bluuebunny/crossref_metadata_2025 huggingface dataset:
Controlling Remotely Operated Vehicles with Deterministic Artificial Intelligence
Authors: Osler Shay , Sands Timothy
Published: March 2022

Unmanned ocean vehicles can be guided and controlled autonomously or remotely, and even remote operation can be automated significantly. Classical methods use trajectory tracking errors in negative feedback. Recently published methods are proposed instead. Deterministic (non-stochastic) artificial intelligence (DAI) combines optimal learning with an asserted self awareness statement in the form of the governing mathematical model (based on physics in this instantiation) to allow control that can be alternatively adaptive (i.e., capable of reacting to changing system dynamics) or learning (i.e., able to provide information about what aspects of the system dynamics have changed). In this manuscript, deterministic artificial intelligence is applied to the heading control of a simulated remotely operated underwater vehicle (ROV). Research is presented illustrating autonomous control of a Seabotix vLBV 300 remotely operated vehicle within milli-degrees on the very first step of a shaped square wave command, and error decreased an additional sixty-two percent by the third step of the square wave command.
System-Level Assessment of Low Complexity Hybrid Precoding Designs for Massive MIMO Downlink Transmissions in Beyond 5G Networks
Authors: Pavia João Pedro , Velez Vasco , Souto Nuno , Ribeiro Marco , Sebastião Pedro , Correia Américo
Published: March 2022

The fast growth experienced by the telecommunications field during the last few decades has been motivating the academy and the industry to invest in the design, testing and deployment of new evolutions of wireless communication systems. Terahertz (THz) communication represents one of the possible technologies to explore in order to achieve the desired achievable rates above 100 Gbps and the extremely low latency required in many envisioned applications. Despite the potentialities, it requires proper system design, since working in the THz band brings a set of challenges, such as the reflection and scattering losses through the transmission path, the high dependency with distance and the severe hardware constraints. One key approach for overcoming some of these challenges relies on the use of massive/ultramassive antenna arrays combined with hybrid precoders based on fully connected phase-shifter architectures or partially connected architectures, such as arrays of subarrays (AoSAs) or dynamic AoSAs (DAoSAs). Through this strategy, it is possible to obtain very high-performance gains while drastically simplifying the practical implementation and reducing the overall power consumption of the system when compared to a fully digital approach. Although these types of solutions have been previously proposed to address some of the limitations of mmWave/THz communications, a lack between link-level and system-level analysis is commonly verified. In this paper, we present a thorough system-level assessment of a cloud radio access network (C-RAN) for beyond 5G (B5G) systems where the access points (APs) operate in the mmWave/THz bands, supporting multi-user MIMO (MU-MIMO) transmission with massive/ultra-massive antenna arrays combined with low-complexity hybrid precoding architectures. Results showed that the C-RAN deployments in two indoor office scenarios for the THz were capable of achieving good throughput and coverage performances, with only a small compromise in terms of gains when adopting reduced complexity hybrid precoders. Furthermore, we observed that the indoor-mixed office scenario can provide higher throughput and coverage performances independently of the cluster size when compared to the indoor-open office scenario.
In Silico Pesticide Discovery for New Anti-Tobacco Mosaic Virus Agents: Reactivity, Molecular Docking, and Molecular Dynamics Simulations
Authors: Abdulhassan Hala A. , Saleh Basil A. , Harkati Dalal , Khelfaoui Hadjer , Hewitt Natalie L. , El-Hiti Gamal A.
Published: March 2022

Considerable data are available regarding the molecular genetics of the tobacco mosaic virus. The disease caused by the tobacco mosaic virus is still out of control due to the lack of an efficient functional antagonist chemical molecule. Extensive research was carried out to try to find effective new anti-tobacco mosaic virus agents, however no study could find an effective agent which could completely inhibit the disease caused by the virus. In recent years, molecular docking, combined with molecular dynamics, which is considered to be one of the most important methods of drug discovery and design, were used to evaluate the type of binding between the ligand and its protein enzyme. The aim of the current work was to assess the in silico anti-tobacco mosaic virus activity for a selection of 41 new and 2 reference standard compounds. These compounds were chosen to examine their reactivity and binding efficiency with the tobacco mosaic virus coat protein (PDB ID: 2OM3). A comparison was made between the activity of the selected compounds and that for ningnanmycin and ribavirin, which are common inhibitors of plant viruses. The simulation results obtained from the molecular docking and molecular dynamics showed that two compounds of the antofine analogues could bind with the tobacco mosaic virus coat protein receptor better than ningnanmycin and ribavirin.
Recovery of Carotenoids from Tomato Pomace Using a Hydrofluorocarbon Solvent in Sub-Critical Conditions
Authors: Colucci Cante Rosa , Gallo Marianna , Varriale Lorenzo , Garella Isidoro , Nigro Roberto
Published: March 2022

The enrichment of oils with nutraceutical bioactive phytomolecules allows the achievement of functional oil-based products of great interest in the food, pharmaceutical, and cosmetic fields. Carotenoids, such as lycopene and β-carotene, are available at a high concentration in tomatoes and tomato waste products, as peels, seeds, and pulp; their recovery is recently attracting growing interest and economic importance in the food industry, and also in consideration of the huge amount of industrial waste produced. The aim of this work is to study the production of an oil functionalized with carotenoids from tomato peels. The extractions were carried out using an innovative process based on the use of commercial Norflurane as solvent in subcritical conditions. Extraction trials were performed on dried tomato peels, with the addition of tomato seeds or wheat germ flour as sources of oily co-solvents, capable of also preserving the biological characteristics of the carotenoids extracted. Although lycopene solubility in Norflurane is quite low, the solvent recirculation and regeneration were allowed to reach a concentration in the oily extracts of approximately 0.3 mg/goil after 2 h of the process. The enrichment in β-carotene was more pronounced, and concentrations of 0.733 mg/goil and 0.952 mg/goil were observed in wheat germ and tomato seed oils, respectively. The results obtained in this study were compared with those obtained by traditional and supercritical CO2 extraction methods.
A Nodal Analysis Based Monitoring of an Electric Submersible Pump Operation in Multiphase Flow
Authors: Iranzi Joseph , Son Hanam , Lee Youngsoo , Wang Jihoon
Published: March 2022

Electrical submersible pump (ESP) operation is compromised by free gas, resulting in premature pump failure and production losses in new wells. It is essential to detect the onset of abnormal operations. We develop a model that predicts abnormal ESP operation when the free gas level increases in the pump. The model compares operation parameters with the parameters of normal operating ranges; it shuts down the ESP when necessary. We used a Schlumberger PIPESIM software (version 2017.01) to perform nodal analysis technique; we tested the model using the other multiphase correlation model and field case studies (where the gas problem in ESP was reported). We employ a homogenous model to calculate the differential pump pressures at various gas volume fractions. Nodal analysis of the intake and discharge point predicted the commencement of abnormal ESP conditions and the associated parameters (critical gas fraction, minimum operating pump intake pressure, and pump discharge pressure). The model results were similar to other surging correlation models (e.g., Romero, Dunbar, Turpin, Cirilo, and Zhou models); they were also identical to field case studies. We identify three performance stability phases when an ESP is exposed to free gas. These are the normal and abnormal operating ranges, as well as the ESP shutdown condition. Modeling permits careful monitoring of ESP operations that can be compromised by free gas.
Dimensioning of Reactive Power Compensation in an Autonomous Island System
Authors: Psarros Georgios N. , Tsourakis Georgios I. , Papathanassiou Stavros A.
Published: March 2022

In this paper, a method for sizing the reactive power compensation in a non-interconnected island power system is presented and applied to determine the necessary inductive reactive power compensation for the autonomous power system of Rhodes Island, Greece. The Rhodes power system is often confronted with an excess of reactive power, as a result—inter alia—of underground high-voltage (HV) cable lines and distributed generation penetration. Reactive power compensation is typically a local issue in power systems, usually aiming at maintaining an acceptable voltage profile on specific transmission segments, e.g., long underground or submarine cables. In autonomous systems, however, where network lengths are relatively short, reactive power compensation is meant to address the overall reactive power equilibrium of the system. The proposed method follows a three-step approach. First, power flow analysis is conducted to determine the size of the maximum compensation that may be necessary, i.e., the compensation size that practically allows unit commitment to be conducted without being constrained by reactive power considerations. Then, a unit commitment and economic dispatch model is executed over the course of a year to determine the optimal compensation size, using the output of the power flow analysis to formulate reactive power balance constraints. Finally, the results of the economic optimization are assessed in terms of dynamic security to verify the feasibility of the optimal solution.
Embedded PSO for Solving FJSP on Embedded Environment (Industry 4.0 Era)
Authors: Zarrouk Rim , Daoud Wided Ben , Mahfoudhi Sami , Jemai Abderrazak
Published: March 2022

Since of the advent of Industry 4.0, embedded systems have become an indispensable component of our life. However, one of the most significant disadvantages of these gadgets is their high power consumption. It was demonstrated that making efficient use of the device’s central processing unit (CPU) enhances its energy efficiency. The use of the particle swarm optimization (PSO) over an embedded environment achieves many resource problems. Difficulties of online implementation arise primarily from the unavoidable lengthy simulation time to evaluate a candidate solution. In this paper, an embedded two-level PSO (E2L-PSO) for intelligent real-time simulation is introduced. This algorithm is proposed to be executed online and adapted to embedded applications. An automatic adaptation of the asynchronous embedded two-level PSO algorithm to CPU is completed. The Flexible Job Shop Scheduling Problem (FJSP) is selected to solve, due to its importance in the Industry 4.0 era. An analysis of the run-time performance on handling E2L-PSO over an STM32F407VG-Discovery card and a Raspberry Pi B+ card is conducted. By the experimental study, such optimization decreases the CPU time consumption by 10% to 70%, according to the CPU reduction needed (soft, medium, or hard reduction).
Metaproteomics, Heterotrophic Growth, and Distribution of Nitrosomonas europaea and Nitrobacter winogradskyi after Long-Term Operation of an Autotrophic Nitrifying Biofilm Reactor
Authors: Mastroleo Felice , Arnau Carolina , Verbeelen Tom , Mysara Mohamed , Gòdia Francesc , Leys Natalie , Van Houdt Rob
Published: March 2022

Bioregenerative life support systems (BLSS) are currently in development to tackle low recovery efficiencies, high energy demands, as well as food, water, and oxygen production challenges through the regeneration of nutrients from waste streams. The MELiSSA pilot plant has been developed as a testbed for regenerative life support system bioreactor operation and characterization. As nitrogen is a vital resource in such systems, we studied the functional composition of a new packed-bed nitrifying bioreactor inoculated with a co-culture of Nitrosomonas europaea (ATCC 25978) and Nitrobacter winogradskyi (ATCC 25391). After 840 days of autotrophic continuous cultivation, the packed-bed was sampled at five vertical positions, each with three horizontal positions, and the biomass at each position was characterized via qPCR, 16S amplicon sequencing, and liquid chromatography tandem mass spectrometry. The total number of cells within the different sections fluctuated around 8.95 ± 5.10 × 107 cells/mL of beads. Based on 16S amplicons and protein content, N. europaea and N. winogradskyi constituted overall 44.07 ± 11.75% and 57.53 ± 12.04% of the nitrifying bioreactor, respectively, indicating the presence of a heterotrophic population that, even after such a long operation time, did not affect the nitrification function of the bioreactor. In addition, DNA-based abundance estimates showed that N. europaea was slightly more abundant than N. winogradskyi, whereas protein-based abundance estimates indicated a much higher abundance of N. europaea. This highlights that single-method approaches need to be carefully interpreted in terms of overall cell abundance and metabolic activity.
Continuous Measurement of Ammonia at an Intensive Pig Farm in Wuhan, China
Authors: Feng Kun , Wang Yan , Hu Ronggui , Xiang Rongbiao
Published: March 2022

Measurements with high time resolution are necessary to capture variation patterns and to facilitate the estimation of uncertainty in ammonia inventories. Continuous real-time monitoring of ammonia was carried out in a naturally ventilated nursery pig house during two periods in winter and summer, respectively. A higher ventilation rate of about 73,799 ± 39,655 m3/h was obtained during the summer period in comparison with 1646 ± 604 m3/h in the winter. Correspondingly, ammonia level observed in summer (0.25 ± 0.10 mg/m3) was lower than that in winter (1.28 ± 0.74 mg/m3). Spatial variation of ammonia concentration was observed during the winter monitoring period. The mean ammonia emission factor was about 0.3221 ± 0.2921 g d−1 pig−1 in summer and 0.1039 ± 0.0550 g d−1 pig−1 in winter, ranging from 0.0094 to 1.9422 g d−1 pig−1 and 0.0046 to 0.2899 g d−1 pig−1, respectively. Significant correlation was found between ammonia emission and indoor temperature and relative humidity during the winter period. For the summer measurement, effects of ventilation rate and ammonia concentration on ammonia emission were significant. Prominent diurnal pattern existed for both ammonia concentration and emission, with higher emission rates during daytime. The results confirmed the existence of considerable uncertainty associated with the ammonia emission factor, acquired by snapshot measurements.
The Effect of Continuous Trapezoidal Straight Spoiler Plates on the Vortex-Induced Vibration of Wind Turbine Towers
Authors: Li Zheng , Zhang Tianhe , Chen Yang , Wang Ziqi
Published: March 2022

This paper proposes a method of controlling the vortex-induced vibration (VIV) of wind turbine towers by adding continuous trapezoidal straight spoiler plates (TS) onto their outer surface: a fluid–solid coupling model was constructed to simulate the processes of Karman vortex generation and shedding on the different surfaces of an original tower (O–tower) and a tower with TS (TS–tower) with assumed and actual Re, while the VIV frequencies were also calculated and compared; the effects of the TS geometry parameters on the VIV frequency of towers were studied to investigate the recommended size; a modal analysis was carried out to research the effects of TS on the vortex-induced resonance risk of towers; and the simulation results as well as relevant research conclusions were validated by an analogical wind tunnel test.
On Large and Small Data Blow-Up Solutions in the Trojan Y Chromosome Model
Authors: Takyi Eric M. , Beauregard Matthew A. , Griffin Thomas , Bobo Landrey , Parshad Rana D.
Published: March 2022

The Trojan Y Chromosome Strategy (TYC) is the only genetic biological control method in practice in North America for controlling invasive populations with an XX–XY sex determinism. Herein a modified organism, that is a supermale or feminised supermale, is introduced into an invasive population to skew the sex ratio over time, causing local extinction. We consider the three species TYC reaction diffusion model, and show that introduction of supermales above certain thresholds, and for certain initial data, solutions can blow-up in finite time. Thus, in order to have biologically meaningful solutions, one needs to restrict parameter and initial data regimes, in TYC type models.
Dynamical Analysis of a Boolean Network Model of the Oncogene Role of lncRNA ANRIL and lncRNA UFC1 in Non-Small Cell Lung Cancer
Authors: Gupta Shantanu , Hashimoto Ronaldo F.
Published: March 2022

Long non-coding RNA (lncRNA) such as ANRIL and UFC1 have been verified as oncogenic genes in non-small cell lung cancer (NSCLC). It is well known that the tumor suppressor microRNA-34a (miR-34a) is downregulated in NSCLC. Furthermore, miR-34a induces senescence and apoptosis in breast, glioma, cervical cancer including NSCLC by targeting Myc. Recent evidence suggests that these two lncRNAs act as a miR-34a sponge in corresponding cancers. However, the biological functions between these two non-coding RNAs (ncRNAs) have not yet been studied in NSCLC. Therefore, we present a Boolean model to analyze the gene regulation between these two ncRNAs in NSCLC. We compared our model to several experimental studies involving gain- or loss-of-function genes in NSCLC cells and achieved an excellent agreement. Additionally, we predict three positive circuits involving miR-34a/E2F1/ANRIL, miR-34a/E2F1/UFC1, and miR-34a/Myc/ANRIL. Our circuit- perturbation analysis shows that these circuits are important for regulating cell-fate decisions such as senescence and apoptosis. Thus, our Boolean network permits an explicit cell-fate mechanism associated with NSCLC. Therefore, our results support that ANRIL and/or UFC1 is an attractive target for drug development in tumor growth and aggressive proliferation of NSCLC, and that a valuable outcome can be achieved through the miRNA-34a/Myc pathway.
Computational Approaches and Use of Chiroptical Probes in the Absolute Configuration Assignment to Natural Products by ECD Spectroscopy: A 1,2,3-Trihydroxy-p-menthane as a Case Study
Authors: Marsico Giulia , Calice Umberto , Scafato Patrizia , Belviso Sandra , Evidente Antonio , Superchi Stefano
Published: March 2022

In this study, the computational analysis of electronic circular dichroism (ECD) spectra and the employment of biphenyl chiroptical probes were compared in the absolute configuration assignment of (-)-1α,2α,3β-trihydroxy-p-menthane (1), taken as a representative example of a UV-transparent chiral natural product. The usefulness of chiroptical probes in the configurational assignments of natural products and their complementarity to the computational protocols is herein highlighted. The biphenyl probe approach proves to be straightforward, reliable, and suitable for conformationally mobile and ECD silent compounds, not treatable by computational analysis of chiroptical data.
Living with Knee Osteoarthritis: The Positive Impact of Reducing the Knee Torque Induced When Sleeping Supine; A Randomised Clinical Trial
Authors: Buckley John G. , Scally Andrew J. , Bhattacharjee Chanchal
Published: March 2022

When lying supine, due to the reaction force from the mattress acting mostly through the heel, an external knee-extension joint-torque is induced that keeps the knee fully extended. This torque becomes zero if the feet are hung over the end of the support. This study investigated, in patients with knee-osteoarthritis (knee-OA) who routinely sleep supine, whether a change to such a sleeping position would ameliorate the knee pain and associated physical problems they suffer. Patients were recruited (General-Practitioners Centre, UK) over a 9-month period; those eligible (51/70) were randomly allocated to an intervention (65% female; age 71.5 [11.3] yrs; BMI, 29.20 [5.54] kg/m2; knee-OA severity, 20 mild–mod/3 severe) or control group (63% female; age, 68.3 [9.7] yrs; BMI, 28.69 [5.51] kg/m2; knee-OA severity, 17 mild–mod/2 severe). The primary outcome was improvements (0 [worst] to 100 [best]) in knee pain at 3 months and was rated in the Knee-Injury-and-Osteoarthritis-Outcome-Score questionnaire (KOOS). Secondary outcomes were improvements (0–100) in the other four KOOS-subscales. There were no differences between groups in KOOS outcomes at baseline, and there were no changes in KOOS outcomes in the control group at 3 months. Relative to the baseline KOOS values in Knee-Pain (50.1), Symptoms (52.5), Activities-of-Daily-Living (53.8) and Quality-of-Life (31.5), were all seen to improve at 3 months in the intervention group (by between 11.9 and 12.9); however, when comparing to controls, only the improvements in the subscale Activities-of-Daily-Living (which improved by 12.2) were statistically significant. Findings indicate that for those with knee-OA who routinely sleep supine, sleeping with the feet over the end of the mattress (to prevent the knee being pushed into/held in full extension) can help ameliorate the physical problems they suffer.
10-Year Evaluation of the First Root Analogue Implant on Humans, Made Using a CT Scan, CAD/CAM and DMLS
Authors: Figliuzzi Michele Mario , Aiello Domenico , Rengo Carlo , Parentela Luca , Mangano Carlo
Published: March 2022

Ten years ago, for the first time in humans, thanks to the DLMS (direct metal laser sintering) technique, we designed, built and inserted an immediate post-extraction custom-made root-analogue implant in Ti-6Al-4v with platform switching. The implant was inserted into the post-extraction socket, respecting the biological width. After 10 years, we wanted to evaluate the dimensional stability of the implant and the eventual crestal bone resorption. The evaluation was performed clinically with periodontal parameters and radiographically by means of an intraoral X-ray with the parallel technique measuring the distance between the base of the bone crest and the implant shoulder. It appears that the implant has maintained dimensional stability of the peri-implant soft tissues, and the crestal resorption is 0 mm. This could represent a step forward to make this experimental method a valid alternative to the current immediate post-extraction implant procedures in use.
Neurofeedback-Augmented Mindfulness Training Elicits Distinct Responses in the Subregions of the Insular Cortex in Healthy Adolescents
Authors: Yu Xiaoqian , Cohen Zsofia , Tsuchiyagaito Aki , Cochran Gabriella , Aupperle Robin , Stewart Jennifer , Singh Manpreet , Misaki Masaya , Bodurka Jerzy , Paulus Martin , Kirlic Namik
Published: March 2022

Mindfulness training (MT) reduces self-referential processing and promotes interoception, the perception of sensations from inside the body, by increasing one’s awareness of and regulating responses to them. The posterior cingulate cortex (PCC) and the insular cortex (INS) are considered hubs for self-referential processing and interoception, respectively. Although MT has been consistently found to decrease PCC, little is known about how MT relates to INS activity. Understanding links between mindfulness and interoception may be particularly important for informing mental health in adolescence, when neuroplasticity and emergence of psychopathology are heightened. We examined INS activity during real-time functional magnetic resonance imaging neurofeedback-augmented mindfulness training (NAMT) targeting the PCC. Healthy adolescents (N = 37; 16 female) completed the NAMT task, including Focus-on-Breath (MT), Describe (self-referential processing), and Rest conditions, across three neurofeedback runs and two non-neurofeedback runs (Observe, Transfer). Regression coefficients estimated from the generalized linear model were extracted from three INS subregions: anterior (aINS), mid (mINS), and posterior (pINS). Mixed model analyses revealed the main effect of run for Focus-on-Breath vs. Describe contrast in aINS [R2 = 0.39] and pINS [R2 = 0.33], but not mINS [R2 = 0.34]. Post hoc analyses revealed greater aINS activity and reduced pINS activity during neurofeedback runs, and such activities were related to lower self-reported life satisfaction and less pain behavior, respectively. These findings revealed the specific involvement of insula subregions in rtfMRI-nf MT.
A Clarion Call for Neuroinflammatory Assays in Brain Stimulation for Chronic Pain
Authors: Kinfe Thomas , Zhao Yining , Viviani Barbara
Published: March 2022

Chronic pain is characterized by an impaired functional state (pain, mood, sleep, cognition, and metabolism) affecting different brain networks relevant for pain perception and neural pain processing [...]
Finite Element Study of Hyperstructure Systems with Modular Light-Frame Construction in High-Rise Buildings
Authors: Labrecque Nicolas , Ménard Sylvain , Oudjene Marc , Blanchet Pierre
Published: March 2022

To answer both the growth of the world’s urban population and the climate changes, new structural systems with high prefabrication levels and renewable materials need to be developed. A novel structural system that could enable the use of modular light-frame construction in high-rise buildings was modeled and analyzed. This system was achieved by having a hyperstructure carrying the loads of four-story light-frame superposed substructures. Two 20-story hyperstructures, one using glulam and another one using reinforced concrete, were designed according to the 2015 National Building Code of Canada and compared. A simplified model for the light-frame modules according to the CSA O86-19 was proposed. The interaction between both systems and the impact on the substructures were analyzed. The results of the response spectrum analysis and dynamic wind analysis show that, with a glulam hyperstructure, modules could be connected to the columns and the floors or only to the floors. With a concrete hyperstructure, the modules must be connected to the columns and the cores. For both systems, the design of shearwalls on the short side of the modules is governed by the lateral deformation imposed by seismic forces, while the design of shearwalls on the long side of the modules is governed by the vertical deformation of the primary beams under gravity loads. Standard shearwall assemblies are sufficient to resist the shear induced by gravitational, wind and seismic loads. The analysis indicates that the system could be viable, but more research should be especially performed on the connections between the substructures and the hyperstructure.
Targeting the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Colorectal Cancer
Authors: Catalano Fabio , Borea Roberto , Puglisi Silvia , Boutros Andrea , Gandini Annalice , Cremante Malvina , Martelli Valentino , Sciallero Stefania , Puccini Alberto
Published: March 2022

Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15–20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors.
Molecular Signatures of Tumour and Its Microenvironment for Precise Quantitative Diagnosis of Oral Squamous Cell Carcinoma: An International Multi-Cohort Diagnostic Validation Study
Authors: Teh Muy-Teck , Ma Hong , Liang Ying-Ying , Solomon Monica Charlotte , Chaurasia Akhilanand , Patil Ranjitkumar , Tekade Satyajit Ashok , Mishra Deepika , Qadir Fatima , Yeung Ji-Yun Stephanie , Liu Xinting , Kriuar Safa , Zhao Ruoqi , Waseem Ahmad , Hutchison Iain L.
Published: March 2022

Background: Heterogeneity in oral potentially malignant disorder (OPMD) poses a problem for accurate prognosis that impacts on treatment strategy and patient outcome. A holistic assessment based on gene expression signatures from both the tumour cells and their microenvironment is necessary to provide a more precise prognostic assessment than just tumour cell signatures alone. Methods: We reformulated our previously established multigene qPCR test, quantitative Malignancy Index Diagnostic System (qMIDS) with new genes involved in matrix/stroma and immune modulation of the tumour microenvironment. An algorithm calculates and converts a panel of 16 gene mRNA expression levels into a qMIDS index to quantify risk of malignancy for each sample. Results: The new qMIDSV2 assay was validated in a UK oral squamous cell carcinoma (OSCC) cohort (n = 282) of margin and tumour core samples demonstrating significantly better diagnostic performance (AUC = 0.945) compared to previous qMIDSV1 (AUC = 0.759). Performance of qMIDSV2 were independently validated in Chinese (n = 35; AUC = 0.928) and Indian (n = 95; AUC = 0.932) OSCC cohorts. Further, 5-year retrospective analysis on an Indian dysplastic lesion cohort (n = 30) showed that qMIDSV2 was able to significantly differentiate between lesions without transformation and those with malignant transformation. Conclusions: This study validated a novel multi-gene qPCR test on a total of 535 tissue specimens from UK, China and India, demonstrating a rapid minimally invasive method that has a potential application for dysplasia risk stratification. Further study is required to establish if qMIDSV2 could be used to improve OPMD patient management, guide treatment strategy and reduce oral cancer burden.
Pro-Inflammatory Cytokines Trigger the Overexpression of Tumour-Related Splice Variant RAC1B in Polarized Colorectal Cells
Authors: Pereira Joana F. S. , Bessa Cláudia , Matos Paulo , Jordan Peter
Published: March 2022

An inflammatory microenvironment is a tumour-promoting condition that provides survival signals to which cancer cells respond with gene expression changes. One example is the alternative splicing variant Rat Sarcoma Viral Oncogene Homolog (Ras)-Related C3 Botulinum Toxin Substrate 1 (RAC1)B, which we previously identified in a subset of V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF)-mutated colorectal tumours. RAC1B was also increased in samples from inflammatory bowel disease patients or in an acute colitis mouse model. Here, we used an epithelial-like layer of polarized Caco-2 or T84 colorectal cancer (CRC) cells in co-culture with fibroblasts, monocytes or macrophages and analysed the effect on RAC1B expression in the CRC cells by RT-PCR, Western blot and confocal fluorescence microscopy. We found that the presence of cancer-associated fibroblasts and M1 macrophages induced the most significant increase in RAC1B levels in the polarized CRC cells, accompanied by a progressive loss of epithelial organization. Under these conditions, we identified interleukin (IL)-6 as the main trigger for the increase in RAC1B levels, associated with Signal Transducer and Activator of Transcription (STAT)3 activation. IL-6 neutralization by a specific antibody abrogated both RAC1B overexpression and STAT3 phosphorylation in polarized CRC cells. Our data identify that pro-inflammatory extracellular signals from stromal cells can trigger the overexpression of tumour-related RAC1B in polarized CRC cells. The results will help to understand the tumour-promoting effect of inflammation and identify novel therapeutic strategies.
Hypofractionated Whole Breast Irradiation and Boost-IOERT in Early Stage Breast Cancer (HIOB): First Clinical Results of a Prospective Multicenter Trial (NCT01343459)
Authors: Fastner Gerd , Reitsamer Roland , Gaisberger Christoph , Hitzl Wolfgang , Urbański Bartosz , Murawa Dawid , Matuschek Christiane , Budach Wilfried , Ciabattoni Antonella , Reiland Juliann , Molnar Marie , Vidali Cristiana , Schumacher Claudia , Sedlmayer Felix ,   on behalf of the HIOB Trialist Group
Published: March 2022

Background and purpose: To investigate intraoperative electron radiation therapy (IOERT) as a tumor bed boost during breast conserving surgery (BCS) followed by hypofractionated whole breast irradiation (HWBI) on age-correlated in-breast recurrence (IBR) rates in patients with low- to high-risk invasive breast cancer. Material and methods: BCS and IOERT (11.1 Gy) preceded a HWBI (40.5 Gy) in 15 fractions. Five-year IBR-rates were compared by a sequential ratio test (SQRT) with best evidences in three age groups (35–40 y and 41–50 y: 3.6%, >50 y: 2%) in a prospective single arm design. Null hypothesis (H0) was defined to undershoot these benchmarks for proof of superiority. Results: Of 1445 enrolled patients, 326 met exclusion criteria, leaving 1119 as eligible for analysis. After a median follow-up of 50 months (range 0.7–104), we detected two local recurrences, both in the age group >50 y. With no observed IBR, superiority was demonstrated for the patient groups 41–50 and >50 y, respectively. For the youngest group (35–40 y), no appropriate statistical evaluation was yet possible due to insufficient recruitment. Conclusions: In terms of five-year IBR-rates, Boost-IOERT followed by HWBI has been demonstrated to be superior in patients older than 50 and in the age group 41–50 when compared to best published evidence until 2010.
Differences in the MRI Signature and ADC Values of Diffuse Midline Gliomas with H3 K27M Mutation Compared to Midline Glioblastomas
Authors: Raab Peter , Banan Rouzbeh , Akbarian Arash , Esmaeilzadeh Majid , Samii Madjid , Samii Amir , Bertalanffy Helmut , Lehmann Ulrich , Krauss Joachim K. , Lanfermann Heinrich , Hartmann Christian , Brüning Roland
Published: March 2022

We conducted a two-center retrospective survey on standard MRI features including apparent diffusion coefficient mapping (ADC) of diffuse midline gliomas H3 K27M-mutant (DMG) compared to midline glioblastomas H3 K27M-wildtype (midGBM-H3wt). We identified 39 intracranial DMG and 18 midGBM-H3wt tumors. Samples were microscopically re-evaluated for microvascular proliferations and necrosis. Image analysis focused on location, peritumoral edema, degree of contrast enhancement and DWI features. Within DMG, MRI features between tumors with or without histomorphological GBM features were compared. DMG occurred in 15/39 samples from the thalamus (38%), in 23/39 samples from the brainstem (59%) and in 1/39 tumors involving primarily the cerebellum (2%). Edema was present in 3/39 DMG cases (8%) versus 78% in the control (midGBM-H3wt) group (p < 0.001). Contrast enhancement at the tumor rim was detected in 17/39 DMG (44%) versus 67% in control (p = 0.155), and necrosis in 24/39 (62%) versus 89% in control (p = 0.060). Strong contrast enhancement was observed in 15/39 DMG (38%) versus 56% in control (p = 0.262). Apparent diffusion coefficient (ADC) histogram analysis showed significantly higher skewness and kurtosis values in the DMG group compared to the controls (p = 0.0016/p = 0.002). Minimum relative ADC (rADC) values, as well as the 10th and 25th rADC-percentiles, were lower in DMGs with GBM features within the DMG group (p < 0.001/p = 0.012/p = 0.027). In conclusion, DMG cases exhibited markedly less edema than midGBM-H3wt, even if histomorphological malignancy was present. Histologically malignant DMGs and midGBM-H3wt more often displayed strong enhancement, as well as rim enhancement, than DMGs without histomorphological malignancy. DMGs showed higher skewness and kurtosis values on ADC-histogram analysis compared to midGBM-H3wt. Lower minimum rADC values in DMGs indicated malignant histomorphological features, likely representing a more complex tissue microstructure.
Metabolic Reprogramming of Ovarian Cancer Spheroids during Adhesion
Authors: Compton Stephanie L. E. , Grieco Joseph P. , Gollamudi Benita , Bae Eric , Van Mullekom Jennifer H. , Schmelz Eva M.
Published: March 2022

Ovarian cancer remains a deadly disease and its recurrence disease is due in part to the presence of disseminating ovarian cancer aggregates not removed by debulking surgery. During dissemination in a dynamic ascitic environment, the spheroid cells’ metabolism is characterized by low respiration and fragmented mitochondria, a metabolic phenotype that may not support secondary outgrowth after adhesion. Here, we investigated how adhesion affects cellular respiration and substrate utilization of spheroids mimicking early stages of secondary metastasis. Using different glucose and oxygen levels, we investigated cellular metabolism at early time points of adherence (24 h and less) comparing slow and fast-developing disease models. We found that adhesion over time showed changes in cellular energy metabolism and substrate utilization, with a switch in the utilization of mostly glutamine to glucose but no changes in fatty acid oxidation. Interestingly, low glucose levels had less of an impact on cellular metabolism than hypoxia. A resilience to culture conditions and the capacity to utilize a broader spectrum of substrates more efficiently distinguished the highly aggressive cells from the cells representing slow-developing disease, suggesting a flexible metabolism contributes to the stem-like properties. These results indicate that adhesion to secondary sites initiates a metabolic switch in the oxidation of substrates that could support outgrowth and successful metastasis.
Updated Prognostic Factors in Localized NSCLC
Authors: Garinet Simon , Wang Pascal , Mansuet-Lupo Audrey , Fournel Ludovic , Wislez Marie , Blons Hélène
Published: March 2022

Lung cancer is the most common cause of cancer mortality worldwide, and non-small cell lung cancer (NSCLC) represents 80% of lung cancer subtypes. Patients with localized non-small cell lung cancer may be considered for upfront surgical treatment. However, the overall 5-year survival rate is 59%. To improve survival, adjuvant chemotherapy (ACT) was largely explored and showed an overall benefit of survival at 5 years < 7%. The evaluation of recurrence risk and subsequent need for ACT is only based on tumor stage (TNM classification); however, more than 25% of patients with stage IA/B tumors will relapse. Recently, adjuvant targeted therapy has been approved for EGFR-mutated resected NSCLC and trials are evaluating other targeted therapies and immunotherapies in adjuvant settings. Costs, treatment duration, emergence of resistant clones and side effects stress the need for a better selection of patients. The identification and validation of prognostic and theranostic markers to better stratify patients who could benefit from adjuvant therapies are needed. In this review, we report current validated clinical, pathological and molecular prognosis biomarkers that influence outcome in resected NSCLC, and we also describe molecular biomarkers under evaluation that could be available in daily practice to drive ACT in resected NSCLC.
Emerging Novel Combined CAR-T Cell Therapies
Authors: Nguyen Anh , Johanning Gary , Shi Yihui
Published: March 2022

Chimeric antigen receptors (CAR) T cells are T cells engineered to express membrane receptors with high specificity to recognize specific target antigens presented by cancer cells and are co-stimulated with intracellular signals to increase the T cell response. CAR-T cell therapy is emerging as a novel therapeutic approach to improve T cell specificity that will lead to advances in precision medicine. CAR-T cells have had impressive outcomes in hematological malignancies. However, there continue to be significant limitations of these therapeutic responses in targeting solid malignancies such as heterogeneous antigens in solid tumors, tumor immunosuppressive microenvironment, risk of on-target/off-tumor, infiltrating CAR-T cells, immunosuppressive checkpoint molecules, and cytokines. This review paper summarizes recent approaches and innovations through combination therapies of CAR-T cells and other immunotherapy or small molecule drugs to counter the above disadvantages to potentiate the activity of CAR-T cells.
Natural Sunlight Driven Photocatalytic Removal of Toxic Textile Dyes in Water Using B-Doped ZnO/TiO2 Nanocomposites
Authors: Shathy Romana Akter , Fahim Shahriar Atik , Sarker Mithun , Quddus Md. Saiful , Moniruzzaman Mohammad , Masum Shah Md. , Molla Md. Ashraful Islam
Published: March 2022

A novel B-doped ZnO/TiO2 (B–ZnO/TiO2) nanocomposite photocatalyst was prepared using a mechanochemical–calcination method. For the characterization of the synthesized B–ZnO/TiO2 photocatalyst, XRD, FESEM-EDS, FTIR, UV-Vis DRS, BET, PL, and XPS techniques were used. The bandgap energy of B–ZnO/TiO2 was reduced, resulting in enhanced visible-light absorption. Significant PL quenching confirmed the reduction in the electron–hole recombination rate. Furthermore, reduced crystallite size and a larger surface area were obtained. Hence, the B–ZnO/TiO2 photocatalyst exhibited better photocatalytic activity than commercial TiO2, ZnO, B–ZnO, and ZnO/TiO2 in the removal of methylene blue (MB) dye under natural sunlight irradiation. The effects of various parameters, such as initial concentration, photocatalyst amount, solution pH, and irradiation time, were studied. Under optimal conditions (MB concentration of 15 mg/L, pH 11, B–ZnO/TiO2 amount of 30 mg, and 15 min of operation), a maximum MB removal efficiency of ~95% was obtained. A plausible photocatalytic degradation mechanism of MB with B–ZnO/TiO2 was estimated from the scavenger test, and it was observed that the •O2− and •OH radicals were potential active species for the MB degradation. Cyclic experiments indicated the high stability and reusability of B–ZnO/TiO2, which confirmed that it can be an economical and environmentally friendly photocatalyst.
Full and Sustainable Electrochemical Production of Chlorine Dioxide
Authors: Moratalla Ángela , Monteiro Mayra K. S. , Sáez Cristina , Dos Santos Elisama V. , Rodrigo Manuel A.
Published: March 2022

With the final purpose of manufacturing electrochemically-based devices that produce chloride dioxide efficiently, this paper focuses on the production of chlorates and hydrogen peroxide in two different electrochemical cells, in which operation conditions are selected to obtain high efficiencies, and in the subsequent combination of both electrochemically manufactured solutions to produce chlorine dioxide. Results demonstrate that suitable reagents can be produced by electrolyzing 20 g L−1 sodium chloride solutions at 50 mA cm−2 and 50 °C, and 3000 mg L−1 NaClO4 solutions at 5.0 mA cm−2 and 15 °C with current efficiencies of 30.9% and 48.0%, respectively. Different tests performed with these electrolyzed solutions, and also with commercial hydrogen peroxide and chlorate solutions, demonstrate that the ratio between both reagents plays a very important role in the efficiency in the production of chlorine dioxide. Results clearly showed that, surplus chlorate should be contained in the reagent media to prevent further reduction of chlorine dioxide by hydrogen peroxide and consequently, loses of efficiency in the process. During the reaction, a gas with a high oxidation capacity and consisting mainly in chloride dioxide is produced. The results contributed to the maximum conversion reached being 89.65% using electrolyzed solutions as precursors of ClO2, confirming that this technology can be promising to manufacture portable ClO2 devices.
GM-CSF Protects Macrophages from DNA Damage by Inducing Differentiation
Authors: Vico Tania , Youssif Catrin , Zare Fathema , Comalada Mònica , Sebastian Carlos , Lloberas Jorge , Celada Antonio
Published: March 2022

At inflammatory loci, pro-inflammatory activation of macrophages produces large amounts of reactive oxygen species (ROS) that induce DNA breaks and apoptosis. Given that M-CSF and GM-CSF induce two different pathways in macrophages, one for proliferation and the other for survival, in this study we wanted to determine if these growth factors are able to protect against the DNA damage produced during macrophage activation. In macrophages treated with DNA-damaging agents we found that GM-CSF protects better against DNA damage than M-CSF. Treatment with GM-CSF resulted in faster recovery of DNA damage than treatment with M-CSF. The number of apoptotic cells induced after DNA damage was higher in the presence of M-CSF. Protection against DNA damage by GM-CSF is not related to its higher capacity to induce proliferation. GM-CSF induces differentiation markers such as CD11c and MHCII, as well as the pro-survival Bcl-2A1 protein, which make macrophages more resistant to DNA damage.
Axon-Targeting Motifs: Mechanisms and Applications of Enhancing Axonal Localisation of Transmembrane Proteins
Authors: Steele-Nicholson Lloyd J. , Andrews Melissa R.
Published: March 2022

Neuronal polarity established in developing neurons ensures proper function in the mature nervous system. As functionally distinct cellular compartments, axons and dendrites often require different subsets of proteins to maintain synaptic transmission and overall order. Although neurons in the mature CNS do not regenerate throughout life, their interactions with their extracellular environment are dynamic. The axon remains an overall protected area of the neuron where only certain proteins have access throughout the lifespan of the cell. This is in comparison to the somatodendritic compartment, where although it too has a specialised subset of proteins required for its maintenance, many proteins destined for the axonal compartment must first be trafficked through the former. Recent research has shown that axonal proteins contain specific axon-targeting motifs that permit access to the axonal compartment as well as downstream targeting to the axonal membrane. These motifs target proteins to the axonal compartment by a variety of mechanisms including: promoting segregation into axon-targeted secretory vesicles, increasing interaction with axonal kinesins and enhancing somatodendritic endocytosis. In this review, we will discuss axon-targeting motifs within the context of established neuron trafficking mechanisms. We will also include examples of how these motifs have been applied to target proteins to the axonal compartment to improve both tools for the study of axon biology, and for use as potential therapeutics for axonopathies.