bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-Layer Fault-Tolerant Robust Filter for Integrated Navigation in Launch Inertial Coordinate System
Authors: Kang Jun , Xiong Zhi , Wang Rong , Zhang Ling
Published: May 2022

As to an aerospace vehicle, the flight span is large and the flight environment is complex. More than that, the existing navigation algorithms cannot meet the needs to provide accurate navigation parameters for aerospace vehicles, which results in the decline of navigation accuracy. This paper proposes a multi-layer, fault-tolerant robust filtering algorithm of aerospace vehicle in the launch inertial coordinate system to address this problem. Firstly, the launch inertial coordinate system is used as the reference coordinate system for navigation calculation, and the state equation and measurement equation of the navigation system are established in this coordinate system to improve the modeling accuracy of the navigation system. On this basis, a multi-layer, fault-tolerant robust filtering algorithm is designed to estimate and compensate the unknown input in the state equation in real time and adjust the noise variance matrix in the measurement equation adaptively. Simulation results show that the errors about the integrated navigation system output parameters are reduced, through this algorithm, which improves the attitude, velocity and position estimation accuracy of the integrated navigation system. In addition, the algorithm enhances the fault tolerance and robustness of the filtering algorithm.
Low-Cost Satellite Launch System—Aerodynamic Feasibility Study
Authors: Olejnik Aleksander , Kiszkowiak Łukasz , Zalewski Piotr , Dziubiński Adam
Published: May 2022

In recent decades, the rapid development of alternative methods for launching satellites into space has been observed. The main purpose of this work is to obtain reliable information about aerodynamic properties, which will be useful in the preliminary design of a low-cost satellite launch system based on a system consisting of a carrier aircraft and a space rocket orbiter. The numerical geometry of the aircraft carrier was developed as a result of the digitization process of the external surface of a real aircraft. Aerodynamic analysis was performed using specialized software based on solving partial differential equations using the finite volumes method. The results of the aerodynamic analysis were presented in a quantitative and qualitative manner. Furthermore, in order to confirm the correctness of the chosen method, the obtained results were compared with the results of experimental tests carried out in a wind tunnel. This will also prove that the adopted method is sufficient for solving this type of problem. The main advantage of the presented method is obtainment of reliable results in a relatively short time, which is extremely important during the preliminary design stage. The results presented in this paper will certainly be helpful for all researchers involved in the development of new and low-cost methods for launching small satellites into LEO.
The Effect of Rootstock Activity for Growth and Root System Soaking in Trichoderma atroviride on the Graft Success and Continued Growth of Beech (Fagus sylvatica L.) Plants
Authors: Świerczyński Sławomir
Published: May 2022

Two independent experiments were conducted on the effect of various factors, such as cultivars, growth activity of the rootstock and its treatment, with Trichoderma atroviride on graft success and growth of annual beech plants. The first experiment concerned the effect of propagation of five beech cultivars on rootstocks that are active (with growth activity), grown before the treatment in multi-cell plant trays (plastic seedling trays) or bare-root in the dormancy period. The highest success rate of the treatment was observed for dormant (without growth activity) and bare-root rootstocks. However, the best plant growth parameters during the first year of cultivation were observed when grafting active rootstocks obtained from multi-cell plant trays, while the worst results were observed for dormant, bare-root rootstocks. The individual cultivars varied significantly in terms of graft success and continued plant growth. The second experiment concerned the effect of rootstock growth activity and soaking of the rootstock root system in Trichoderma atroviride on graft success, growth parameters, and the intensity of some physiological processes in beech plants. The simultaneous use of both above-mentioned treatments resulted in the most intensive growth and accelerated physiological processes of the plants tested. Inoculation of rootstocks with Trichoderma atroviride did not affect the graft success. On the other hand, the growth activity of rootstocks at the time of grafting increased the success rate of the treatment. The treatments similarly differentiated the results obtained for two beech cultivars tested.
Delineating the Crop-Land Dynamic due to Extreme Environment Using Landsat Datasets: A Case Study
Authors: Halder Bijay , Bandyopadhyay Jatisankar , Afan Haitham Abdulmohsin , Naser Maryam H. , Abed Salwan Ali , Khedher Khaled Mohamed , Falih Khaldoon T. , Deo Ravinesh , Scholz Miklas , Yaseen Zaher Mundher
Published: May 2022

Extreme climatic conditions and natural hazard-related phenomenon have been affecting coastal regions and riverine areas. Floods, cyclones, and climate change phenomena have hammered the natural environment and increased the land dynamic, socio-economic vulnerability, and food scarcity. Saltwater intrusion has also triggered cropland vulnerability and, therefore, increased the area of inland brackish water fishery. The cropland area has decreased due to low soil fertility; around 252.06 km2 of cropland area has been lost, and 326.58 km2 of water bodies or inland fishery area has been added in just thirty years in the selected blocks of the North 24 Parganas district, West Bengal, India. After saltwater intrusion, soil fertility appears to have been decreased and crop production has been greatly reduced. The cropland areas were 586.52 km2 (1990), 419.92 km2 (2000), 361.67 km2 (2010) and 334.46 km2 (2020). Gradually the water body areas were increased 156.21 km2 (1990), 328.15 km2 (2000), 397.77 km2 (2010) and 482.78 km2 (2020). The vegetated land area also decreased due to it being converted into inland fishery areas, and around 79.15 km2 were degraded during the last thirty years. The super cyclone Aila, along with other super cyclones and other environmental stresses, like water-logging, soil salinity, and irrigation water scarcity were the reasons for the development of the new fishery areas in the selected blocks. There is a need for proper planning for sustainable development of this area.
Detection of Low MAP Shedder Prevalence in Large Free-Stall Dairy Herds by Repeated Testing of Environmental Samples and Pooled Milk Samples
Authors: Wichert Annika , Kasbohm Elisa , Einax Esra , Wehrend Axel , Donat Karsten
Published: May 2022

An easy-to-use and affordable surveillance system is crucial for paratuberculosis control. The use of environmental samples and milk pools has been proven to be effective for the detection of Mycobacterium avium subsp. paratuberculosis (MAP)-infected herds, but not for monitoring dairy herds certified as MAP non-suspect. We aimed to evaluate methods for the repeated testing of large dairy herds with a very low prevalence of MAP shedders, using different sets of environmental samples or pooled milk samples, collected monthly over a period of one year in 36 herds with known MAP shedder prevalence. Environmental samples were analyzed by bacterial culture and fecal PCR, and pools of 25 and 50 individual milk samples were analyzed by ELISA for MAP-specific antibodies. We estimated the cumulative sensitivity and specificity for up to twelve sampling events by adapting a Bayesian latent class model and taking into account the between- and within-test correlation. Our study revealed that at least seven repeated samplings of feces from the barn environment are necessary to achieve a sensitivity of 95% in herds with a within-herd shedder prevalence of at least 2%. The detection of herds with a prevalence of less than 2% is more challenging and, in addition to numerous repetitions, requires a combination of different samples.
Exploring the Evacuation of Dairy Cattle at Night in Collaboration with the Fire Brigade: How to Prepare Openings for Swift Rescue in Case of Barn Fire
Authors: Diel Florian , Rauch Elke , Palme Rupert , Sauter-Louis Carola , Zeiler Eva
Published: May 2022

The aim of this study was to investigate the influencing factors of successfully rescuing year-round housed cattle in case of a barn fire. Empirical research indicates the reluctance of cattle to leave their familiar barn. Subsequent retreat back to the perceived safety inside, which stands in contrast to the unknown and thus adversary elements outside, for example, the fire brigade, is to be expected. We examined the evacuation of 69 dairy cattle, split into three groups, to an adjacent pasture by night and inspected the animals’ acceptance of two differently designed escape routes and the effect of preceding training. Along with the time needed for evacuating all animals, we measured faecal cortisol metabolites and daily milk yield to assess stress in the animals. Our preliminary assumption was that cattle trained for pasture would have a decisive advantage over untrained cattle. However, adapting the exits to the sensory physiology of the cattle resulted in an extensive impact on the animals’ readiness to leave the familiar housing, as the evacuation of the cattle non-habituated to the exit was comparatively quick and successful. We consider this study instructional for fire brigades and farmers, encouraging them to develop a customised concept for rescuing their cattle in case of an emergency.
Mathematical Modeling and Optimal Control for a Class of Dynamic Supply Chain: A Systems Theory Approach
Authors: Taboada Heidi , Davizón Yasser A. , Espíritu José F. , Sánchez-Leal Jaime
Published: May 2022

Dynamic supply chains (SC) are important to reduce inventory, enable the flow of materials, maximize profits, and minimize costs. This research work presents a capacity–inventory management model via system dynamics for a dynamic supply SC, applying model-based optimal control techniques. In the context of high-volume manufacturing (HVM) that present low variability and predictable demand, for mathematical modeling purposes, a set of coupled first-order ordinary differential equations, with an analogy from the mixing problem, is presented, which relates capacity and inventory levels, taking into account a production rate at each node of interaction. The application of ordinary differential equations via the mixing problem (or compartmental analysis) is important based on the idea of a balance between the influx and outflux of raw material along the supply chain. A proper literature review on optimal control for supply chains is analyzed. The mathematical model introduced is presented in a linear time-invariant (LTI) state-space formulation. Stability analysis for the dynamic serial SC is presented, and a sensitivity analysis is also conducted for the capacity and production rate parameters considering the effects of variations in parameters along the SC. An energy-based optimal control is also developed with proper simulations.
On the Spatio-Temporal Characteristics of Aerosol Optical Depth in the Arabian Gulf Zone
Authors: Bărbulescu Alina
Published: May 2022

The article investigates some of the available measurements (Terra MODIS satellite data) of the aerosol optical depth (AOD) taken in the Arabian Gulf, a zone traditionally affected by intense sand-related (or even sand-driven) meteorological events. The Principal Component Analysis (PCA) reveals the main subspace of the data. Clustering of the series was performed after selecting the optimal number of groups using 30 different methods, such as the silhouette, gap, Duda, Dunn, Hartigan, Hubert, etc. The AOD regional and temporal tendency detection was completed utilizing an original algorithm based on the dominant cluster found at the previous stage, resulting in the regional time series (RTS) and temporal time series (TTS). It was shown that the spatially-indexed time series (SITS) agglomerates along with the first PC. In contrast, six PCs are responsible for 60.5% of the variance in the case of the temporally-indexed time series (TITS). Both RTS and TTS are stationary in trend and fit the studied data series set well.
Advances in Ionospheric Space Weather by Using FORMOSAT-7/COSMIC-2 GNSS Radio Occultations
Authors: Liu Jann-Yenq , Lin Chien-Hung , Rajesh Panthalingal Krishnanunni , Lin Chi-Yen , Chang Fu-Yuan , Lee I-Te , Fang Tzu-Wei , Fuller-Rowell Dominic , Chen Shih-Ping
Published: May 2022

This paper provides an overview of the contributions of the space-based global navigation satellite system (GNSS) radio occultation (RO) measurements from the FORMOSAT-7/COSMIC2 (F7/C2) mission in advancing our understanding of ionospheric plasma physics in the purview of space weather. The global positioning system (GPS) occultation experiment (GOX) onboard FORMOSAT-3/COSMIC (F3/C), with more than four and half million ionospheric RO soundings during April 2006–May 2020, offered a unique three-dimensional (3D) perspective to examine the global electron density distribution and unravel the underlying physical processes. The current F7/C2 carries TGRS (Tri-GNSS radio occultation system) has tracked more than 4000 RO profiles within ±35° latitudes per day since 25 June 2019. Taking advantage of the larger number of low-latitude soundings, the F7/C2 TGRS observations were used here to examine the 3D electron density structures and electrodynamics of the equatorial ionization anomaly, plasma depletion bays, and four-peaked patterns, as well as the S4 index of GNSS signal scintillations in the equatorial and low-latitude ionosphere, which have been previously investigated by using F3/C measurements. The results demonstrated that the denser low-latitude soundings enable the construction of monthly global electron density maps as well the altitude-latitude profiles with higher spatial and temporal resolution windows, and revealed longitudinal and seasonal characteristics in greater detail. The enhanced F7/C2 RO observations were further applied by the Central Weather Bureau/Space Weather Operation Office (CWB/SWOO) in Taiwan and the National Oceanic and Atmospheric Administration/Space Weather Prediction Center (NOAA/SWPC) in the United States to specify the ionospheric conditions for issuing alerts and warnings for positioning, navigation, and communication customers. A brief description of the two models is also provided.
Response of Very Small Glaciers to Climate Variations and Change: Examples from the Pirin Mountains, Bulgaria
Authors: Gachev Emil M.
Published: May 2022

Very small glaciers (glacierets) react strongly to climatic variations. This is well expressed in their interannual size changes, which are most evident in autumn, at the end of the glacial mass balance year. This study presents results from the detailed research of two very small glaciers in the highest northern part of the Pirin Mountains of Bulgaria: Snezhnika and Banski suhodol. Systematic size measurements of these firn-ice bodies, which started in the 1990s and have been made simultaneously for a period of 13 years, show large inter-annual amplitudes against the background of a decreasing trend in response to climate warming. However, the relations are not straightforward, which is demonstrated when comparing size changes to climate data, including logger data obtained from glacier vicinity. This fact makes predictions for the changes in the local climate of high mountain cirques still relatively uncertain.
Analysis of Particulate Matter (PM10) Behavior in the Caribbean Area Using a Coupled SARIMA-GARCH Model
Authors: Alexis Esdra , Plocoste Thomas , Nuiro Silvere Paul
Published: May 2022

The aim of this study was to model the behavior of particles with aerodynamic diameter lower or equal to 10μm (PM10) in the Caribbean area according to African dust seasonality. To carry out this study, PM10 measurement from Guadeloupe (GPE) and Puerto Rico (PR) between 2006 and 2010 were used. Firstly, the missing data issues were addressed using algorithms that we elaborated. Thereafter, the coupled SARIMA-GARCH (Seasonal Autoregressive Integrated Moving Average and Generalized Autoregressive Conditional Heteroscedastic) model was developed and compared to PM10 empirical data. The SARIMA process is representative of the main PM10 sources, while the heteroskedasticity is also taken into account by the GARCH process. In this framework, PM10 data from GPE and PR are decomposed into the sum of the background atmosphere (Bt = anthropogenic activities + marine aerosol), African dust seasonality (St = mineral dust), and extreme events processes (Ct). Akaike’s information criterion (AIC) helped us to choose the best model. Forecast evaluation indexes such as the Mean Absolute Percentage Error (MAPE), the Mean Absolute Scale Error (MASE), and Theil’s U statistic provided significant results. Specifically, the MASE and U values were found to be almost zero. Thus, these indexes validated the forecasts of the coupled SARIMA-GARCH model. To sum up, the SARIMA-GARCH combination is an efficient tool to forecast PM10 behavior in the Caribbean area.
Thermospheric Neutral Wind Measurements and Investigations across the African Region—A Review
Authors: Okoh Daniel , Bounhir Aziza , Habarulema John Bosco , Rabiu Babatunde , Katamzi-Joseph Zama , Ojo Taiwo , Wu Qian , Makela Jonathan J.
Published: May 2022

This paper briefly reviews studies of thermospheric neutral wind dynamics over the African region. The literature includes a review of the observations of neutral winds over five African locations using the Fabry–Perot Interferometer (FPI), and the comparison between the FPI observations and predictions of the horizontal wind model (HWM-14). So far, there are reports of FPI thermospheric wind measurements in South Africa and Morocco representing the mid-latitude regions in the southern and northern hemispheres, respectively. Within the low latitudes, FPI instruments are installed in the Ivory Coast, Ethiopia, and Nigeria. For the literature reviewed, the years covered in the FPI data are 2018–2019 (South Africa), 2016–2017 (Nigeria), 2015–2016 (Ethiopia), 2013–2016 (Morocco), and 1994–1995 (Ivory Coast). Overall, the HWM-14 reproduces the climatological behavior of the meridional and zonal winds, with varying levels of fidelity for the different regions. The HWM-14 is more accurate in the stations located in the northern hemisphere of the African region; a result attributed to the presence of data during the development of this empirical model.
Skill and Intercomparison of Global Climate Models in Simulating Wind Speed, and Future Changes in Wind Speed over South Asian Domain
Authors: Lakku Naresh K. G. , Behera Manasa R.
Published: May 2022

Investigating the role of complex dynamical components of a global climate model (GCM) in improving near-surface wind speed (WS) simulation is vital for the climate community in building reliable future WS projections. The relative skill of GCMs in representing WS at diverse climate variable scales (daily, monthly, seasonal, and annual) over land and ocean areas of the South Asian domain is not clear yet. With this in mind, this paper evaluated the skill of 28 Coupled Model Intercomparison Project phase five GCMs in reproducing the WS using a devised relative score approach. It is recommended to use the mean ensemble of MPI-ESM-MR, CSIRO-Mk3.6.0, and GFDL-ESM2G GCMs for understanding future changes in wind–wave climate and offshore wind energy potential. The inter-comparison of GCMs shows that the GCM with high or low atmospheric resolution does not necessarily exhibit the best or worst performance, respectively, whereas the dynamic components in the model configuration play the major role, especially the atmosphere component relative to other dynamical components. The strengthening of annual and seasonal mean WS is observed over coastal plains of the United Republic of Tanzania, Oman, eastern Thailand, eastern Gulf of Thailand and Sumatra, and weakening over the central northern equatorial region of the Indian Ocean in the 21st century for RCP4.5 and RCP8.5 emission scenarios.
Modification of Fraser’s Method for the Atmospheric CO2 Mass Estimation by Using Satellite Data
Authors: Pellegrini Marco , Aghakhani Arash , Guzzini Alessandro , Saccani Cesare
Published: May 2022

One of the most critical greenhouse gases in the atmosphere is carbon dioxide (CO2) due to its long-lasting and negative impact on climate change. The global atmospheric monthly mean CO2 concentration is currently greater than 410 ppm which has changed dramatically since the industrial era. To choose suitable climate change mitigation and adaptation strategies it is necessary to define carbon dioxide mass distribution and global atmospheric carbon dioxide mass. The available method to estimate the global atmospheric CO2 mass was proposed in 1980. In this study, to increase the accuracy of the available method, various observation platforms such as ground-based stations, ground-based tall towers, aircrafts, balloons, ships, and satellites are compared to define the best available observations, considering the temporal and spatial resolution. In the method proposed in this study, satellite observations (OCO2 data), from January 2019 to December 2021, are used to estimate atmospheric CO2 mass. The global atmospheric CO2 mass is estimated around 3.24 × 1015 kg in 2021. For the sake of comparison, global atmospheric CO2 mass was estimated by Fraser’s method using NOAA data for the mentioned study period. The proposed methodology in this study estimated slightly greater amounts of CO2 in comparison to Fraser’s method. This comparison resulted in 1.23% and 0.15% maximum and average difference, respectively, between the proposed method and Fraser’s method. The proposed method can be used to estimate the required capacity of systems for carbon capturing and can be applied to smaller districts to find the most critical locations in the world to plan for climate change mitigation and adaptation.
Cognitive Remediation in Psychiatric Disorders: State of the Evidence, Future Perspectives, and Some Bold Ideas
Authors: Trapp Wolfgang , Heid Andreas , Röder Susanne , Wimmer Franziska , Hajak Göran
Published: May 2022

Many people with psychiatric disorders experience impairments in cognition. These deficits have a significant impact on daily functioning and sometimes even on the further course of their disease. Cognitive remediation (CR) is used as an umbrella term for behavioral training interventions to ameliorate these deficits. In most but not all studies, CR has proven effective in improving cognition and enhancing everyday functional outcomes. In this paper, after quickly summarizing the empirical evidence, practical advice to optimize the effects of CR interventions is provided. We advocate that CR interventions should be as fun and motivating as possible, and therapists should at least consider using positively toned emotional stimuli instead of neutral stimuli. Participants should be screened for basic processing deficits, which should be trained before CR of higher-order cognitive domains. CR should stimulate metacognition and utilize natural settings to invoke social cognition. Wherever possible, CR tasks should link to tasks that participants face in their everyday life. Therapists should consider that participants might also benefit from positive side effects on symptomatology. Finally, the CR approach might even be utilized in settings where the treatment of cognitive impairments is not a primary target.
Immediate Early Gene c-fos in the Brain: Focus on Glial Cells
Authors: Cruz-Mendoza Fernando , Jauregui-Huerta Fernando , Aguilar-Delgadillo Adriana , García-Estrada Joaquín , Luquin Sonia
Published: May 2022

The c-fos gene was first described as a proto-oncogene responsible for the induction of bone tumors. A few decades ago, activation of the protein product c-fos was reported in the brain after seizures and other noxious stimuli. Since then, multiple studies have used c-fos as a brain activity marker. Although it has been attributed to neurons, growing evidence demonstrates that c-fos expression in the brain may also include glial cells. In this review, we collect data showing that glial cells also express this proto-oncogene. We present evidence demonstrating that at least astrocytes, oligodendrocytes, and microglia express this immediate early gene (IEG). Unlike neurons, whose expression changes used to be associated with depolarization, glial cells seem to express the c-fos proto-oncogene under the influence of proliferation, differentiation, growth, inflammation, repair, damage, plasticity, and other conditions. The collected evidence provides a complementary view of c-fos as an activity marker and urges the introduction of the glial cell perspective into brain activity studies. This glial cell view may provide additional information related to the brain microenvironment that is difficult to obtain from the isolated neuron paradigm. Thus, it is highly recommended that detection techniques are improved in order to better differentiate the phenotypes expressing c-fos in the brain and to elucidate the specific roles of c-fos expression in glial cells.
Effect of High-Rise Residential Building Layout on the Spatial Vertical Wind Environment in Harbin, China
Authors: Lu Ming , Song Di , Shi Da , Liu Jing , Wang Lu
Published: May 2022

Reasonable building height distribution in urban residential areas is conducive to smoother vertical airflow exchange and promotes sustainable development. This paper studies the influence of building layouts on vertical ventilation in high-rise residential areas in Harbin, China, and discusses typical building layout objectives. The ideal area of 220 × 220 m was determined using statistical analysis and specification requirements, and seven typical layouts were defined based on the distribution of building heights. The computation fluid dynamics (CFD) simulation was verified using wind tunnel testing to improve the accuracy of the Phoenics simulation software. Wind speed, wind pressure, and the Universal Thermal Climate Index (UTCI) in residential areas distributed at different heights were analyzed and evaluated. The results indicated that the Phoenics simulation parameter settings, verified via wind tunnel testing, could achieve reasonable simulation results and different height distribution modes had an impact on the changes in wind speed and wind pressure. The equal-height layout that conformed to the row spacing of the buildings and the layout of taller buildings on the east side could provide higher comfort, and did not require enclosed and downwind layouts. This research can inform the green and livable design of residential buildings and provide a new perspective for the construction of high-rise residential areas in cold cities.
Outcomes of Patients with Small Intestine Adenocarcinoma in a Canadian Province: A Retrospective Multi-Center Population-Based Cohort Study
Authors: Yanko Emma , Le Duc , Mahmood Shazia , Ginther David Nathan , Chalchal Haji Ibraheem , Kanthan Rani , Haider Kamal , Zaidi Adnan , Dueck Dorie-Anna , Ahmed Osama , Gowrishankar Branawan , Ahmed Shahid
Published: May 2022

Background: Small intestine adenocarcinoma is a rare cancer. The current study aims to determine the outcomes of patients with small intestine adenocarcinoma in a Canadian province. Methods: This retrospective population-based cohort study assessed patients with small intestine adenocarcinoma who were diagnosed from 2008 to 2017 in Saskatchewan. A Cox proportional multivariate regression analysis was performed to determine the correlation between survival and exploratory factors. Results: 112 eligible patients with a median age of 73 years and M:F of 47:53 were identified. Overall, 75% had a comorbid illness, and 45% had a WHO performance status >1. Of the 112 patients, 51 (46%) had early-stage disease and 61 (54%) had advanced-stage disease. The median overall survival (mOS) was as follows: stage one, 59 months; stage two, 30 months; stage three, 20 months; and stage four, 3 months (p < 0.001). The median disease-free survival of patients with stage three disease who received adjuvant chemotherapy was 26 months (95% CI:23.1–28.9) vs. 4 months (0.0–9.1) with observation (p = 0.04). Patients who received chemotherapy for advanced disease had a mOS of 10 months (3.5–16.5) vs. 2 months (0.45–3.6) without chemotherapy (p < 0.001). In the multivariate analysis, stage four disease, hazard ratio (HR), 3.20 (1.84–5.40); WHO performance status >1, HR, 2.22 (1.42–3.45); lack of surgery, HR, 2.10 (1.25–3.50); and a neutrophil:lymphocyte ratio of >4.5, HR, 1.72 (1.10–2.71) were significantly correlated with inferior survival. Conclusions: Most patients with small intestine adenocarcinoma were diagnosed with advanced-stage disease. Advanced-stage disease, poor performance status, lack of surgery and a baseline neutrophil:lymphocyte ratio >4.5 were correlated with inferior survival.
ED-B-Containing Isoform of Fibronectin in Tumor Microenvironment of Thymomas: A Target for a Theragnostic Approach
Authors: Petrini Iacopo , Sollini Martina , Bartoli Francesco , Barachini Serena , Montali Marina , Pardini Eleonora , Burzi Irene Sofia , Erba Paola Anna
Published: May 2022

Aim: to exploit tissue-specific interactions among thymic epithelial tumor (TETs) cells and extra-domain B fibronectin (ED-B FN). Material and methods: The stromal pattern of ED-B FN expression was investigated through tumor specimen collection and molecular profiling in 11 patients with recurrent TETs enrolled in prospective theragnostic phase I/II trials with Radretumab, an ED-B FN specific recombinant human antibody. Radretumab radioimmunotherapy (R-RIT) was offered to patients who exhibited the target expression. Experiments included immunochemical analysis (ICH), cell cultures, immunophenotypic analysis, Western blot, slot-blot assay, and quantitative RT-PCR of two primary thymoma cultures we obtained from patients’ samples and in the Ty82 cell line. Results: The in vivo scintigraphic demonstration of ED-B FN expression resulted in R-RIT eligibility in 8/11 patients, of which seven were treated. The best observed response was disease stabilization (n = 5/7) with a duration of 4.3 months (range 3–5 months). IHC data confirmed high ED-B FN expression in the peripherical microenvironment rather than in the center of the tumor, which was more abundant in B3 thymomas. Further, there was a predominant expression of ED-B FN by the stromal cells of the thymoma microenvironment rather than the epithelial cells. Conclusions: Our data support the hypothesis that thymomas induce stromal cells to shift FN production to the ED-B subtype, likely representing a favorable hallmark for tumor progression and metastasis. Collectively, results derived from clinical experience and molecular insights of the in vitro experiments suggested that R-RIT inefficacy is unlikely related to low target expression in TET, being the mechanism of R-RIT resistance eventually related to patients’ susceptibility (i.e., inherent characteristics), the pattern expression of the target (i.e., at periphery), the biological characteristics of the tumor (i.e., aggressive and resistant phenotypes), and/or to format of the target agent (i.e., 131I-L19-SIP).
BERENICE Final Analysis: Cardiac Safety Study of Neoadjuvant Pertuzumab, Trastuzumab, and Chemotherapy Followed by Adjuvant Pertuzumab and Trastuzumab in HER2-Positive Early Breast Cancer
Authors: Dang Chau , Ewer Michael S. , Delaloge Suzette , Ferrero Jean-Marc , Colomer Ramon , de la Cruz-Merino Luis , Werner Theresa L. , Dadswell Katherine , Verrill Mark , Eiger Daniel , Sarkar Sriparna , de Haas Sanne Lysbet , Restuccia Eleonora , Swain Sandra M.
Published: May 2022

BERENICE (NCT02132949) assessed the cardiac safety of the neoadjuvant–adjuvant pertuzumab–trastuzumab-based therapy for high-risk, HER2-positive early breast cancer (EBC). We describe key secondary objectives at final analysis. Eligible patients received dose-dense doxorubicin and cyclophosphamide q2w × 4 ➝ paclitaxel qw × 12 (Cohort A) or 5-fluorouracil, epirubicin, cyclophosphamide q3w × 4 ➝ docetaxel q3w × 4 (B) as per physician’s choice. Pertuzumab–trastuzumab (q3w) was initiated from the taxane start and continued post-surgery to complete 1 year. Median follow-up: 64.5 months. There were no new cardiac issues and a low incidence of Class III/IV heart failure (Cohort B only: one patient (0.5%) in the adjuvant and treatment-free follow-up (TFFU) periods). Fourteen patients (7.7%) had LVEF declines of ≥10% points from baseline to <50% in Cohort A, as did 20 (10.5%) in B during the adjuvant period (12 (6.2%) in A and 7 (3.6%) in B during TFFU). The five-year event-free survival rates in Cohorts A and B were 90.8% (95% CI: 86.5, 95.2) and 89.2% (84.8, 93.6), respectively. The five-year overall survival rates were 96.1% (95% CI: 93.3, 98.9) and 93.8% (90.3, 97.2), respectively. The final analysis of BERENICE further supports pertuzumab–trastuzumab-based therapies as standard of care for high-risk, HER2-positive EBC.
Epigenetic Crosstalk between Malignant Plasma Cells and the Tumour Microenvironment in Multiple Myeloma
Authors: Allegra Alessandro , Casciaro Marco , Barone Paola , Musolino Caterina , Gangemi Sebastiano
Published: May 2022

In multiple myeloma, cells of the bone marrow microenvironment have a relevant responsibility in promoting the growth, survival, and drug resistance of multiple myeloma plasma cells. In addition to the well-recognized role of genetic lesions, microenvironmental cells also present deregulated epigenetic systems. However, the effect of epigenetic changes in reshaping the tumour microenvironment is still not well identified. An assortment of epigenetic regulators, comprising histone methyltransferases, histone acetyltransferases, and lysine demethylases, are altered in bone marrow microenvironmental cells in multiple myeloma subjects participating in disease progression and prognosis. Aberrant epigenetics affect numerous processes correlated with the tumour microenvironment, such as angiogenesis, bone homeostasis, and extracellular matrix remodelling. This review focuses on the interplay between epigenetic alterations of the tumour milieu and neoplastic cells, trying to decipher the crosstalk between these cells. We also evaluate the possibility of intervening specifically in modified signalling or counterbalancing epigenetic mechanisms.
A Potential New Treatment for High-Grade Glioma: A Study Assessing Repurposed Drug Combinations against Patient-Derived High-Grade Glioma Cells
Authors: Lastakchi Sarah , Olaloko Mary Kanyinsola , McConville Christopher
Published: May 2022

Repurposed drugs have demonstrated in vitro success against high-grade gliomas; however, their clinical success has been limited due to the in vitro model not truly representing the clinical scenario. In this study, we used two distinct patient-derived tumour fragments (tumour core (TC) and tumour margin (TM)) to generate a heterogeneous, clinically relevant in vitro model to assess if a combination of repurposed drugs (irinotecan, pitavastatin, disulfiram, copper gluconate, captopril, celecoxib, itraconazole and ticlopidine), each targeting a different growth promoting pathway, could successfully treat high-grade gliomas. To ensure the clinical relevance of our data, TC and TM samples from 11 different patients were utilized. Our data demonstrate that, at a concentration of 100µm or lower, all drug combinations achieved lower LogIC50 values than temozolomide, with one of the combinations almost eradicating the cancer by achieving cell viabilities below 4% in five of the TM samples 6 days after treatment. Temozolomide was unable to stop tumour growth over the 14-day assay, while combination 1 stopped tumour growth, with combinations 2, 3 and 4 slowing down tumour growth at higher doses. To validate the cytotoxicity data, we used two distinct assays, end point MTT and real-time IncuCyte life analysis, to evaluate the cytotoxicity of the combinations on the TC fragment from patient 3, with the cell viabilities comparable across both assays. The local administration of combinations of repurposed drugs that target different growth promoting pathways of high-grade gliomas have the potential to be translated into the clinic as a novel treatment strategy for high-grade gliomas.
Tumor Necrosis Factor Receptor 2 (TNFR2): An Emerging Target in Cancer Therapy
Authors: Medler Juliane , Kucka Kirstin , Wajant Harald
Published: May 2022

Despite the great success of TNF blockers in the treatment of autoimmune diseases and the identification of TNF as a factor that influences the development of tumors in many ways, the role of TNFR2 in tumor biology and its potential suitability as a therapeutic target in cancer therapy have long been underestimated. This has been fundamentally changed with the identification of TNFR2 as a regulatory T-cell (Treg)-stimulating factor and the general clinical breakthrough of immunotherapeutic approaches. However, considering TNFR2 as a sole immunosuppressive factor in the tumor microenvironment does not go far enough. TNFR2 can also co-stimulate CD8+ T-cells, sensitize some immune and tumor cells to the cytotoxic effects of TNFR1 and/or acts as an oncogene. In view of the wide range of cancer-associated TNFR2 activities, it is not surprising that both antagonists and agonists of TNFR2 are considered for tumor therapy and have indeed shown overwhelming anti-tumor activity in preclinical studies. Based on a brief summary of TNFR2 signaling and the immunoregulatory functions of TNFR2, we discuss here the main preclinical findings and insights gained with TNFR2 agonists and antagonists. In particular, we address the question of which TNFR2-associated molecular and cellular mechanisms underlie the observed anti-tumoral activities of TNFR2 agonists and antagonists.
Receptor, Signal, Nucleus, Action: Signals That Pass through Akt on the Road to Head and Neck Cancer Cell Migration
Authors: Alzawi Albashir , Iftikhar Anem , Shalgm Basher , Jones Sarah , Ellis Ian , Islam Mohammad
Published: May 2022

This review aims to provide evidence for the role of the tumour microenvironment in cancer progression, including invasion and metastasis. The tumour microenvironment is complex and consists of tumour cells and stromal-derived cells, in addition to a modified extracellular matrix. The cellular components synthesise growth factors such as EGF, TGFα and β, VEGF, and NGF, which have been shown to initiate paracrine signalling in head and neck cancer cells by binding to cell surface receptors. One example is the phosphorylation, and hence activation, of the signalling protein Akt, which can ultimately induce oral cancer cell migration in vitro. Blocking of Akt activation by an inhibitor, MK2206, leads to a significant decrease, in vitro, of cancer-derived cell migration, visualised in both wound healing and scatter assays. Signalling pathways have therefore been popular targets for the design of chemotherapeutic agents, but drug resistance has been observed and is related to direct tumour–tumour cell communication, the tumour–extracellular matrix interface, and tumour–stromal cell interactions. Translation of this knowledge to patient care is reliant upon a comprehensive understanding of the complex relationships present in the tumour microenvironment and could ultimately lead to the design of efficacious treatment regimens such as targeted therapy or novel therapeutic combinations.
Repurposing Vitamin C for Cancer Treatment: Focus on Targeting the Tumor Microenvironment
Authors: Li Wen-Ning , Zhang Shi-Jiao , Feng Jia-Qing , Jin Wei-Lin
Published: May 2022

Based on the enhanced knowledge on the tumor microenvironment (TME), a more comprehensive treatment landscape for targeting the TME has emerged. This microenvironment provides multiple therapeutic targets due to its diverse characteristics, leading to numerous TME-targeted strategies. With multifaced activities targeting tumors and the TME, vitamin C is renown as a promising candidate for combination therapy. In this review, we present new advances in how vitamin C reshapes the TME in the immune, hypoxic, metabolic, acidic, neurological, mechanical, and microbial dimensions. These findings will open new possibilities for multiple therapeutic avenues in the fight against cancer. We also review the available preclinical and clinical evidence of vitamin C combined with established therapies, highlighting vitamin C as an adjuvant that can be exploited for novel therapeutics. Finally, we discuss unresolved questions and directions that merit further investigation.
Neoadjuvant Carboplatin/Paclitaxel versus 5-Fluorouracil/Cisplatin in Combination with Radiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma: A Multicenter Comparative Study
Authors: Gao Xing , Tsai Ping-Chung , Chuang Kai-Hao , Pai Chu-Pin , Hsu Po-Kuei , Li Shau-Hsuan , Lu Hung-I , van Lanschot Joseph Jan-Baptist , Chao Yin-Kai
Published: May 2022

Background: The most beneficial neoadjuvant chemoradiotherapy (nCRT) combination for esophageal squamous cell carcinoma (ESCC) in Asia remains uncertain. Herein, we compared the neoadjuvant carboplatin/paclitaxel (CROSS) regimen versus the cisplatin/5-fluorouracil (PF) regimen in combination with 41.4–50.4 Gy of radiotherapy. Methods: Patients were stratified according to their nCRT regimen: CROSS + 41.4–45.0 Gy (CROSS), PF + 45.0 Gy (PF4500) or PF + 50.4 Gy (PF5040). Propensity score matching by inverse probability of treatment weighting (IPTW) was used to balance the baseline variables. Results: Before IPTW, a total of 334 patients were included. The lowest chemotherapy completion rate was observed in the PF5040 group (76.2% versus 89.4% and 92.0% in the remaining two groups, respectively). Compared with CROSS, both PF groups showed more severe weight loss during nCRT and a higher frequency of post-esophagectomy anastomotic leaks. The use of PF5040 was associated with the highest rate of pathological complete response (45.3%). While CROSS conferred a significant overall survival benefit over PF4500 (hazard ratio [HR] = 1.30, 95% CI = 1.05 to 1.62, p = 0.018), similar survival figures were observed when compared with PF5040 (HR = 1.17, 95% CI = 0.94 to 1.45, p = 0.166). Conclusions: The CROSS regimen conferred a significant survival benefit over PF4500, although the similar survival figures were similar to those observed with PF5040. Considering the lower incidences of severe weight loss and post-esophagectomy anastomotic leaks, CROSS represents a safe and effective neoadjuvant treatment for Taiwanese patients with ESCC.
Long-Term Survival Following Minimally Invasive Lung Cancer Surgery: Comparing Robotic-Assisted and Video-Assisted Surgery
Authors: Montagne François , Chaari Zied , Bottet Benjamin , Sarsam Matthieu , Mbadinga Frankie , Selim Jean , Guisier Florian , Gillibert André , Baste Jean-Marc
Published: May 2022

Background: Nowadays, video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracoscopic surgery (RATS) are known to be safe and efficient surgical procedures to treat early-stage non-small cell lung cancer (NSCLC). We assessed whether RATS increased disease-free survival (DFS) compared with VATS for lobectomy and segmentectomy. Methods: This retrospective cohort study included patients treated for resectable NSCLC performed by RATS or VATS, in our tertiary care center from 2012 to 2019. Patients’ data were prospectively recorded and reviewed in the French EPITHOR database. Primary outcomes were 5-year DFS for lobectomy and 3-year DFS for segmentectomy, compared by propensity-score adjusted difference of Kaplan–Meier estimates. Results: Among 844 lung resections, 436 VATS and 234 RATS lobectomies and 46 VATS and 128 RATS segmentectomies were performed. For lobectomy, the adjusted 5-year DFS was 60.9% (95% confidence interval (CI) 52.9–68.8%) for VATS and 52.7% (95%CI 41.7–63.7%) for RATS, with a difference estimated at −8.3% (−22.2–+4.9%, p = 0.24). For segmentectomy, the adjusted 3-year DFS was 84.6% (95%CI 69.8–99.0%) for VATS and 72.9% (95%CI 50.6–92.4%) for RATS, with a difference estimated at −11.7% (−38.7–+7.8%, p = 0.21). Conclusions: RATS failed to show its superiority over VATS for resectable NSCLC.
Different Methods for Evaluating Microglial Activation Using Anti-Ionized Calcium-Binding Adaptor Protein-1 Immunohistochemistry in the Cuprizone Model
Authors: Wittekindt Mariela , Kaddatz Hannes , Joost Sarah , Staffeld Anna , Bitar Yamen , Kipp Markus , Frintrop Linda
Published: May 2022

Microglia play an important role in the pathology of various central nervous system disorders, including multiple sclerosis (MS). While different methods exist to evaluate the extent of microglia activation, comparative studies investigating the sensitivity of these methods are missing for most models. In this study, we systematically evaluated which of the three commonly used histological methods (id est, quantification of microglia density, densitometrically evaluated staining intensity, or cellular morphology based on the determination of a ramification index, all measured in anti-ionized calcium-binding adaptor protein-1 (IBA1) immunohistochemical stains) is the most sensitive method to detect subtle changes in the microglia activation status in the context of MS. To this end, we used the toxin-induced cuprizone model which allows the experimental induction of a highly reproducible demyelination in several central nervous system regions, paralleled by early microglia activation. In this study, we showed that after 3 weeks of cuprizone intoxication, all methods reveal a significant microglia activation in the white matter corpus callosum. In contrast, in the affected neocortical grey matter, the evaluation of anti-IBA1 cell morphologies was the most sensitive method to detect subtle changes of microglial activation. The results of this study provide a useful guide for future immunohistochemical evaluations in the cuprizone and other neurodegenerative models.
Leonurine Protects Bone Mesenchymal Stem Cells from Oxidative Stress by Activating Mitophagy through PI3K/Akt/mTOR Pathway
Authors: Zhao Bingkun , Peng Qian , Wang Dan , Zhou Rong , Wang Raorao , Zhu Yizhun , Qi Shengcai
Published: May 2022

Osteoporosis bears an imbalance between bone formation and resorption, which is strongly related to oxidative stress. The function of leonurine on bone marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress is still unclear. Therefore, this study was aimed at identifying the protective effect of leonurine on H2O2 stimulated rat BMSCs. We found that leonurine can alleviate cell apoptosis and promote the differentiation ability of rat BMSCs induced by oxidative stress at an appropriate concentration at 10 μM. Meanwhile, the intracellular ROS level and the level of the COX2 and NOX4 mRNA decreased after leonurine treatment in vitro. The ATP level and mitochondrial membrane potential were upregulated after leonurine treatment. The protein level of PINK1 and Parkin showed the same trend. The mitophage in rat BMSCs blocked by 3-MA was partially rescued by leonurine. Bioinformatics analysis and leonurine-protein coupling provides a strong direct combination between leonurine and the PI3K protein at the position of Asp841, Glu880, Val882. In conclusion, leonurine protects the proliferation and differentiation of BMSCs from oxidative stress by activating mitophagy, which depends on the PI3K/Akt/mTOR pathway. The results showed that leonurine may have potential usage in osteoporosis and bone defect repair in osteoporosis patients.