bluuebunny/crossref_metadata_2025 huggingface dataset:
Notarization and Anti-Plagiarism: A New Blockchain Approach
Authors: Palmisano Tonino , Convertini Vito Nicola , Sarcinella Lucia , Gabriele Luigia , Bonifazi Mariangela
Published: December 2021

In traditional notarization processes, the correctness of the activities between the parties is guaranteed by a central authority or guaranteeing institution. In this case, the authority is not able to quickly establish the originality of the content to be notarized, or at least to have a large degree of certainty without the use of automated systems. This paper presents a new notarization platform that uses blockchain technology and integrates advanced anti-plagiarism approaches able to effectively detect copyright violations of documents that users want to notarize. In addition, our proposal includes the use of models, methods, and techniques, through which a very high level of privacy and information security can be guaranteed.
Dynamic and Wrench-Feasible Workspace Analysis of a Cable-Driven Parallel Robot Considering a Nonlinear Cable Tension Model
Authors: Kieu Vu N. D. , Huang Shyh-Chour
Published: December 2021

Cable-driven parallel robots (CDPRs) have several advantages and have been widely used in many industrial fields, especially industrial applications that require high dynamics, high payload capacity, and a large workspace. In this study, a design model for a CDPR system was proposed, and kinematic and dynamic modeling of the system was performed. Experiments were carried out to identify the dynamic modulus of elastic cables based on the dynamic mechanical analysis (DMA) method. A modified kinematic equation considering cable nonlinear tension was developed to determine the optimal cable tension at each position of the end-effector, and the wrench-feasible workspace was analyzed at various motion accelerations. The simulation results show that the proposed CDPR system obtains a large workspace, and the overall workspace is satisfactory and unrestricted for moving ranges in directions limited by the X-axis and the Y-axis from −0.3 to 0.3 m and by the Z-axis from 0.1 to 0.7 m. The overall workspace was found to depend on the condition of acceleration as well as the moving ranges limited by the end-effector. With an increase in external acceleration, the cable tension distribution increased and reached a maximum in the case of 100 m/s2.
Design and Implementation of Spring Cable Shaping Method Based on Fuzzy Control
Authors: Yang Runxian , Zhou Jie , Tao Tao , Hua Lianghao , Zhang Jianfeng
Published: December 2021

In order to improve the production efficiency and elastic quality of spring cable, and meet the market demand of automatic mass production, based on the market research and experimental analysis of common spring cable shaping methods, a rapid shaping method of coil bar current heating spring cable is innovatively proposed. After the spring cable is wound on the coil bar once, the coil bar is directly heated to realize the spring wire temperature rising and setting. The process temperature is input from the man-machine interface, and the temperature control is based on a fuzzy algorithm, which is automatically adjusted by PLC. The experimental results show that, compared with the traditional sizing method, the current heating method proposed in this paper can greatly shorten the product sizing time and has good sizing effect, which can well meet the market requirement of high-quality mass production of spring cable.
Dynamics Investigation on Axial-Groove Gas Bearing-Rotor System with Rod-Fastened Structure
Authors: Li Sha , Lu Yanjun , Zhang Yongfang , Hei Di , Zhao Xiaowei
Published: December 2021

This research report discusses the dynamic behaviors of an axial-groove gas bearings-rotor system with rod-fastened structure. The time-based dependency-compressible Reynolds equation in the gas bearing nonlinear system is solved by the differential transformation method, and the continuous gas film forces of a three-axial-groove gas bearing are obtained. A dynamic mathematical model of the rotor system with rod-fastened structure supported in two- and three-axial-groove gas bearings with eight degrees of freedom is established. The dynamic motion equation of the rod-fastened rotor system is solved by the modified Newmark-β method based on disturbance compensation, which can reduce the computing error and improve computing stability. The dynamic characteristics of the rod-fastened rotor-gas bearing system are analyzed efficiently by the diversiform unbalance responses. The influence of the position angle of the pad on the nonlinear characteristics of the rod-fastened rotor system is also studied.
Estimation of Tibiofemoral and Patellofemoral Joint Forces during Squatting and Kneeling
Authors: Glitsch Ulrich , Heinrich Kai , Ellegast Rolf Peter
Published: December 2021

This study examined the differences of knee joint forces between lowering to, or rising from squat, and typical final postures of squatting and kneeling. A biomechanical model of the lower limb was configured considering large knee flexion angles, multiple floor contact points, and the soft tissue contact between the thigh and calf. Inverse dynamics were used to determine muscle and compressive joint forces in the tibiofemoral and patellofemoral joints. Data were obtained from a group of 13 male subjects by means of 3D motion capturing, two force plates, a pressure-sensitive pad, and electromyography. During lowering into the kneeling/squatting positions and rising from them, the model exhibited the anticipated high maximum forces of 2.6 ± 0.39 body weight (BW) and 3.4 ± 0.56 BW in the tibiofemoral and patellofemoral joints. Upon attainment of the static terminal squatting and kneeling positions, the forces fell considerably, remaining within a range of between 0.5 and 0.7 BW for the tibiofemoral joint and 0.9 to 1.1 BW for the patellofemoral joint. The differences of the knee joint forces between the final postures of squatting and kneeling remained on average below 0.25 BW and were significant only for the tibiofemoral joint force.
Innovative Collaborative Method for Interaction between a Human Operator and Robotic Manipulator Using Pointing Gestures
Authors: Čorňák Marek , Tölgyessy Michal , Hubinský Peter
Published: December 2021

The concept of “Industry 4.0” relies heavily on the utilization of collaborative robotic applications. As a result, the need for an effective, natural, and ergonomic interface arises, as more workers will be required to work with robots. Designing and implementing natural forms of human–robot interaction (HRI) is key to ensuring efficient and productive collaboration between humans and robots. This paper presents a gestural framework for controlling a collaborative robotic manipulator using pointing gestures. The core principle lies in the ability of the user to send the robot’s end effector to the location towards, which he points to by his hand. The main idea is derived from the concept of so-called “linear HRI”. The framework utilizes a collaborative robotic arm UR5e and the state-of-the-art human body tracking sensor Leap Motion. The user is not required to wear any equipment. The paper describes the overview of the framework’s core method and provides the necessary mathematical background. An experimental evaluation of the method is provided, and the main influencing factors are identified. A unique robotic collaborative workspace called Complex Collaborative HRI Workplace (COCOHRIP) was designed around the gestural framework to evaluate the method and provide the basis for the future development of HRI applications.
AlGaInAs Multi-Quantum Well Lasers on Silicon-on-Insulator Photonic Integrated Circuits Based on InP-Seed-Bonding and Epitaxial Regrowth
Authors: Besancon Claire , Néel Delphine , Make Dalila , Ramírez Joan Manel , Cerulo Giancarlo , Vaissiere Nicolas , Bitauld David , Pommereau Frédéric , Fournel Frank , Dupré Cécilia , Mehdi Hussein , Bassani Franck , Decobert Jean
Published: December 2021

The tremendous demand for low-cost, low-consumption and high-capacity optical transmitters in data centers challenges the current InP-photonics platform. The use of silicon (Si) photonics platform to fabricate photonic integrated circuits (PICs) is a promising approach for low-cost large-scale fabrication considering the CMOS-technology maturity and scalability. However, Si itself cannot provide an efficient emitting light source due to its indirect bandgap. Therefore, the integration of III-V semiconductors on Si wafers allows us to benefit from the III-V emitting properties combined with benefits offered by the Si photonics platform. Direct epitaxy of InP-based materials on 300 mm Si wafers is the most promising approach to reduce the costs. However, the differences between InP and Si in terms of lattice mismatch, thermal coefficients and polarity inducing defects are challenging issues to overcome. III-V/Si hetero-integration platform by wafer-bonding is the most mature integration scheme. However, no additional epitaxial regrowth steps are implemented after the bonding step. Considering the much larger epitaxial toolkit available in the conventional monolithic InP platform, where several epitaxial steps are often implemented, this represents a significant limitation. In this paper, we review an advanced integration scheme of AlGaInAs-based laser sources on Si wafers by bonding a thin InP seed on which further regrowth steps are implemented. A 3 µm-thick AlGaInAs-based MutiQuantum Wells (MQW) laser structure was grown onto on InP-SiO2/Si (InPoSi) wafer and compared to the same structure grown on InP wafer as a reference. The 400 ppm thermal strain on the structure grown on InPoSi, induced by the difference of coefficient of thermal expansion between InP and Si, was assessed at growth temperature. We also showed that this structure demonstrates laser performance similar to the ones obtained for the same structure grown on InP. Therefore, no material degradation was observed in spite of the thermal strain. Then, we developed the Selective Area Growth (SAG) technique to grow multi-wavelength laser sources from a single growth step on InPoSi. A 155 nm-wide spectral range from 1515 nm to 1670 nm was achieved. Furthermore, an AlGaInAs MQW-based laser source was successfully grown on InP-SOI wafers and efficiently coupled to Si-photonic DBR cavities. Altogether, the regrowth on InP-SOI wafers holds great promises to combine the best from the III-V monolithic platform combined with the possibilities offered by the Si photonics circuitry via efficient light-coupling.
25-hydroxyvitamin D3 Levels and Their Clinical Associations in a Polish Cohort of Systemic Sclerosis Patients: A Cross-Sectional Study
Authors: Żebryk Paweł , Nowak Jan Krzysztof , Piorunek Tomasz , Mularek-Kubzdela Tatiana , Puszczewicz Mariusz
Published: December 2021

Vitamin D exhibits immunomodulatory effects in autoimmune diseases. We aimed to evaluate the associations of vitamin D levels with clinical and laboratory features of systemic sclerosis (SSc) in a Polish cohort. The study was prospective in design. SSc patients who met ACR-EULAR 2013 criteria underwent comprehensive clinical and laboratory investigations using the European Scleroderma Trials and Research group (EUSTAR) methodology. We assessed patients’ sera for 25(OH)D3 using a radioimmunoassay, and the cutoff value for vitamin D deficiency was set at 20 ng/mL. Statistical analyses were performed using the Mann–Whitney U test, the Fisher’s exact, and the Spearman’s rho, where appropriate, with a significance threshold set at 0.05. We recruited 68 SSc patients (85% female). The mean 25(OH)D3 level was 21.6 ± 10 ng/mL, and 50% of subjects (n = 34) presented vitamin D deficiency (mean 13.7 ± 3.9 ng/mL). Vitamin D-deficient SSc patients exhibited higher prevalence of arterial hypertension (p = 0.002), proteinuria (p = 0.002), and lung fibrosis (p = 0.032), as well as higher CRP (p = 0.035). The modified Rodnan skin score correlated negatively with 25(OH)D3 in diffuse cutaneous SSc (dcSSc). We found no correlation with the disease duration, age, joints, and the heart. Vitamin D deficiency was common in the studied population of Polish SSc patients and was associated with arterial hypertension, proteinuria, lung involvement, and increased CRP.
Statistical Modelling for the Source Rock Parameters of the Montney Formation, NE British Columbia, Canada
Authors: Barham Azzam , Ismail Mohd Suhaili , Hermana Maman
Published: December 2021

Hydrocarbons in self-sourced reservoirs are determined by the concentration and maturation of organic matter in sediments. As a result, lowering risk in unconventional resource research and development requires knowledge of hydrocarbon potentiality factors. The geochemical data for the Montney Formation samples studied suggest that it is a fair to good source rock with type IV kerogen that can generate gas in general. The statistical modelling of the analyzed data reveals a valuable technique for identifying characteristics, clusters, and linkages that affect source rock assessment. The Spearman’s correlation coefficient showed a good positive correlation between the total organic carbon (TOC) and free hydrocarbons (S1), generating potential (S2), and potential yield (GP). There was a weak correlation with the maturity index (Tmax) and hydrogen index (HI) and a highly negative correlation between the TOC and oxygen index (OI). On the other hand, the principal component analysis (PCA) showed the presence of three factors affecting the source rock evaluation. Factor 1 included TOC, S1, and S2, which are related to organic richness and hydrocarbon potentiality; factor 2 contained the production index (PI), and the generated CO2 (S3) was related to the organic matter source. Factor 3 included the Tmax and HI related to the type of organic matter and thermal maturity. In addition, the TwoStep cluster analysis separated the source rock in the study area into two major groups. Cluster 1 is characterized relatively by high HI, TOC, S1, S2, and PI, with Tmax < 455 °C indicating good source rock in the mature level with the capability to generate little oil and condensate gas. Cluster 2 is characterized by relatively low HI, TOC, S1, S2, and PI, with Tmax > 455 °C, indicating an over-mature source rock in the dry gas window.
Cooperative Multi-Robot Task Allocation with Reinforcement Learning
Authors: Park Bumjin , Kang Cheongwoong , Choi Jaesik
Published: December 2021

This paper deals with the concept of multi-robot task allocation, referring to the assignment of multiple robots to tasks such that an objective function is maximized. The performance of existing meta-heuristic methods worsens as the number of robots or tasks increases. To tackle this problem, a novel Markov decision process formulation for multi-robot task allocation is presented for reinforcement learning. The proposed formulation sequentially allocates robots to tasks to minimize the total time taken to complete them. Additionally, we propose a deep reinforcement learning method to find the best allocation schedule for each problem. Our method adopts the cross-attention mechanism to compute the preference of robots to tasks. The experimental results show that the proposed method finds better solutions than meta-heuristic methods, especially when solving large-scale allocation problems.
Comparison of Activation Methods for 3D-Printed Electrodes for Microbial Electrochemical Technologies
Authors: Alonso Raúl M. , San Martín Isabel , Morán Antonio , Escapa Adrián
Published: December 2021

Three-dimensional printing could provide flexibility in the design of a new generation of electrodes to be used in microbial electrochemical technologies (MET). In this work, we demonstrate the feasibility of using polylactic acid (PLA)/graphene—a common 3D-printing material—to build custom bioelectrodes. We also show that a suitable activation procedure is crucial to achieve an acceptable electrochemical performance (plain PLA/graphene bioanodes produce negligible amounts of current). Activation with acetone and dimethylformamide resulted in current densities similar to those typically observed in bioanodes built with more conventional materials (about 5 Am−2). In addition, the electrodes thus activated favored the proliferation of electroactive bacteria.
Aerodynamics of a Train and Flat Closed-Box Bridge System with Train Model Mounted on the Upstream Track
Authors: Wang Hui , Li Huan , He Xuhui
Published: December 2021

The aerodynamic features of a train and flat closed-box bridge system may be highly sensitive to train-bridge aero interactions. For the generally utilized railway bridge-deck with two tracks (the upstream and downstream ones), the aero interactions above are occupied-track-dependent. The present paper thus aims to reveal the aero interactions stated above via a series of wind tunnel tests. The results showed that the aero interactions of the present train-bridge system display four typical behaviors, namely, the underbody flow restraining effect, bridge deck shielding effect, flow transition promoting effect, and the flow separation intensifying effect. The above four aero interactions result in obvious reductions in the aerodynamic forces of the train in wind angle of attack α of [−4°, 12°] and in the static stall angle of the bridge-deck, and leads to sensible increases in the absolute values of the bridge aerodynamic forces in α of [−4°, 12°]. Upon comparing the results with the same train and bridge system but with the train model mounted on the downstream track, the quasi-Reynolds number effect was non-detectable when the train model was moved to the upstream track. Thus, no drag crisis and other saltatory aerodynamic behaviors were observed in the present study in α of [0°, 12°].
Assessment of Mercury Concentrations and Fluxes Deposited from the Atmosphere on the Territory of the Yamal-Nenets Autonomous Area
Authors: Eyrikh Stella , Shol Liliya , Shinkaruk Elena
Published: December 2021

The problem of mercury input and its further distribution in the Arctic environment is actively debated, especially in recent times, due to the observed processes of permafrost thawing causing the enhanced release of mercury into the Arctic atmosphere and further distribution in the terrestrial and aquatic ecosystem. The atmospheric mercury deposition occurs via dry deposition and wet scavenging by precipitation events. Here we present a study of Hg in wet precipitation on the remote territory of the Russian Arctic; the data were obtained at the monitoring stations Nadym and Salekhard in 2016–2018. Mercury pollution of the Salekhard atmosphere in cold time is mainly determined by regional and local sources, while in Nadym, long-range transport of mercury and local fuel combustion are the main sources of pollutants in the cold season, while internal regional sources have a greater impact on the warm season. Total mercury concentrations in wet precipitation in Nadym varied from <0.5 to 63.3 ng/L. The highest Hg concentrations in the springtime were most likely attributed to atmospheric mercury depletion events (AMDE). The contributions of wet atmospheric precipitation during the AMDE period to the annual Hg deposition were 16.7% and 9.8% in 2016/2017 and 2017/2018, respectively. The average annual volume-weighted Hg concentration (VWC) in the atmospheric precipitation in Nadym is notably higher than the values reported for the remote regions in the Arctic and comparable with the values obtained for the other urbanized regions of the world. Annual Hg fluxes in Nadym are nevertheless close to the average annual fluxes for remote territories of the Arctic zone and significantly lower than the annual fluxes reported for unpolluted sites of continental-scale monitoring networks of the different parts of the world (USA, Europe, and China). The increase of Hg deposition flux with wet precipitation in Nadym in 2018 might be caused by regional emissions of gas and oil combustion, wildfires, and Hg re-emission from soils due to the rising air temperature. The 37 cm increase of the seasonally thawed layer (STL) in 2018 compared to the 10-year average reflects that the climatic changes in the Nadym region might increase Hg(0) evasion, considering a great pool of Hg is contained in permafrost.
The Effects of Topography and Urban Agglomeration on the Sea Breeze Evolution over the Pearl River Delta Region
Authors: He Guoqing , Yuan Guanghui , Liu Yubao , Jiang Yin , Liu Yuewei , Shu Zhuozhi , Ma Xiaodan , Li Yang , Huo Zhaoyang
Published: December 2021

Sea breezes are one of the most important weather processes affecting the environmental and climatic features over coastal areas, and the sea breeze from the Pearl River Estuary (PRE) has significant effects on the Pearl River Delta (PRD) region. We simulated a typical sea breeze process that occurred on 27 December 2020 in the PRD region using the Weather Research and Forecasting (WRF) model to quantify the effects of topography and city clusters on the development of the sea breeze circulation. The results show that: (1) the topography on the west coast of the PRD tends to block the intrusion of the sea breeze and detour it along the eastern part of the terrain in the southeast of Jiangmen. The depth of sea breeze along the position of the detour is increased by 120 m, the penetration distance is increased by 40 km, the maximum intensity of sea breeze decreases by ~0.4 m/s, and the time of maximum speed delays for 4 h. However, on the east coast, the topography promotes the sea breeze, resulting in an occurrence about 4 h earlier due to the heating effects. The depth and the speed of the sea breeze are increased by 466 m and 1.2 m/s, respectively. (2) Under the influence of Urban Heat Island Circulation (UHIC), the sea breezes reach cities near the coast an hour earlier and are later inhibited from propagating further inland. Moreover, a wind convergence zone with a speed of 3–5 m/s and a width of about 25 km is formed along the boundary of suburbs and cities in the PRD region. As a result, two important convergence areas: Foshan–Guangzhou, and Dongguan–Shenzhen are formed. (3) Overall, the topography has a more remarkable impact on the mesoscale wind field especially in the mountain and bay areas, resulting in an average speed disturbance of 2.8 m/s. The urban heat island effect is relatively small and on average it causes only ± 0.9–1.8 m/s wind speed perturbations in the periphery of two convergence areas and over PRE.
Evaluation Schoolyard Wind Comfort Changes Due to Rapid Developments: Case Study of Nanjing, China
Authors: Xu Qiuxia , Xu Zhen , Sun Chayn
Published: December 2021

(1) Background: Evaluation of wind environments regarding pedestrian comfort may unveil potential hotspot areas, particularly in the context of the rapid urban development in China since the 1990s. (2) Method: With primary schools in Nanjing as case studies, the authors simulated the wind environment of schoolyards with the computational fluid dynamics (CFD) approach and evaluated relevant wind comfort criteria. (3) Results: The study showed that the comfortable wind environment of schoolyards generally expanded in three primary schools in summer and winter, and wind speed and the comfortable wind level decreased in some outdoor schoolyard spaces. The results also indicate that the mean wind speed of the schoolyards did not linearly correlate to the building density either within or outside the schools. An increase in the building height of the primary schools could improve the wind comfort of the schoolyard, but the increased building height in the vicinity may worsen the wind comfort in the schools. Meanwhile, a lift-up or step-shaped building design for schools can improve wind comfort in schoolyards. (4) Conclusions: This study provided simulated results and an approach for urban designers to evaluate and improve the wind environment for school children’s outdoor activities.
Precision Preventive Medicine of Relapse in Smoking Cessation: Can MRI Inform the Search of Intermediate Phenotypes?
Authors: Rabat Yolaine , Chanraud Sandra , Abdallah Majd , Sibon Igor , Berthoz Sylvie
Published: December 2021

Chronic tobacco smoking remains a major health problem worldwide. Numerous smokers wish to quit but most fail, even if they are helped. The possibility of identifying neuro-biomarkers in smokers at high risk of relapse could be of incredible progress toward personalized prevention therapy. Our aim is to provide a scoping review of this research topic in the field of Magnetic Resonance Imaging (MRI) and to review the studies that investigated if MRI defined markers predicted smoking cessation treatment outcome (abstainers versus relapsers). Based on the available literature, a meta-analysis could not be conducted. We thus provide an overview of the results obtained and take stock of methodological issues that will need to be addressed to pave the way toward precision medicine. Based on the most consistent findings, we discuss the pivotal role of the insula in light of the most recent neurocognitive models of addiction.
Interlaboratory Validation of Toxicity Testing Using the Duckweed Lemna minor Root-Regrowth Test
Authors: Park Jihae , Yoo Eun-Jin , Shin Kisik , Depuydt Stephen , Li Wei , Appenroth Klaus-J. , Lillicrap Adam D. , Xie Li , Lee Hojun , Kim Geehyoung , Saeger Jonas De , Choi Soyeon , Kim Geonhee , Brown Murray T. , Han Taejun
Published: December 2021

The common duckweed (Lemna minor), a freshwater monocot that floats on the surfaces of slow-moving streams and ponds, is commonly used in toxicity testing. The novel Lemna root- regrowth test is a toxicity test performed in replicate test vessels (24-well plates), each containing 3 mL test solution and a 2–3 frond colony. Prior to exposure, roots are excised from the plant, and newly developed roots are measured after 3 days of regrowth. Compared to the three internationally standardized methods, this bioassay is faster (72 h), simpler, more convenient (requiring only a 3-mL) and cheaper. The sensitivity of root regrowth to 3,5-dichlorophenol was statistically the same as using the conventional ISO test method. The results of interlaboratory comparison tests conducted by 10 international institutes showed 21.3% repeatability and 27.2% reproducibility for CuSO4 and 21.28% repeatability and 18.6% reproducibility for wastewater. These validity criteria are well within the generally accepted levels of <30% to 40%, confirming that this test method is acceptable as a standardized biological test and can be used as a regulatory tool. The Lemna root regrowth test complements the lengthier conventional protocols and is suitable for rapid screening of wastewater and priority substances spikes in natural waters.
Characterization of the Gastrointestinal and Reproductive Tract Microbiota in Fertile and Infertile Pakistani Couples
Authors: Manzoor Ammara , Amir Saira , Gul Farzana , Sidique Muhammad Abubakar , Kayani Masood ur Rehman , Zaidi Syed Shujaat Ali , Javed Sundus , Abbas Shah Syed Tahir , Nasir Arshan
Published: December 2021

The human microbiota is recognized as a vital “virtual” organ of the human body that influences human health, metabolism, and physiology. While the microbiomes of the gut, oral cavity, and skin have been extensively studied in the literature, relatively little work has been done on characterizing the microbiota of the human reproductive tract organs, and specifically on investigating its association to fertility. Here, we implemented a 16S ribosomal RNA (rRNA) amplicon sequencing approach to sequence and characterize the gut and genital tract microbiomes from several married Pakistani couples. The recruited individuals included 31 fertile and 35 infertile individuals, with ages ranging from 19–45 years. We identified several fluctuations in the diversity and composition of the gut and genital microbiota among fertile and infertile samples. For example, measures of α-diversity varied significantly between the genital samples donated by fertile and infertile men and there was overall greater between-sample variability in genital samples regardless of gender. In terms of taxonomic composition, Actinobacteria, Bacteroidetes, and Firmicutes fluctuated significantly between the gut microbiomes of fertile and infertile samples. Finally, biomarker analyses identified features (genera and molecular functions and pathways) that differed significantly between the fertile and infertile samples and in the past have been associated with bacterial vaginosis. However, we emphasize that 16S amplicon data alone has no bearing on individual health and is merely representative of microbial taxonomic differences that could also arise due to multiple other factors. Our findings, however, represent the first effort to characterize the microbiome associated with fertile and infertile couples in Pakistan and will hopefully pave the way for more comprehensive and broad-scale investigations in the future.
RTP801/REDD1 Is Involved in Neuroinflammation and Modulates Cognitive Dysfunction in Huntington’s Disease
Authors: Pérez-Sisqués Leticia , Solana-Balaguer Júlia , Campoy-Campos Genís , Martín-Flores Núria , Sancho-Balsells Anna , Vives-Isern Marcel , Soler-Palazón Ferran , Garcia-Forn Marta , Masana Mercè , Alberch Jordi , Pérez-Navarro Esther , Giralt Albert , Malagelada Cristina
Published: December 2021

RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson’s, Alzheimer’s, and Huntington’s diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples, and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction in inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease.
Secondary Metabolites Coordinately Protect Grapes from Excessive Light and Sunburn Damage during Development
Authors: Gambetta Joanna M. , Romat Valentina , Schmidtke Leigh M. , Holzapfel Bruno P.
Published: December 2021

Sunburn is a physiological disorder that reduces grape quality and vineyard yield. It is the result of excessive sunlight and high temperatures. As climate change continues to increase air temperatures, reports of sunburn damage in vineyards worldwide are becoming more frequent. Grapes produce secondary metabolites (carotenoids, polyphenols and aroma compounds) to counter photooxidative stress and acclimate to higher radiation environments. This study evaluated changes in these compounds in during ripening when grapes were exposed post-flowering (ED) and at véraison (LD), and compared them to a nondefoliated control (ND). ND contained more α-terpineol and violaxanthin, and the defoliated treatments contained more zeaxanthin, β-carotene, C6 compounds and flavonoids. ED berries adapted better to higher-light environments, displayed larger changes in secondary metabolite concentrations and lower levels of sunburn damage than LD berries did. The composition of berries with increasing sunburn damage was evaluated for the first time. Berries with no damage had the lowest concentrations of flavonoids and oxidized glutathione, and the highest concentrations of chlorophyll and α-terpineol. As damage increased, destruction of photosynthetic pigments, increase in polyphenols and loss of aroma compounds were evidenced. A significant effect of temperature and developmental stage on grape composition was also observed. This study provides a holistic overview of changes in secondary metabolites experienced by grape berries when exposed to excessive light, how these vary along development and how they affect sunburn incidence.
Analysis of Clinical Characteristics, Background, and Paroxysmal Activity in EEG of Patients with Juvenile Myoclonic Epilepsy
Authors: Santiago-Rodríguez Efraín , Zaldívar-Uribe Elba
Published: December 2021

Juvenile myoclonic epilepsy (JME) appears in adolescence with myoclonic, absence, and generalized tonic clonic (GTC) seizures with paroxysmal activity of polyspike and slow wave (PSW), or spike and wave (SW) complexes in EEG. Our aim was to analyze the clinical characteristics, background EEG activity, and paroxysmal events in 41 patients with JME. Background EEG activity was analyzed with visual, quantitative (QEEG), and neurometric parameters. Our JME patients started with absence seizures at 11.4 ± 1.5 years old, myoclonic seizures at 13.6 ± 2.5 years, and GTC seizures at 15.1 ± 0.8 years. The seizures presented in awakening at 7:39 h with sleep deprivation, alcoholic beverage intake, and stress as the most frequent precipitant factors. Paroxysmal activity was of PSW and fast SW complexes with 40.5 ± 62.6 events/hour and a duration of 1.7 s. Right asymmetric paroxysmal activity was present in 68.3% of patients. Background EEG activity was abnormal in 31.7% of patients with visual analysis. With QEEG beta AP (absolute power) increase and AP delta decrease were the most frequent abnormalities found. Spectral analysis showed that 48.7% of patients had normal results, and 26.83% and 24.4% had higher and lower frequencies than 10.156 Hz, respectively. We concluded that, with visual analysis, background EEG activity was abnormal in a few patients and the abnormalities increased when QEEG was used.
Identification of Neoantigens in Two Murine Gastric Cancer Cell Lines Leading to the Neoantigen-Based Immunotherapy
Authors: Nagaoka Koji , Sun Changbo , Kobayashi Yukari , Kanaseki Takayuki , Tokita Serina , Komatsu Toshihiro , Maejima Kazuhiro , Futami Junichiro , Nomura Sachiyo , Udaka Keiko , Nakagawa Hidewaki , Torigoe Toshihiko , Kakimi Kazuhiro
Published: December 2021

To develop combination immunotherapies for gastric cancers, immunologically well-characterized preclinical models are crucial. Here, we leveraged two transplantable murine gastric cancer cell lines, YTN2 and YTN16, derived from the same parental line but differing in their susceptibility to immune rejection. We established their differential sensitivity to immune checkpoint inhibitors (ICI) and identified neoantigens. Although anti-CTLA-4 mAbs eradicated YTN16 tumors in 4 of 5 mice, anti-PD-1 and anti-PD-L1 mAbs failed to eradicate YTN16 tumors. Using whole-exome and RNA sequencing, we identified two and three neoantigens in YTN2 and YTN16, respectively. MHC class I ligandome analysis detected the expression of only one of these neoantigens, mutated Cdt1, but the exact length of MHC binding peptide was determined. Dendritic cell vaccine loaded with neoepitope peptides and adoptive transfer of neoantigen-specific CD8+ T cells successfully inhibited the YTN16 tumor growth. Targeting mutated Cdt1 had better efficacy for controlling the tumor. Therefore, mutated Cdt1 was the dominant neoantigen in these tumor cells. More mCdt1 peptides were bound to MHC class I and presented on YTN2 surface than YTN16. This might be one of the reasons why YTN2 was rejected while YTN16 grew in immune-competent mice.
Efficacy of Neoadjuvant Targeted Therapy for Borderline Resectable III B-D or IV Stage BRAF V600 Mutation-Positive Melanoma
Authors: Czarnecka Anna M. , Ostaszewski Krzysztof , Borkowska Aneta , Szumera-Ciećkiewicz Anna , Kozak Katarzyna , Świtaj Tomasz , Rogala Paweł , Kalinowska Iwona , Koseła-Paterczyk Hanna , Zaborowski Konrad , Teterycz Paweł , Tysarowski Andrzej , Makuła Donata , Rutkowski Piotr
Published: December 2021

Neoadjuvant therapy for locally advanced disease or potentially resectable metastatic melanoma is expected to improve operability and clinical outcomes over upfront surgery and adjuvant treatment as it is for sarcoma, breast, rectal, esophageal, or gastric cancers. Patients with locoregional recurrence after initial surgery and those with advanced regional lymphatic metastases are at a high risk of relapse and melanoma-related death. There is an unmet clinical need to improve the outcomes for such patients. Patients with resectable bulky stage III or resectable stage IV histologically confirmed melanoma were enrolled and received standard-dose BRAFi/MEKi for at least 12 weeks before feasible resection of the pre-therapy target and then received at least for the next 40 weeks further BRAFi/MEKi. Of these patients, 37 were treated with dabrafenib and trametinib, three were treated with vemurafenib and cobimetinib, five with vemurafenib, and one with dabrafenib alone. All patients underwent surgery with 78% microscopically margin-negative resection (R0) resection. Ten patients achieved a complete pathological response. In patients with a major pathological response with no, or less than 10%, viable cells in the tumor, median disease free survival and progression free survival were significantly longer than in patients with a minor pathological response. No patient discontinued neoadjuvant BRAFi/MEKi due to toxicity. BRAFi/MEKi pre-treatment did not result in any new specific complications of surgery. Fourteen patients experienced disease recurrence or progression during post-operative treatment. We confirmed that BRAFi/MEKi combination is an effective and safe regimen in the perioperative treatment of melanoma. Pathological response to neoadjuvant treatment may be considered as a surrogate biomarker of disease recurrence.
Proton Minibeam Radiation Therapy and Arc Therapy: Proof of Concept of a Winning Alliance
Authors: Ortiz Ramon , De Marzi Ludovic , Prezado Yolanda
Published: December 2021

(1) Background: Proton Arc Therapy and Proton Minibeam Radiation Therapy are two novel therapeutic approaches with the potential to lower the normal tissue complication probability, widening the therapeutic window for radioresistant tumors. While the benefits of both modalities have been individually evaluated, their combination and its potential advantages are being assessed in this proof-of-concept study for the first time. (2) Methods: Monte Carlo simulations were employed to evaluate the dose and LET distributions in brain tumor irradiations. (3) Results: a net reduction in the dose to normal tissues (up to 90%), and the preservation of the spatial fractionation of the dose were achieved for all configurations evaluated. Additionally, Proton Minibeam Arc Therapy (pMBAT) reduces the volumes exposed to high-dose and high-LET values at expense of increased low-dose and intermediate-LET values. (4) Conclusions: pMBAT enhances the individual benefits of proton minibeams while keeping those of conventional proton arc therapy. These results might facilitate the path towards patients’ treatments since lower peak doses in normal tissues would be needed than in the case of a single array of proton minibeams.
The Pre-Operative GRADE Score Is Associated with 5-Year Survival among Older Patients with Cancer Undergoing Surgery
Authors: Wind Philippe , ap Thomas Zoe , Laurent Marie , Aparicio Thomas , Siebert Matthieu , Audureau Etienne , Paillaud Elena , Bousquet Guilhem , Pamoukdjian Frédéric
Published: December 2021

We aimed to assess the prognostic value of the pre-operative GRADE score for long-term survival among older adults undergoing major surgery for digestive or non-breast gynaecological cancers. Between 2013 and 2019, 136 consecutive older adults with cancer were prospectively recruited from the PF-EC cohort study before major cancer surgery and underwent a geriatric assessment. The GRADE score includes weight loss, gait speed at the threshold of 0.8 m/s, cancer site and cancer extension. The primary outcome was post-operative 5-year mortality. Patients were classified as low risk (GRADE ≤ 8) or high risk (GRADE > 8) on the basis of the median score. A Cox multivariate proportional hazards regression model was performed to assess the association between pre-operative factors and 5-year mortality expressed by adjusted hazard ratio (aHR) and 95% CI. The median age was 80 years, 52% were men, 73% had colorectal cancer. The 30-day post-operative severe complication rate (Clavien-Dindo ≥ 3) was 37%. The 5-year post-operative mortality rate was 34.5%. A GRADE score ≥ 8 (aHR = 2.64 [1.34–5.21], p = 0.0002) was associated with post-operative mortality after adjustment for Body Mass Index < 21 kg/m2 and Instrumental Activities of Daily Living <3/4. By combining very simple geriatric and cancer parameters, the pre-operative GRADE score provides a discriminant prognosis and could help to choose the most suitable treatment strategy for older cancer patients, avoiding under or over-treatment.
Percutaneous Hepatic Perfusion (PHP) with Melphalan in Liver-Dominant Metastatic Uveal Melanoma: The German Experience
Authors: Dewald Cornelia L. A. , Warnke Mia-Maria , Brüning Roland , Schneider Martin A. , Wohlmuth Peter , Hinrichs Jan B. , Saborowski Anna , Vogel Arndt , Wacker Frank K.
Published: December 2021

Percutaneous hepatic perfusion (PHP) delivers high-dose melphalan to the liver while minimizing systemic toxicity via filtration of the venous hepatic blood. This two-center study aimed to examine the safety, response to therapy, and survival of patients with hepatic-dominant metastatic uveal melanoma (UM) treated with PHP. A total of 66 patients with liver-dominant metastasized uveal melanoma, treated with 145 PHP between April 2014 and May 2020, were retrospectively analyzed with regard to adverse events (AEs; CTCAE v5.0), response (overall response rate (ORR)), and disease control rate (DCR) according to RECIST1.1, as well as progression-free and overall survival (PFS and OS). With an ORR of 59% and a DCR of 93.4%, the response was encouraging. After initial PHP, median hepatic PFS was 12.4 (confidence interval (CI) 4–18.4) months and median OS was 18.4 (CI 7–24.6) months. Hematologic toxicity was the most frequent AE (grade 3 or 4 thrombocytopenia after 24.8% of the procedures); less frequent was grade 3 or 4 hepatic toxicity (increased aspartate transaminase (AST) and alanine transaminase (ALT) after 7.6% and 6.9% of the interventions, respectively). Cardiovascular events included four cases of ischemic stroke (2.8%) and one patient with central pulmonary embolism (0.7%). In conclusion, PHP is a safe and effective salvage treatment for liver-dominant metastatic uveal melanoma. Serious AEs—though rare—demand careful patient selection.
Increased Production of B-Cell Activating Cytokines and Altered Peripheral B-Cell Subset Distribution during HIV-Related Classical Hodgkin Lymphoma
Authors: Lievin Raphael , Hendel-Chavez Houria , Baldé Aliou , Lancar Rémi , Algarte-Génin Michèle , Krzysiek Roman , Costagliola Dominique , Assoumou Lambert , Taoufik Yassine , Besson Caroline
Published: December 2021

Classical Hodgkin Lymphoma incidence increases in HIV-1-infected patients (HIV-cHL). HIV infection is associated with higher B-cell activation. Here, in 38 HIV-cHL patients from the French cohort ANRS-CO16 Lymphovir, we examined longitudinally over 24 months the serum levels of the B-cell activating cytokines IL10, IL6, and BAFF, and blood distribution of B-cell subsets. Fourteen HIV-cHL patients were also compared to matched HIV-infected controls without cHL. IL10, IL6, and BAFF levels were higher in HIV-cHL patients than in controls (p < 0.0001, p = 0.002, and p < 0.0001, respectively). Cytokine levels increased in patients with advanced-stage lymphoma compared to those with limited-stage (p = 0.002, p = 0.03, and p = 0.01, respectively). Cytokine levels significantly decreased following HIV-cHL diagnosis and treatment. Blood counts of whole B-cells were similar in HIV-cHL patients and controls, but the distribution of B-cell subsets was different with higher ratios of naive B-cells over memory B-cells in HIV-cHL patients. Blood accumulation of naive B-cells was more marked in patients with advanced cHL stages (p = 0.06). During the follow-up, total B-cell counts increased (p < 0.0001), and the proportion of naive B-cells increased further (p = 0.04). Together the results suggest that in HIV-infected patients, cHL is associated with a particular B-cell-related environment that includes increased production of B-cell-activating cytokines and altered peripheral distribution of B-cell subsets. This B-cell-related environment may fuel the process of tumorigenesis.
Patient-Oriented Perspective on Chemokine Receptor Expression and Function in Glioma
Authors: Isci Damla , D’Uonnolo Giulia , Wantz May , Rogister Bernard , Lombard Arnaud , Chevigné Andy , Szpakowska Martyna , Neirinckx Virginie
Published: December 2021

Gliomas are severe brain malignancies, with glioblastoma (GBM) being the most aggressive one. Despite continuous efforts for improvement of existing therapies, overall survival remains poor. Over the last years, the implication of chemokines and their receptors in GBM development and progression has become more evident. Recently, large amounts of clinical data have been made available, prompting us to investigate chemokine receptors in GBM from a still-unexplored patient-oriented perspective. This study aims to highlight and discuss the involvement of chemokine receptors—CCR1, CCR5, CCR6, CCR10, CX3CR1, CXCR2, CXCR4, ACKR1, ACKR2, and ACKR3—most abundantly expressed in glioma patients based on the analysis of publicly available clinical datasets. Given the strong intratumoral heterogeneity characterizing gliomas and especially GBM, receptor expression was investigated by glioma molecular groups, by brain region distribution, emphasizing tissue-specific receptor functions, and by cell type enrichment. Our study constitutes a clinically relevant and patient-oriented guide that recapitulates the expression profile and the complex roles of chemokine receptors within the highly diversified glioma landscape. Additionally, it strengthens the importance of patient-derived material for development and precise amelioration of chemokine receptor-targeting therapies.
New Perspectives for Eye-Sparing Treatment Strategies in Primary Uveal Melanoma
Authors: Bilmin Krzysztof , Synoradzki Kamil J. , Czarnecka Anna M. , Spałek Mateusz J. , Kujawska Tamara , Solnik Małgorzata , Merks Piotr , Toro Mario Damiano , Rejdak Robert , Fiedorowicz Michał
Published: December 2021

Uveal melanoma is the most common intraocular malignancy and arises from melanocytes in the choroid, ciliary body, or iris. The current eye-sparing treatment options include surgical treatment, plaque brachytherapy, proton beam radiotherapy, stereotactic photon radiotherapy, or photodynamic therapy. However, the efficacy of these methods is still unsatisfactory. This article reviews several possible new treatment options and their potential advantages in treating localized uveal melanoma. These methods may be based on the physical destruction of the cancerous cells by applying ultrasounds. Two examples of such an approach are High-Intensity Focused Ultrasound (HIFU)—a promising technology of thermal destruction of solid tumors located deep under the skin and sonodynamic therapy (SDT) that induces reactive oxygen species. Another approach may be based on improving the penetration of anti-cancer agents into UM cells. The most promising technologies from this group are based on enhancing drug delivery by applying electric current. One such approach is called transcorneal iontophoresis and has already been shown to increase the local concentration of several different therapeutics. Another technique, electrically enhanced chemotherapy, may promote drug delivery from the intercellular space to cells. Finally, new advanced nanoparticles are developed to combine diagnostic imaging and therapy (i.e., theranostics). However, these methods are mostly at an early stage of development. More advanced and targeted preclinical studies and clinical trials would be needed to introduce some of these techniques to routine clinical practice.