lightweight design. Secondly, the mass of the lower rocker arm was taken as the optimization target, the stress and displacement generated by the load of the lower rocker arm were taken as the constraint conditions, the structural size of the internal cavity of the lower rocker arm was taken as the optimization design parameter, and the mathematical model of the optimization design was established. Finally, the structural size of the internal cavity of the lower rocker arm was optimized by using the response surface optimization module and multi-objective genetic algorithm in ANSYS Workbench. The optimum results show that, compared with the original design model, the lower rocker mass was reduced by 346.3 kg and the decrease was about 5.29%, while the strength and deformation were nearly unchanged. Therefore, by optimizing the design, the material is saved and the cost is reduced, which can provide a reference basis for the design and light weight of the lower rocker arm.
Estimating Destination of Bus Trips Considering Trip Type Characteristics
Authors: Lee Soongbong , Lee Jongwoo , Bae Bumjoon , Nam Daisik , Cheon Seunghoon
Published: November 2021

Recently, local governments have been using transportation card data to monitor the use of public transport and improve the service. However, local governments that are applying a single-fare scheme are experiencing difficulties in using data for accurate identification of real travel patterns or policy decision support due to missing information on alighting stops of users. This policy limits its functionality of utilizing data such as accurate identification of real travel patterns, policy decision support, etc. In order to overcome these limitations, various methods for estimating alighting stops have been developed. This study classifies trips with missing alighting stop information into trip four types and then applies appropriate alighting stop estimation methodology for each trip type in stages. The proposed method is evaluated by utilizing transportation card data of the Seoul metropolitan area and checking the accuracy for each standard of allowable error for sensitivity analysis. The analysis shows that the stage-by-stage estimation methodology based on the trip type proposed in this study can estimate users’ destinations more accurately than the methodologies of previous studies. Furthermore, based on the construction of nearly 100% valid tag data, this study differs from prior studies.
Autonomous Service Drones for Multimodal Detection and Monitoring of Archaeological Sites
Authors: Khelifi Adel , Ciccone Gabriele , Altaweel Mark , Basmaji Tasnim , Ghazal Mohammed
Published: November 2021

Constant detection and monitoring of archaeological sites and objects have always been an important national goal for many countries. The early identification of changes is crucial to preventive conservation. Archaeologists have always considered using service drones to automate collecting data on and below the ground surface of archaeological sites, with cost and technical barriers being the main hurdles against the wide-scale deployment. Advances in thermal imaging, depth imaging, drones, and artificial intelligence have driven the cost down and improved the quality and volume of data collected and processed. This paper proposes an end-to-end framework for archaeological sites detection and monitoring using autonomous service drones. We mount RGB, depth, and thermal cameras on an autonomous drone for low-altitude data acquisition. To align and aggregate collected images, we propose two-stage multimodal depth-to-RGB and thermal-to-RGB mosaicking algorithms. We then apply detection algorithms to the stitched images to identify change regions and design a user interface to monitor these regions over time. Our results show we can create overlays of aligned thermal and depth data on RGB mosaics of archaeological sites. We tested our change detection algorithm and found it has a root mean square error of 0.04. To validate the proposed framework, we tested our thermal image stitching pipeline against state-of-the-art commercial software. We cost-effectively replicated its functionality while adding a new depth-based modality and created a user interface for temporally monitoring changes in multimodal views of archaeological sites.
Comparison of Reanalysis and Observational Precipitation Datasets Including ERA5 and WFDE5
Authors: Hassler Birgit , Lauer Axel
Published: November 2021

Precipitation is a key component of the hydrological cycle and one of the most important variables in weather and climate studies. Accurate and reliable precipitation data are crucial for determining climate trends and variability. In this study, eleven different precipitation datasets are compared, six reanalysis and five observational datasets, including the reanalysis datasets ERA5 and WFDE5 from the ECMWF family, to quantify the differences between the widely used precipitation datasets and to identify their particular strengths and shortcomings. The comparisons are focused on the common time period 1983 through 2016 and on monthly, seasonal, and inter-annual times scales in regions representing different precipitation regimes, i.e., the Tropics, the Pacific Inter Tropical Convergence Zone (ITCZ), Central Europe, and the South Asian Monsoon region. For the analysis, satellite-gauge precipitation data from the Global Precipitation Climatology Project (GPCP-SG) are used as a reference. The comparison shows that ERA5 and ERA5-Land are a clear improvement over ERA-Interim and show in most cases smaller biases than the other reanalysis datasets (e.g., around 13% high bias in the Tropics compared to 17% for MERRA-2 and 36% for JRA-55). ERA5 agrees well with observations for Central Europe and the South Asian Monsoon region but underestimates very low precipitation rates in the Tropics. In particular, the tropical ocean remains challenging for reanalyses with three out of four products overestimating precipitation rates over the Atlantic and Indian Ocean.
Sustainability as a Function of an Area: Application of Multi-Criteria Evaluation in Assessing the Effectiveness of Nature-Based Solutions
Authors: Podhajska Ewa , Burszta-Adamiak Ewa , Drzeniecka-Osiadacz Anetta , Zienowicz Magdalena , Podhajski Bronisław , Sawiński Tymoteusz , Jasińska Agnieszka
Published: November 2021

One of the essential factors influencing the overall urban experience is the presence of biologically active surfaces. Despite widespread awareness of the beneficial effects of such spaces, the natural tissue in cities is still being significantly limited by the priority given to functionality and the economy. The aim of this article is to assess the potential of using a hybrid infrastructure in the grey–green–blue system (GGB) on a public site. In order to assess the efficiency of the implemented solutions, a multi-criteria method was developed, thereby recognising this research aspect as necessary in the process of designing urban built-up spaces. The assessment compared indicators of biological activity in the area using the biotope area factor and green space factor scales. The rainwater retention potential was estimated using a quantitative method. The change in the site’s thermal conditions was analysed by conducting numerous experiments with the use of micrometeorogical computational fluid dynamics models ENVI-met. The demonstrated improvement in the proportion of the biologically active area, water retention, and thermal conditions, ranging from a few to a dozen percent compared to the initial state, confirms the legitimacy of using grey–green–blue infrastructure systems as a method of shaping a sustainable and climate-responsive urban design.
Down-Regulation of Phosphoenolpyruvate Carboxylase Kinase in Grapevine Cell Cultures and Leaves Is Linked to Enhanced Resveratrol Biosynthesis
Authors: Hurtado-Gaitán Elías , Sellés-Marchart Susana , Hartwell James , Martínez-Esteso Maria José , Bru-Martínez Roque
Published: November 2021

In grapevine, trans-Resveratrol (tR) is produced as a defence mechanism against stress or infection. tR is also considered to be important for human health, which increases its interest to the scientific community. Transcriptomic analysis in grapevine cell cultures treated with the defence response elicitor methyl-β-cyclodextrin (CD) revealed that both copies of PHOSPHOENOLPYRUVATE CARBOXYLASE KINASE (PPCK) were down-regulated significantly. A role for PPCK in the defence response pathway has not been proposed previously. We therefore analysed the control of PPCK transcript levels in grapevine cell cultures and leaves elicited with CD. Moreover, phosphoenolpyruvate carboxylase (PPC), stilbene synthase (STS), and the transcription factors MYB14 and WRKY24, which are involved in the activation of STS transcription, were also analysed by RT-qPCR. The results revealed that under CD elicitation conditions PPCK down-regulation, increased stilbene production and loss of PPC activity occurs in both tissues. Moreover, STS transcripts were co-induced with MYB14 and WRKY24 in cell cultures and leaves. These genes have not previously been reported to respond to CD in grape leaves. Our findings thus support the hypothesis that PPCK is involved in diverting metabolism towards stilbene biosynthesis, both for in vitro cell culture and whole leaves. We thus provide new evidence for PEP being redirected between primary and secondary metabolism to support tR production and the stress response.
Characteristics of Dental Resin-Based Composites in Leukemia Saliva: An In Vitro Analysis
Authors: Mester Alexandru , Moldovan Marioara , Cuc Stanca , Tomuleasa Ciprian , Pasca Sergiu , Filip Miuta , Piciu Andra , Onisor Florin
Published: November 2021

Background: The aim was to analyze, in vitro, four resin based composite systems (RBCs) immersed in saliva of leukemia patients before starting chemotherapy regiments. Material and methods: Saliva was collected from 20 patients (4 healthy patients, 16 leukemia patients). Resin disks were made for each RBC and were immersed in the acute leukemia (acute lymphocytic (ALL), acute myeloid (AML)), chronic leukemia (chronic lymphocytic (CLL), chronic myeloid (CML)), Artificial saliva and Control environment, and maintained for seven days. At the end of the experiment, the characteristics and the effective response of saliva from the studied salivas’ on RBCs was assessed using water sorption, water solubility, residual monomer and scanning electron microscopy (SEM). Data analysis was performed and a p-value under 0.05 was considered statistically significant. Results: The behaviour of RBCs in different immersion environments varies according to the characteristics of the RBCs. RBCs with a higher filler ratio have a lower water sorption. The solubility is also deteriorated by the types of organic matrix and filler; the results of solubility being inversely proportional on the scale of negative values compared to sorption values. Chromatograms of residual monomers showed the highest amount of unreacted monomers in ALL and AML, and the Control and artificial saliva environments had the smallest residual monomer peaks. Because of the low number of differences between the experimental conditions, we further considered that there were no important statistical differences between experimental conditions and analysed them as a single group. Conclusion: The influence of saliva on RBCs depends on the type of leukemia; acute leukemia influenced the most RBCs by changing their properties compared to chronic leukemia.
T-Cell Acute Lymphoblastic Leukemia—Current Concepts in Molecular Biology and Management
Authors: Shiraz Parveen , Jehangir Waqas , Agrawal Vaibhav
Published: November 2021

T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, yet aggressive leukemia that accounts for approximately one-fourth of acute lymphoblastic leukemia (ALL) cases. CDKN2A/CDKN2B and NOTCH1 are the most common mutated genes in T-ALL. Children and young adults are treated with pediatric intensive regimens and have superior outcomes compared to older adults. In children and young adults, Nelarabine added to frontline chemotherapy improves outcomes and end of consolidation measurable residual disease has emerged as the most valuable prognostic marker. While outcomes for de-novo disease are steadily improving, patients with relapsed and refractory T-ALL fare poorly. Newer targeted therapies are being studied in large clinical trials and have the potential to further improve outcomes. The role of allogeneic stem cell transplant (HSCT) is evolving due to the increased use of pediatric-inspired regimens and MRD monitoring. In this review we will discuss the biology, treatment, and outcomes in pediatric and adult T-ALL.
Adipose-Derived Stem Cell: “Treat or Trick”
Authors: Airuddin Siti Syahira , Halim Ahmad Sukari , Wan Sulaiman Wan Azman , Kadir Ramlah , Nasir Nur Azida Mohd
Published: November 2021

Stem cells have been widely used for treating disease due to the various benefits they offer in the curing process. Several treatments using stem cells have undergone clinical trials, such as cell-based therapies for heart disease, sickle cell disease, thalassemia, etc. Adipose-derived stem cells are some of the many mesenchymal stem cells that exist in our body that can be harvested from the abdomen, thighs, etc. Adipose tissue is easy to harvest, and its stem cells can be obtained in higher volumes compared to stem cells harvested from bone marrow, for which a more invasive technique is required with a smaller volume obtained. Many scientists have expressed interest in investigating the role of adipose-derived stem cells in treating disease since their use was first described. This is due to these stem cells’ ability to differentiate into multiple lineages and secrete a variety of growth factors and proteins. Previous studies have found that the hormones, cytokines, and growth factors contained in adipose tissue play major roles in the metabolic regulation of adipose tissue, as well as in energy balance and whole-body homeostasis through their endocrine, autocrine, and paracrine functions. These are thought to be important contributors to the process of tissue repair and regeneration. However, it remains unclear how effective and safe ADSCs are in treating diseases. The research that has been carried out to date is in order to investigate the impact of ADSCs in disease treatment, as described in this review, to highlight its “trick or treat” effect in medical treatment.
The Paradox of Fiction Revisited—Improvised Fictional and Real-Life Social Rejections Evoke Associated and Relatively Similar Psychophysiological Responses
Authors: Seppänen Sirke , Toivanen Tapio , Makkonen Tommi , Jääskeläinen Iiro , Tiippana Kaisa
Published: November 2021

Theatre-based practices, such as improvisation, are frequently applied to simulate everyday social interactions. Although the improvisational context is acknowledged as fictional, realistic emotions may emerge, a phenomenon labelled the ‘paradox of fiction’. This study investigated how manipulating the context (real-life versus fictional) modulates psychophysiological reactivity to social rejection during dyadic interactions. We measured psychophysiological responses elicited during real-life (interview) and fictional (improvisation exercises) social rejections. We analysed the heart rate (HR), skin conductance, facial muscle activity, and electrocortical activity (electroencephalographic (EEG) alpha asymmetry) of student teachers (N = 39) during various social rejections (devaluing, interrupting, nonverbal rejection). All social rejections evoked negative EEG alpha asymmetry, a measure reflecting behavioural withdrawal motivation. Psychophysiological responses during real-life and fictional rejections correlated, and rejection type modified the responses. When comparing responses across all rejection types, facial muscle activity and EEG alpha asymmetry did not differ between real-life and fictional rejections, whereas HR decelerated and skin conductance increased during fictional rejections. These findings demonstrate that regardless of cognitive awareness of fictionality, relatively subtle social rejections elicited psychophysiological reactivity indicating emotional arousal and negative valence. These findings provide novel, biological evidence for the application of theatre-based improvisation to studying experientially everyday social encounters.
TPPU Pre-Treatment Rescues Dendritic Spine Loss and Alleviates Depressive Behaviours during the Latent Period in the Lithium Chloride-Pilocarpine-Induced Status Epilepticus Rat Model
Authors: Peng Weifeng , Shen Yijun , Wang Qiang , Ding Jing , Wang Xin
Published: November 2021

Epileptogenesis may be responsible for both of recurrent seizures and comorbid depression in epilepsy. Disease-modifying treatments targeting the latent period before spontaneous recurrent seizures may contribute to the remission of seizures and comorbid depression. We hypothesized that pre-treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), a soluble epoxide hydrolase (sEH) inhibitor, which has anti-inflammatory and neuroprotective effects might rescue status epilepticus (SE)-induced dendritic spine loss and alleviate depressive behaviours. Rats were either pre-treated with TPPU (0.1 mg/kg/d) intragastrically or with vehicle (40% polyethylene glycol 400) from 7 days before to 7 days after SE that was induced with lithium chloride and pilocarpine intraperitoneally. Rats in the Control group were given saline instead. The forced swim test (FST) was performed on the 8th day after SE to evaluate the depression-like behaviours in rats. The results showed that seizures severity during SE was significantly decreased, and the immobility time during FST was significantly increased through TPPU pre-treatment. Moreover, pre-treatment with TPPU attenuated inflammations including microglial gliosis and the level of proinflammatory cytokine IL-1β in the hippocampus; in addition, neuronal and dendritic spine loss in the subfields of hippocampus was selectively rescued, and the expression of NR1 subunit of N-methyl-D-aspartate (NMDA) receptor, ERK1/2, CREB, and their phosphorylated forms involved in the dendritic spine development were all significantly increased. We concluded that pre-treatment with TPPU attenuated seizures severity during SE and depressive behaviours during the period of epileptogenesis probably by rescuing dendritic spine loss in the hippocampus.
Selective Microfluidic Capture and Detection of Prostate Cancer Cells from Urine without Digital Rectal Examination
Authors: Chan Kit Man , Gleadle Jonathan M. , Gregory Philip A. , Phillips Caroline A. , Shirazi Hanieh Safizadeh , Whiteley Amelia , Li Jordan , Vasilev Krasimir , MacGregor Melanie
Published: November 2021

Urine-based biomarkers have shown suitable diagnostic potential for prostate cancer (PCa) detection. Yet, until now, prostatic massage remains required prior to urine sampling. Here, we test a potential diagnostic approach using voided urine collected without prior digital rectal examination (DRE). In this study, we evaluated the diagnostic performance of a microfluidic-based platform that combines the principle of photodynamic diagnostic with immunocapture for the detection of PCa cells. The functionality and sensitivity of this platform were validated using both cultured cells and PCa patient urine samples. Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) demonstrated this platform had a detection limit of fewer than 10 cells per 60 µL and successfully validated the presence of a PCa biomarker in the urine of cancer patients without prior DRE. This biosensing platform exhibits a sensitivity of 72.4% and a specificity of 71.4%, in suitable agreement with qRT-PCR data. The results of this study constitute a stepping stone in the future development of noninvasive prostate cancer diagnostic technologies that do not require DRE.
Radiogenomics: Hunting Down Liver Metastasis in Colorectal Cancer Patients
Authors: de la Pinta Carolina , Castillo María E. , Collado Manuel , Galindo-Pumariño Cristina , Peña Cristina
Published: November 2021

Radiomics is a developing new discipline that analyzes conventional medical images to extract quantifiable data that can be mined for new biomarkers that show the biology of pathological processes at microscopic levels. These data can be converted into image-based signatures to improve diagnostic, prognostic and predictive accuracy in cancer patients. The combination of radiomics and molecular data, called radiogenomics, has clear implications for cancer patients’ management. Though some studies have focused on radiogenomics signatures in hepatocellular carcinoma patients, only a few have examined colorectal cancer metastatic lesions in the liver. Moreover, the need to differentiate between liver lesions is fundamental for accurate diagnosis and treatment. In this review, we summarize the knowledge gained from radiomics and radiogenomics studies in hepatic metastatic colorectal cancer patients and their use in early diagnosis, response assessment and treatment decisions. We also investigate their value as possible prognostic biomarkers. In addition, the great potential of image mining to provide a comprehensive view of liver niche formation is examined thoroughly. Finally, new challenges and current limitations for the early detection of the liver premetastatic niche, based on radiomics and radiogenomics, are also discussed.
Comparison of Efficacy in Patients with Metastatic Melanoma Treated with Ipilimumab and Nivolumab Who Did or Did Not Discontinue Treatment Due to Immune-Related Adverse Events: A Real-World Data Study
Authors: Fink Morten , Vittrup Anders Schwartz , Bastholt Lars , Svane Inge Marie , Donia Marco , Luczak Adam A. , Ruhlmann Christina H. , Guldbrandt Louise Mahncke , Koehler Ulrich Heide , Winther Mette Lerche , Ellebaek Eva , Haslund Charlotte Aaquist , Schmidt Henrik
Published: November 2021

Immune-related adverse events (irAEs) are very prevalent when treating patients with ipilimumab and nivolumab in combination, and 30–40% of patients discontinue the treatment for this reason. It is of high clinical relevance to investigate the consequences of discontinuing the treatment early since combination therapy with ipilimumab and nivolumab is the first line of treatment for many patients with metastatic melanoma. In this follow-up study, with real-world data from the nationwide DAMMED database, we investigated whether there was a difference in progression-free survival (PFS) and overall survival (OS) for patients who discontinued or did not discontinue treatment within the first four doses of treatment due to irAEs. In total, 448 patients were treated with ipilimumab and nivolumab. Of these, 133 patients discontinued due to irAEs in the induction phase. Using the Cox proportional hazards model, there was no significant difference in PFS when comparing the group that discontinued with the group that did not discontinue. The group that discontinued had a significantly longer OS than the group that received the full length of treatment. Therefore, we conclude that there is no significant negative impact on efficacy for patients who discontinue due to irAEs in the induction phase of combination immunotherapy for metastatic melanoma.
H3.3K27M Mutation Controls Cell Growth and Resistance to Therapies in Pediatric Glioma Cell Lines
Authors: Rakotomalala Andria , Bailleul Quentin , Savary Clara , Arcicasa Mélanie , Hamadou Maud , Huchedé Paul , Hochart Audrey , Restouin Audrey , Castellano Remy , Collette Yves , Dieny Emma , Vincent Audrey , Angrand Pierre-Olivier , Le Bourhis Xuefen , Leblond Pierre , Furlan Alessandro , Castets Marie , Pasquier Eddy , Meignan Samuel
Published: November 2021

High-grade gliomas represent the most lethal class of pediatric tumors, and their resistance to both radio- and chemotherapy is associated with a poor prognosis. Recurrent mutations affecting histone genes drive the tumorigenesis of some pediatric high-grade gliomas, and H3K27M mutations are notably characteristic of a subtype of gliomas called DMG (Diffuse Midline Gliomas). This dominant negative mutation impairs H3K27 trimethylation, leading to profound epigenetic modifications of genes expression. Even though this mutation was described as a driver event in tumorigenesis, its role in tumor cell resistance to treatments has not been deciphered so far. To tackle this issue, we expressed the H3.3K27M mutated histone in three initially H3K27-unmutated pediatric glioma cell lines, Res259, SF188, and KNS42. First, we validated these new H3.3K27M-expressing models at the molecular level and showed that K27M expression is associated with pleiotropic effects on the transcriptomic signature, largely dependent on cell context. We observed that the mutation triggered an increase in cell growth in Res259 and SF188 cells, associated with higher clonogenic capacities. Interestingly, we evidenced that the mutation confers an increased resistance to ionizing radiations in Res259 and KNS42 cells. Moreover, we showed that H3.3K27M mutation impacts the sensitivity of Res259 cells to specific drugs among a library of 80 anticancerous compounds. Altogether, these data highlight that, beyond its tumorigenic role, H3.3K27M mutation is strongly involved in pediatric glioma cells’ resistance to therapies, likely through transcriptomic reprogramming.
A Review of Breast Cancer Risk Factors in Adolescents and Young Adults
Authors: McVeigh Una Mary , Tepper John William , McVeigh Terri Patricia
Published: November 2021

Cancer in adolescents and young adults (AYAs) deserves special consideration for several reasons. AYA cancers encompass paediatric malignancies that present at an older age than expected, or early-onset of cancers that are typically observed in adults. However, disease diagnosed in the AYA population is distinct to those same cancers which are diagnosed in a paediatric or older adult setting. Worse disease-free and overall survival outcomes are observed in the AYA setting, and the incidence of AYA cancers is increasing. Knowledge of an individual’s underlying cancer predisposition can influence their clinical care and may facilitate early tumour surveillance strategies and cascade testing of at-risk relatives. This information can further influence reproductive decision making. In this review we discuss the risk factors contributing to AYA breast cancer, such as heritable predisposition, environmental, and lifestyle factors. We also describe a number of risk models which incorporate genetic factors that aid clinicians in quantifying an individual’s lifetime risk of disease.
Antisense Oligonucleotide-Mediated Splice Switching: Potential Therapeutic Approach for Cancer Mitigation
Authors: Raguraman Prithi , Balachandran Akilandeswari Ashwini , Chen Suxiang , Diermeier Sarah D. , Veedu Rakesh N.
Published: November 2021

Splicing is an essential process wherein precursor messenger RNA (pre-mRNA) is reshaped into mature mRNA. In alternative splicing, exons of any pre-mRNA get rearranged to form mRNA variants and subsequently protein isoforms, which are distinct both by structure and function. On the other hand, aberrant splicing is the cause of many disorders, including cancer. In the past few decades, developments in the understanding of the underlying biological basis for cancer progression and therapeutic resistance have identified many oncogenes as well as carcinogenic splice variants of essential genes. These transcripts are involved in various cellular processes, such as apoptosis, cell signaling and proliferation. Strategies to inhibit these carcinogenic isoforms at the mRNA level are promising. Antisense oligonucleotides (AOs) have been developed to inhibit the production of alternatively spliced carcinogenic isoforms through splice modulation or mRNA degradation. AOs can also be used to induce splice switching, where the expression of an oncogenic protein can be inhibited by the induction of a premature stop codon. In general, AOs are modified chemically to increase their stability and binding affinity. One of the major concerns with AOs is efficient delivery. Strategies for the delivery of AOs are constantly being evolved to facilitate the entry of AOs into cells. In this review, the different chemical modifications employed and delivery strategies applied are discussed. In addition to that various AOs in clinical trials and their efficacy are discussed herein with a focus on six distinct studies that use AO-mediated exon skipping as a therapeutic strategy to combat cancer.
The Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions
Authors: Vallée Alexandre , Lecarpentier Yves , Vallée Jean-Noël
Published: November 2021

The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth.
Preparation of Reduced-Graphene-Oxide-Supported CoPt and Ag Nanoparticles for the Catalytic Reduction of 4-Nitrophenol
Authors: Zhang Xiaolong , Chen Lei , Liu Yang , Duan Qian
Published: November 2021

Composite nanostructure materials are widely used in catalysis. They exhibit several characteristics, such as the unique structural advantage and the synergism among their components, which significantly enhances their catalytic performance. In this work, CoPt nanoparticles and reduced-graphene-oxide-based nanocomposite catalysts (rGO/CoPt, rGO/CoPt/Ag) were prepared by using a facile co-reduction strategy. The crystalline structure, morphology, composition, and optical characteristics of the CoPt nanoparticles, rGO/CoPt nanocomposite, and rGO/CoPt/Ag nanocomposite catalysts were investigated by a set of techniques. The ID/IG value of the rGO/CoPt/Ag nanocomposite is 1.158, higher than that of rGO/CoPt (1.042). The kinetic apparent rate constant, k, of the rGO/CoPt/Ag nanocomposite against 4-nitrophenol (4-NP) reduction is 5.306 min−1, which is higher than that of CoPt (0.495 min−1) and rGO/CoPt (1.283 min−1). The normalized rate constant, knor, of the rGO/CoPt/Ag nanocomposite is 56.76 min−1mg−1, which is higher than some other catalytic materials. The rGO/CoPt/Ag nanocomposite shows a significantly enhanced catalytic performance when compared to CoPt nanoparticles and the rGO/CoPt nanocomposite, which may confirm that the novel rGO/CoPt/Ag nanocomposite is a promising catalyst for the application of catalytic fields.
Highly Enhanced Electrocatalytic Performances with Dendritic Bimetallic Palladium-Based Nanocrystals
Authors: Pramadewandaru Respati K. , Shim Jeong-Hu , Lee Young Wook , Hong Jong Wook
Published: November 2021

The exploration of efficient nanocatalysts with high activity and stability towards water electrolysis and fuel cell applications is extremely important for the advancement of electrochemical reactions. However, it remains challenging. Controlling the morphology of bimetallic Pd–Pt nanostructures can be a great way to improve their electrocatalytic properties compared with previously developed catalysts. Herein, we synthesize bimetallic Pd–Pt nanodendrites, which consist of a dense matrix of unsaturated coordination atoms and high porosity. The concentration of cetyltrimethylammonium chloride was significant for the morphology and size of the Pd–Pt nanodendrites. Pd–Pt nanodendrites prepared by cetyltrimethylammonium chloride (200 mM) showed higher activities towards both the hydrogen evolution reaction and methanol oxidation reaction compared to their different Pd–Pt nanodendrite counterparts, commercial Pd, and Pt catalysts, which was attributed to numerous unsaturated surface atoms in well-developed single branches.
Porphyromonas gingivalis Induces Proinflammatory Cytokine Expression Leading to Apoptotic Death through the Oxidative Stress/NF-κB Pathway in Brain Endothelial Cells
Authors: Charoensaensuk Vichuda , Chen Yen-Chou , Lin Yun-Ho , Ou Keng-Liang , Yang Liang-Yo , Lu Dah-Yuu
Published: November 2021

Porphyromonas gingivalis, a periodontal pathogen, has been proposed to cause blood vessel injury leading to cerebrovascular diseases such as stroke. Brain endothelial cells compose the blood-brain barrier that protects homeostasis of the central nervous system. However, whether P. gingivalis causes the death of endothelial cells and the underlying mechanisms remain unclear. This study aimed to investigate the impact and regulatory mechanisms of P. gingivalis infection in brain endothelial cells. We used bEnd.3 cells and primary mouse endothelial cells to assess the effects of P. gingivalis on endothelial cells. Our results showed that infection with live P. gingivalis, unlike heat-killed P. gingivalis, triggers brain endothelial cell death by inducing cell apoptosis. Moreover, P. gingivalis infection increased intracellular reactive oxygen species (ROS) production, activated NF-κB, and up-regulated the expression of IL-1β and TNF-α. Furthermore, N-acetyl-L-cysteine (NAC), a most frequently used antioxidant, treatment significantly reduced P. gingivalis-induced cell apoptosis and brain endothelial cell death. The enhancement of ROS production, NF-κB p65 activation, and proinflammatory cytokine expression was also attenuated by NAC treatment. The impact of P. gingivalis on brain endothelial cells was also confirmed using adult primary mouse brain endothelial cells (MBECs). In summary, our results showed that P. gingivalis up-regulates IL-1β and TNF-α protein expression, which consequently causes cell death of brain endothelial cells through the ROS/NF-κB pathway. Our results, together with the results of previous case-control studies and epidemiologic reports, strongly support the hypothesis that periodontal infection increases the risk of developing cerebrovascular disease.
Neurodevelopmental Processes in the Prefrontal Cortex Derailed by Chronic HIV-1 Viral Protein Exposure
Authors: McLaurin Kristen A. , Li Hailong , Booze Rosemarie M. , Mactutus Charles F.
Published: November 2021

Due to the widespread access to, and implementation of, combination antiretroviral therapy, individuals perinatally infected with human immunodeficiency virus type 1 (HIV-1) are living into adolescence and adulthood. Perinatally infected adolescents living with HIV-1 (pALHIV) are plagued by progressive, chronic neurocognitive impairments; the pathophysiological mechanisms underlying these deficits, however, remain understudied. A longitudinal experimental design from postnatal day (PD) 30 to PD 180 was utilized to establish the development of pyramidal neurons, and associated dendritic spines, from layers II-III of the medial prefrontal cortex (mPFC) in HIV-1 transgenic (Tg) and control animals. Three putative neuroinflammatory markers (i.e., IL-1β, IL-6, and TNF-α) were evaluated early in development (i.e., PD 30) as a potential mechanism underlying synaptic dysfunction in the mPFC. Constitutive expression of HIV-1 viral proteins induced prominent neurodevelopmental alterations and progressive synaptodendritic dysfunction, independent of biological sex, in pyramidal neurons from layers II-III of the mPFC. From a neurodevelopmental perspective, HIV-1 Tg rats exhibited prominent deficits in dendritic and synaptic pruning. With regards to progressive synaptodendritic dysfunction, HIV-1 Tg animals exhibited an age-related population shift towards dendritic spines with decreased volume, increased backbone length, and decreased head diameter; parameters associated with a more immature dendritic spine phenotype. There was no compelling evidence for neuroinflammation in the mPFC during early development. Collectively, progressive neuronal and dendritic spine dysmorphology herald synaptodendritic dysfunction as a key neural mechanism underlying chronic neurocognitive impairments in pALHIV.
Characteristics and Research Techniques Associated with the Journal Impact Factor and Other Key Metrics in Pharmacology Journals
Authors: Na Takuathung Mingkwan , Sakuludomkan Wannachai , Teekachunhatean Supanimit , Koonrungsesomboon Nut
Published: November 2021

In the present age, there is intense pressure on researchers to publish their research in ‘high-impact factor’ journals. It would be interesting to understand the trend of research publications in the field of pharmacology by exploring the characteristics of research articles, including research techniques, in relation to the journal’s key bibliometrics, particularly journal impact factor (JIF), the seemingly most mentioned metric. This study aimed to determine the characteristics and research techniques in relation to research articles in pharmacology journals with higher or lower JIF values. A cross-sectional study was conducted on primary research journals under the ‘Pharmacology and Pharmacy’ category. Analysis of 768 original research articles across 32 journals (with an average JIF of 2.565 ± 0.887) demonstrated that research studies involving molecular techniques, in vivo experiments on animals, and bioinformatics and computational modeling were significantly associated with a higher JIF value of the journal in which such contributions were published. Our analysis suggests that research studies involving such techniques/approaches are more likely to be published in higher-ranked pharmacology journals.