bluuebunny/crossref_metadata_2025 huggingface dataset:
Fuzzy Logic Controller for Automating Electrical Conductivity and pH in Hydroponic Cultivation
Authors: Chen Cheng-Hung , Jeng Shiou-Yun , Lin Cheng-Jian
Published: January 2022

This study proposes a fuzzy logic controller for adjusting the electrical conductivity (EC) and pH of the nutrient solution in a hydroponic system. The proposed control system detects the EC and pH of the solution through sensors and adjusts the working time of the solution pump through the fuzzy controller. Specifically, the EC and pH of the nutrient solution are maintained at specific values. A Raspberry Pi3 development board is used in the proposed control system to realize and solve the problem of adjusting the EC and pH of the solution. In the fuzzy controller, the inputs are EC and pH sensors, and the output is the operating time of the pump. Experimental results indicate that the proposed control system can effectively reduce the measurement burden and complex calculations of producers by adjusting nutrient solutions.
Detecting the Speed Change Intention from EEG Signals: From the Offline and Pseudo-Online Analysis to an Online Closed-Loop Validation
Authors: Quiles Vicente , Ferrero Laura , Iáñez Eduardo , Ortiz Mario , Cano José M. , Azorín José M.
Published: January 2022

Control of assistive devices by voluntary user intention is an underdeveloped topic in the Brain–Machine Interfaces (BMI) literature. In this work, a preliminary real-time BMI for the speed control of an exoskeleton is presented. First, an offline analysis for the selection of the intention patterns based on the optimum features and electrodes is proposed. This is carried out comparing three different classification models: monotonous walk vs. increasing and decreasing change speed intentions, monotonous walk vs. only increasing intention, and monotonous walk vs. only decreasing intention. The results indicate that, among the features tested, the most suitable parameter to represent these models are the Hjorth statistics in alpha and beta frequency bands. The average offline classification accuracy for the offline cross-validation of the three models obtained is 68 ± 11%. This selection is also tested following a pseudo-online analysis, simulating a real-time detection of the subject’s intentions to change speed. The average results indices of the three models during this pseudoanalysis are of a 42% true positive ratio and a false positive rate per minute of 9. Finally, in order to check the viability of the approach with an exoskeleton, a case of study is presented. During the experimental session, the pros and cons of the implementation of a closed-loop control of speed change for the H3 exoskeleton through EEG analysis are commented.
Intelligent Traffic Signal Phase Distribution System Using Deep Q-Network
Authors: Joo Hyunjin , Lim Yujin
Published: January 2022

Traffic congestion is a worsening problem owing to an increase in traffic volume. Traffic congestion increases the driving time and wastes fuel, generating large amounts of fumes and accelerating environmental pollution. Therefore, traffic congestion is an important problem that needs to be addressed. Smart transportation systems manage various traffic problems by utilizing the infrastructure and networks available in smart cities. The traffic signal control system used in smart transportation analyzes and controls traffic flow in real time. Thus, traffic congestion can be effectively alleviated. We conducted preliminary experiments to analyze the effects of throughput, queue length, and waiting time on the system performance according to the signal allocation techniques. Based on the results of the preliminary experiment, the standard deviation of the queue length is interpreted as an important factor in an order allocation technique. A smart traffic signal control system using a deep Q-network, which is a type of reinforcement learning, is proposed. The proposed algorithm determines the optimal order of a green signal. The goal of the proposed algorithm is to maximize the throughput and efficiently distribute the signals by considering the throughput and standard deviation of the queue length as reward parameters.
A Methodology for Exploiting Smart Prosumers’ Flexibility in a Bottom-Up Aggregation Process
Authors: Arnone Diego , Cacioppo Michele , Ippolito Mariano Giuseppe , Mammina Marzia , Mineo Liliana , Musca Rossano , Zizzo Gaetano
Published: January 2022

The electrical power system is evolving in a way that requires new measures for ensuring its secure and reliable operation. Demand-side aggregation represents one of the more interesting ways to provide ancillary services by the coordinated management of a multitude of different distributed resources. In this framework, aggregators play the main role in ensuring the effectiveness of the coordinated action of the distributed resources, usually becoming mediators in the relation between distribution system operators and smart prosumers. The research project DEMAND recently introduced a new concept in demand-side aggregation by proposing a scheme without a central aggregator where prosumers can share and combine their flexibility with a collaboration–competition mechanism in a platform called Virtual Aggregation Environment (VAE). This paper, after a brief introduction to the DEMAND project, presents the algorithm for the day-ahead estimation of prosumers’ flexibility and the cooperative–competitive algorithm for the bottom-up aggregation. The first algorithm evaluates various couples of power variation and desired remuneration to be sent to the VAE for further elaborations and, for showing its potentiality, is applied to two different case studies: a passive user with only controllable loads and prosumers with controllable loads, photovoltaics and a storage system. The aggregation algorithm is instead discussed in detail, and its performance is evaluated for different population sizes.
A Novel Remaining Useful Life Prediction Method for Hydrogen Fuel Cells Based on the Gated Recurrent Unit Neural Network
Authors: Long Bing , Wu Kunping , Li Pengcheng , Li Meng
Published: January 2022

The remaining useful life (RUL) prediction for hydrogen fuel cells is an important part of its prognostics and health management (PHM). Artificial neural networks (ANNs) are proven to be very effective in RUL prediction, as they do not need to understand the failure mechanisms behind hydrogen fuel cells. A novel RUL prediction method for hydrogen fuel cells based on the gated recurrent unit ANN is proposed in this paper. Firstly, the data were preprocessed to remove outliers and noises. Secondly, the performance of different neural networks is compared, including the back propagation neural network (BPNN), the long short-term memory (LSTM) network and the gated recurrent unit (GRU) network. According to our proposed method based on GRU, the root mean square error was 0.0026, the mean absolute percentage error was 0.0038 and the coefficient of determination was 0.9891 for the data from the challenge datasets provided by FCLAB Research Federation, when the prediction starting point was 650 h. Compared with the other RUL prediction methods based on the BPNN and the LSTM, our prediction method is better in both prediction accuracy and convergence rate.
Effect of the Distribution of Mass and Structural Member Discretization on the Seismic Response of Steel Buildings
Authors: Valenzuela-Beltrán Federico , Llanes-Tizoc Mario D. , Bojórquez Edén , Bojórquez Juan , Chávez Robespierre , Leal-Graciano Jesus Martin , Serrano Juan A. , Reyes-Salazar Alfredo
Published: January 2022

The response of steel moment frames is estimated by first considering that the mass matrix is the concentrated type (ML) and then consistent type (MC). The effect of considering more than one element per beam is also evaluated. Low-, mid- and high-rise frames, modeled as complex-2D-MDOF systems, are used in the numerical study. Results indicate that if ML is used, depending upon the response parameter under consideration, the structural model, the seismic intensity and the structural location, the response can be significantly overestimated, precisely calculated, or significantly underestimated. Axial loads at columns, on an average basis, are significantly overestimated (up to 60%), while lateral drifts and flexural moments at beams are precisely calculated. Inter-story shears and flexural moments at columns, on average, are underestimated by up to 15% and 35%, respectively; however, underestimations of up to 60% can be seen for some individual strong motions. Similarly, if just one element per beam is used in the structural modeling, inter-story shears and axial loads on columns are overestimated, on average, by up to 21% and 95%, respectively, while the lateral drifts are precisely calculated. Flexural moments at columns and beams can be considerably underestimated (on average up to 14% and 35%, respectively), but underestimations larger than 50% can be seen for some individual cases. Hence, there is no error in terms of lateral drifts if ML or one element per beam is used, but significant errors can be introduced in the design due to the overestimation and underestimation of the design forces. It is strongly suggested to use MC and at least two elements per beam in the structural modeling.
The Effect of Acceleration on the Separation Force in Constrained-Surface Stereolithography
Authors: Gritsenko Dmitry , Paoli Roberto , Xu Jie
Published: January 2022

Constrained-surface-based stereolithography has recently attracted much attention from both academic and industrial communities. Despite numerous experimental, numerical and theoretical efforts, the fundamental need to reduce the separation force between the newly cured part and constrained surface has not yet been completely solved. In this paper, we develop a fluid dynamics approach, proposed in our previous work, to theoretically model the separation force in 3D printing of a cylindrical part for flat and patterned windows. We demonstrate the possibility of separation force reduction with an accelerated movement of the printing platform. In particular, we investigate behaviors of transient parameter, its reduction rate, and separation force reduction with respect to elevation speed and time. The proposed approach involves deceleration and acceleration stages and allows to achieve the force reduction for the entire printing process. Finally, we provide implicit analytical solutions for time moments when switching between the stages can be done without noticeable increase of separation force and explicit expression for separation force in case of patterned window.
A Study of Solar Flare Effects on the Geomagnetic Field Components during Solar Cycles 23 and 24
Authors: Grodji Oswald Didier Franck , Doumbia Vafi , Amaechi Paul Obiakara , Amory-Mazaudier Christine , N’guessan Kouassi , Diaby Kassamba Abdel Aziz , Zie Tuo , Boka Kouadio
Published: January 2022

In this paper, we investigated the impact of solar flares on the horizontal (H), eastward (Y) and vertical (Z) components of the geomagnetic field during solar cycles 23 and 24 (SC23/24) using data of magnetometer measurements on the sunlit side of the Earth. We examined the relation between sunspot number and solar flare occurrence of various classes during both cycles. During SC23/24, we obtained correlation coefficient of 0.93/0.97, 0.96/0.96 and 0.60/0.56 for C-class, M-class and X-class flare, respectively. The three components of the geomagnetic field reached a peak a few minutes after the solar flare occurrence. Generally, the magnetic crochet of the H component was negative between the mid-latitudes and Low-latitudes in both hemispheres and positive at low latitudes. By contrast, the analysis of the latitudinal variation of the Y and Z components showed that unlike the H component, their patterns of variations were not coherent in latitude. The peak amplitude of solar flare effect (sfe) on the various geomagnetic components depended on many factors including the local time at the observing station, the solar zenith angle, the position of the station with respect to the magnetic equator, the position of solar flare on the sun and the intensity of the flare. Thus, these peaks were stronger for the stations around the magnetic equator and very low when the geomagnetic field components were close to their nighttime values. Both cycles presented similar monthly variations with the highest sfe value (ΔHsfe = 48.82 nT for cycle 23 and ΔHsfe = 24.68 nT for cycle 24) registered in September and lowest in June for cycle 23 (ΔHsfe = 8.69 nT) and July for cycle 24 (ΔHsfe = 10.69 nT). Furthermore, the sfe was generally higher in cycle 23 than in cycle 24.
Electromagnetic Induction Measurements for Investigating Soil Salinization Caused by Saline Reclaimed Water
Authors: De Carlo Lorenzo , Vivaldi Gaetano Alessandro , Caputo Maria Clementina
Published: January 2022

This paper focused on the use of electromagnetic induction measurements in order to investigate soil salinization caused by irrigation with saline reclaimed water. An experimental activity was carried out during the growing season of tomato crop in order to evaluate expected soil salinization effects caused by different saline agro-industrial wastewaters used as irrigation sources. Soil electrical conductivity, strictly related to the soil salinity, has been monitored for three months by means of Electromagnetic Induction (EMI) measurements, and evident differences in the soil response have been observed. The study highlighted two aspects that can improve soil investigation due to the utilization of geophysical tools. First, EMI data can map large areas in a short period of time with an unprecedented level of detail by overcoming practical difficulties in order to massively sample soil. At the same time, repeated measurements over time allow updating real-time soil salinity maps by using accurate correlations with soil electrical conductivity. This application points out how integrated agro-geophysical research approaches can play a strategic role in agricultural saline water management in order to prevent soil salinization risks in medium to long-term periods.
Forecast of Hourly Airport Visibility Based on Artificial Intelligence Methods
Authors: Ding Jin , Zhang Guoping , Wang Shudong , Xue Bing , Yang Jing , Gao Jinbing , Wang Kuoyin , Jiang Ruijiao , Zhu Xiaoxiang
Published: January 2022

Based on the hourly visibility data, visibility and its changes during 2010–2020 at monthly and annual time scales over 47 international airports in China are investigated, and nine artificial-intelligence-based hourly visibility prediction models are trained (hourly data in 2018–2019) and tested (hourly data in 2020) at these airports. The analyses show that the visibility of airports in eastern and central China is at a poor level all year round, and LXA (in Lhasa) has good visibility all year round. Airports in south and the northwest China have better visibility from May to October and poorer visibility from November to April. In all months, the increasing visibility mainly occurs in the central, northeast and coastal areas of China, while decreasing visibility mainly appears in the western and northern parts of China. In spring, summer and autumn, the changes difference between east and west is particularly obvious. This East–West distribution of trends is obviously different from the North–South distribution shown by the mean. For all airports, good visibility mainly occurs from 14:00–18:00 p.m. Beijing Time, while poor visibility mainly concentrates from 22:00 p.m. to 12:00 p.m. the next day, especially between 3:00–9:00 a.m. Our proposed artificial intelligence algorithm models can be reasonably used in airport visibility prediction. In particular, most algorithm models have the best results in the visibility prediction over HFE (in Hefei) and SJW (in Shijiazhuang). On the contrary, the worst forecast results appear at LXA and LHW (in Lanzhou) airports. The prediction results of airport visibility in the cold season (October–December) are better than those in the warm season (May–September). Among the algorithm models, the prediction performance of the RF-based model is the best.
New Fixed Point Theorem on Triple Controlled Metric Type Spaces with Applications to Volterra–Fredholm Integro-Dynamic Equations
Authors: Gopalan Kalpana , Zubair Sumaiya Tasneem , Abdeljawad Thabet , Mlaiki Nabil
Published: January 2022

The objective of the research article is two-fold. Firstly, we present a fixed point result in the context of triple controlled metric type spaces with a distinctive contractive condition involving the controlled functions. Secondly, we consider an initial value problem associated with a nonlinear Volterra–Fredholm integro-dynamic equation and examine the existence and uniqueness of solutions via fixed point theorem in the setting of complete triple controlled metric type spaces. Furthermore, the theorem is applied to illustrate the existence of a unique solution to an integro-dynamic equation.
Drug Repositioning Ketamine as a New Treatment for Bipolar Disorder Using Text Mining
Authors: Manikandan Shivani , Misra Suchir , McCalla Serena
Published: January 2022

Bipolar Disorder (BD), a chronic mental illness, does not have an ideal treatment, and patients with BD have a higher chance of being diagnosed with alcohol abuse, liver disease, and diabetes. The goal of treatment is to prevent a relapse in BD episodes and find a new treatment. The research here looks at the genetics of BD and ignores environmental factors, as they are subjective. Therapy treats known environmental triggers and stressors and explores methods to reduce them. However, therapy alone cannot fully alleviate the symptoms of BD. My research employs text-mining as a primary strategy to obtain relevant genes and drugs pertaining to BD. The main gene involved is the Brain-Derived Neurotrophic Factor (BDNF). Popular drugs currently used for treatment of BD are Lithium and Carbamazepine. Using CMapPy to look at gene expression data, one sees a relationship between the two drug therapies and BDNF. Lithium fails to treat mania and Carbamazepine fails to treat depression, relatively speaking. When comparing gene expression data of Lithium and Carbamazepine with Ketamine, a newer therapy for BD, Ketamine, raises the BDNF level, keeps it elevated, and effectively controls BD episodes. Ketamine does not have the shortcomings that Lithium and Carbamazepine have. Next steps would include conducting a clinical trial with the hopeful application of Ketamine as a new treatment for BD.
Knee Flexor Eccentric Strength, Hamstring Muscle Volume and Sprinting in Elite Professional Soccer Players with a Prior Strained Hamstring
Authors: Mendez-Villanueva Alberto , Nuñez Francisco Javier , Lazaro-Ramirez Jose Luis , Rodriguez-Sanchez Pablo , Guitart Marc , Rodas Gil , Martin-Garetxana Imanol , Lekue Josean , Di Salvo Valter , Suarez-Arrones Luis
Published: January 2022

The aim was to determine if players with a prior hamstring strain injury (HSI) exhibit bilateral deficits in knee flexor eccentric strength and hamstring muscle volume and differences in sprinting performance compared with players without a history of HSIs. Forty-six male professional soccer players participated in this study. Eccentric knee flexor strength, hamstring muscle volume (MRI), and a 20-m running sprint test (5- and 10-m split time) were assessed at the start of the preseason. Eccentric knee strength of the previously injured limbs of injured players was greater (ES: 1.18–1.36) than the uninjured limbs in uninjured players. Previously injured limbs showed possibly larger biceps femoris short heads (BFSh) and likely semitendinosus (ST) muscle volumes than the contralateral uninjured limbs among the injured players (ES: 0.36) and the limbs of the uninjured players (ES: 0.56), respectively. Players who had experienced a previous HSI were possibly slower in the 5-m (small ES: 0.46), while unclear differences were found in both the 10-m and 20-m times. Players with a prior HSI displayed greater eccentric knee flexor strength, possibly relatively hypertrophied ST and BFSh muscles, and possibly reduced 5-m sprinting performances than previously uninjured players. This can have implication for the design of secondary hamstring muscle injury prevention strategies.
Site-Specific Proteasome Inhibitors
Authors: Kisselev Alexei F.
Published: January 2022

Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory proteins, in the regulation of numerous cell functions. Proteasome inhibitors are essential tools for biomedical research. Three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib are approved by the FDA for the treatment of multiple myeloma; another inhibitor, marizomib, is undergoing clinical trials. The proteolytic core of the proteasome has three pairs of active sites, β5, β2, and β1. All clinical inhibitors and inhibitors that are widely used as research tools (e.g., epoxomicin, MG-132) inhibit multiple active sites and have been extensively reviewed in the past. In the past decade, highly specific inhibitors of individual active sites and the distinct active sites of the lymphoid tissue-specific immunoproteasome have been developed. Here, we provide a comprehensive review of these site-specific inhibitors of mammalian proteasomes and describe their utilization in the studies of the biology of the active sites and their roles as drug targets for the treatment of different diseases.
Liver Progenitor Cells in Massive Hepatic Necrosis—How Can a Patient Survive Acute Liver Failure?
Authors: Lin Tao , Feng Rilu , Liebe Roman , Weng Hong-Lei
Published: January 2022

Massive hepatic necrosis is the most severe lesion in acute liver failure, yet a portion of patients manage to survive and recover from this high-risk and harsh disease syndrome. The mechanisms underlying recovery remain largely unknown to date. Recent research progress highlights a key role of liver progenitor cells, the smallest biliary cells, in the maintenance of liver homeostasis and thus survival. These stem-like cells rapidly proliferate and take over crucial hepatocyte functions in a severely damaged liver. Hence, the new findings not only add to our understanding of the huge regenerative capability of the liver, but also provide potential new targets for the pharmacological management of acute liver failure in clinical practice.
Pyridoxine-Dependent Epilepsy and Antiquitin Deficiency Resulting in Neonatal-Onset Refractory Seizures
Authors: Kaminiów Konrad , Pająk Magdalena , Pająk Renata , Paprocka Justyna
Published: January 2022

Pyridoxine-dependent epilepsy (PDE) is an autosomal recessive neurometabolic disorder due to a deficiency of α-aminoadipic semialdehyde dehydrogenase (mutation in ALDH7A1 gene), more commonly known as antiquitin (ATQ). ATQ is one of the enzymes involved in lysine oxidation; thus, its deficiency leads to the accumulation of toxic metabolites in body fluids. PDE is characterized by persistent, recurrent neonatal seizures that cannot be well controlled by antiepileptic drugs but are responsive clinically and electrographically to daily pyridoxine (vitamin B6) supplementation. Although the phenotypic spectrum distinguishes between typical and atypical, pyridoxine-dependent is true for each. Diagnosis may pose a challenge mainly due to the rarity of the disorder and the fact that seizures may not occur until childhood or even late adolescence. Moreover, patients may not demonstrate an obvious clinical or electroencephalography response to the initial dose of pyridoxine. Effective treatment requires lifelong pharmacologic supplements of pyridoxine, and dietary lysine restriction and arginine enrichment should improve prognosis and avoid developmental delay and intellectual disability. The purpose of this review is to summarize briefly the latest reports on the etiology, clinical symptoms, diagnosis, and management of patients suffering from pyridoxine-dependent epilepsy.
The Contagion of Psychopathology across Different Psychiatric Disorders: A Comparative Theoretical Analysis
Authors: Horesh Danny , Hasson-Ohayon Ilanit , Harwood-Gross Anna
Published: January 2022

Psychopathology is often studied and treated from an individual-centered approach. However, studies have shown that psychological distress is often best understood from a contextual, environmental perspective. This paper explores the literature on emotional contagion and symptom transmission in psychopathology, i.e., the complex ways in which one person’s psychological distress may yield symptoms among others in his/her close environment. We argue that emotions, cognitions, and behaviors often do not stay within the borders of the individual, but rather represent intricate dynamic experiences that are shared by individuals, as well as transmitted between them. While this claim was comprehensively studied in the context of some disorders (e.g., secondary traumatization and the “mimicking” of symptoms among those close to a trauma survivor), it was very scarcely examined in the context of others. We aim to bridge this gap in knowledge by examining the literature on symptom transmission across four distinct psychiatric disorders: PTSD, major depression, OCD, and psychosis. We first review the literature on emotional contagion in each disorder separately, and then we subsequently conduct a comparative analysis highlighting the shared and differential mechanisms underlying these processes in all four disorders. In this era of transdiagnostic conceptualizations of psychopathology, such an examination is timely, and it may carry important clinical implications.
Conventional and HD-tDCS May (or May Not) Modulate Overt Attentional Orienting: An Integrated Spatio-Temporal Approach and Methodological Reflections
Authors: Diana Lorenzo , Scotti Giulia , Aiello Edoardo N. , Pilastro Patrick , Eberhard-Moscicka Aleksandra K. , Müri René M. , Bolognini Nadia
Published: January 2022

Transcranial Direct Current Stimulation (tDCS) has been employed to modulate visuo-spatial attentional asymmetries, however, further investigation is needed to characterize tDCS-associated variability in more ecological settings. In the present research, we tested the effects of offline, anodal conventional tDCS (Experiment 1) and HD-tDCS (Experiment 2) delivered over the posterior parietal cortex (PPC) and Frontal Eye Field (FEF) of the right hemisphere in healthy participants. Attentional asymmetries were measured by means of an eye tracking-based, ecological paradigm, that is, a Free Visual Exploration task of naturalistic pictures. Data were analyzed from a spatiotemporal perspective. In Experiment 1, a pre-post linear mixed model (LMM) indicated a leftward attentional shift after PPC tDCS; this effect was not confirmed when the individual baseline performance was considered. In Experiment 2, FEF HD-tDCS was shown to induce a significant leftward shift of gaze position, which emerged after 6 s of picture exploration and lasted for 200 ms. The present results do not allow us to conclude on a clear efficacy of offline conventional tDCS and HD-tDCS in modulating overt visuospatial attention in an ecological setting. Nonetheless, our findings highlight a complex relationship among stimulated area, focality of stimulation, spatiotemporal aspects of deployment of attention, and the role of individual baseline performance in shaping the effects of tDCS.
Current Status of Old Housing for Low-Income Elderly Households in Seoul and Green Remodeling Support Plan: Economic Analysis Considering the Social Cost of Green Remodeling
Authors: Kim Jaemoon , Nam Seunghoon , Lee Duhwan
Published: January 2022

In this study, the economic feasibility of green remodeling (GR), which could improve the health, safety, and energy of elderly households considering social cost, was analyzed. As a result, the net present value of GR was ‘−10,267 USD (49.7%)’, which was found to be uneconomical compared to the total construction cost (20,981 USD, 100%) despite benefits of energy saving, carbon reduction, and air pollutant reduction. Based on this result, in order to expand GR for low-income elderly households, who cannot afford to perform GR, a GR support measure linked to the currently implemented energy conversion and old-age housing support policies was proposed. It allows the government to perform GR for low-income elderly households with 1/4 of the total construction cost. This result could revitalize GR to reduce greenhouse gas and contribute to housing stability for low-income elderly households who are vulnerable to COVID-19 and climate change.
Combined Fluorescence and Optoacoustic Imaging for Monitoring Treatments against CT26 Tumors with Photoactivatable Liposomes
Authors: Turchin Ilya , Bano Shazia , Kirillin Mikhail , Orlova Anna , Perekatova Valeriya , Plekhanov Vladimir , Sergeeva Ekaterina , Kurakina Daria , Khilov Aleksandr , Kurnikov Alexey , Subochev Pavel , Shirmanova Marina , Komarova Anastasiya , Yuzhakova Diana , Gavrina Alena , Mallidi Srivalleesha , Hasan Tayyaba
Published: January 2022

The newly developed multimodal imaging system combining raster-scan optoacoustic (OA) microscopy and fluorescence (FL) wide-field imaging was used for characterizing the tumor vascular structure with 38/50 μm axial/transverse resolution and assessment of photosensitizer fluorescence kinetics during treatment with novel theranostic agents. A multifunctional photoactivatable multi-inhibitor liposomal (PMILs) nano platform was engineered here, containing a clinically approved photosensitizer, Benzoporphyrin derivative (BPD) in the bilayer, and topoisomerase I inhibitor, Irinotecan (IRI) in its inner core, for a synergetic therapeutic impact. The optimized PMIL was anionic, with the hydrodynamic diameter of 131.6 ± 2.1 nm and polydispersity index (PDI) of 0.05 ± 0.01, and the zeta potential between −14.9 ± 1.04 to −16.9 ± 0.92 mV. In the in vivo studies on BALB/c mice with CT26 tumors were performed to evaluate PMILs’ therapeutic efficacy. PMILs demonstrated the best inhibitory effect of 97% on tumor growth compared to the treatment with BPD-PC containing liposomes (PALs), 81%, or IRI containing liposomes (L-[IRI]) alone, 50%. This confirms the release of IRI within the tumor cells upon PMILs triggering by NIR light, which is additionally illustrated by FL monitoring demonstrating enhancement of drug accumulation in tumor initiated by PDT in 24 h after the treatment. OA monitoring revealed the largest alterations of the tumor vascular structure in the PMILs treated mice as compared to BPD-PC or IRI treated mice. The results were further corroborated with histological data that also showed a 5-fold higher percentage of hemorrhages in PMIL treated mice compared to the control groups. Overall, these results suggest that multifunctional PMILs simultaneously delivering PDT and chemotherapy agents along with OA and FL multi-modal imaging offers an efficient and personalized image-guided platform to improve cancer treatment outcomes.
Rethinking the TNM Classification Regarding Direct Lymph Node Invasion in Pancreatic Ductal Adenocarcinoma
Authors: Speichinger Fiona , Dragomir Mihnea P. , Schallenberg Simon , Loch Florian N. , Degro Claudius E. , Baukloh Ann-Kathrin , Hartmann Lisa , Pozios Ioannis , Schineis Christian , Margonis Georgios Antonios , Lauscher Johannes C. , Beyer Katharina , Kamphues Carsten
Published: January 2022

Mechanisms of lymph node invasion seem to play a prognostic role in pancreatic ductal adenocarcinoma (PDAC) after resection. However, the 8th edition of the TNM classification of the American Joint Committee on Cancer (AJCC) does not consider this. The aim of this study was to analyse the prognostic role of different mechanisms of lymph node invasion on PDAC. One hundred and twenty-two patients with resected PDAC were examined. We distinguished three groups: direct (per continuitatem, Nc) from the main tumour, metastasis (Nm) without any contact to the main tumour, and a mixed mechanism (Ncm). Afterwards, the prognostic power of the different groups was analysed concerning overall survival (OS). In total, 20 patients displayed direct lymph node invasion (Nc = 16.4%), 44 were classed as Nm (36.1%), and 21 were classed as Ncm (17.2%). The difference in OS was not statistically significant between N0 (no lymph node metastasis, n = 37) and Nc (p = 0.134), while Nm had worse OS than N0 (p < 0.001). Direct invasion alone had no statistically significant effect on OS (p = 0.885). Redefining the N0 stage by including Nc patients showed a more precise OS prediction among N stages (p = 0.001 vs. p = 0.002). Nc was more similar to N0 than to Nm; hence, we suggest a rethinking of TNM classification based on the mechanisms of lymph node metastases in PDAC. Overall, this novel classification is more precise.
Natural and Synthetic Estrogens in Chronic Inflammation and Breast Cancer
Authors: Maharjan Chandra K. , Mo Jiao , Wang Lei , Kim Myung-Chul , Wang Sameul , Borcherding Nicholas , Vikas Praveen , Zhang Weizhou
Published: January 2022

The oncogenic role of estrogen receptor (ER) signaling in breast cancer has long been established. Interaction of estrogen with estrogen receptor (ER) in the nucleus activates genomic pathways of estrogen signaling. In contrast, estrogen interaction with the cell membrane-bound G-protein-coupled estrogen receptor (GPER) activates the rapid receptor-mediated signaling transduction cascades. Aberrant estrogen signaling enhances mammary epithelial cell proliferation, survival, and angiogenesis, hence is an important step towards breast cancer initiation and progression. Meanwhile, a growing number of studies also provide evidence for estrogen’s pro- or anti-inflammatory roles. As other articles in this issue cover classic ER and GPER signaling mediated by estrogen, this review will discuss the crucial mechanisms by which estrogen signaling influences chronic inflammation and how that is involved in breast cancer. Xenoestrogens acquired from plant diet or exposure to industrial products constantly interact with and alter innate estrogen signaling at various levels. As such, they can modulate chronic inflammation and breast cancer development. Natural xenoestrogens generally have anti-inflammatory properties, which is consistent with their chemoprotective role in breast cancer. In contrast, synthetic xenoestrogens are proinflammatory and carcinogenic compounds that can increase the risk of breast cancer. This article also highlights important xenoestrogens with a particular focus on their role in inflammation and breast cancer. Improved understanding of the complex relationship between estrogens, inflammation, and breast cancer will guide clinical research on agents that could advance breast cancer prevention and therapy.
Efficacy of Front-Line Ibrutinib and Rituximab Combination and the Impact of Treatment Discontinuation in Unfit Patients with Chronic Lymphocytic Leukemia: Results of the Gimema LLC1114 Study
Authors: Mauro Francesca Romana , Paoloni Francesca , Molica Stefano , Reda Gianluigi , Trentin Livio , Sportoletti Paolo , Marchetti Monia , Pietrasanta Daniela , Marasca Roberto , Gaidano Gianluca , Coscia Marta , Stelitano Caterina , Mannina Donato , Di Renzo Nicola , Ilariucci Fiorella , Liberati Anna Marina , Orsucci Lorella , Re Francesca , Tani Monica , Musuraca Gerardo , Gottardi Daniela , Zinzani Pier Luigi , Gozzetti Alessandro , Molinari Annalia , Gentile Massimo , Chiarenza Annalisa , Laurenti Luca , Varettoni Marzia , Ibatici Adalberto , Murru Roberta , Ruocco Valeria , Del Giudice Ilaria , De Propris Maria Stefania , Della Starza Irene , Raponi Sara , Nanni Mauro , Fazi Paola , Neri Antonino , Guarini Anna , Rigolin Gian Matteo , Piciocchi Alfonso , Cuneo Antonio , Foà Robin
Published: January 2022

The GIMEMA group investigated the efficacy, safety, and rates of discontinuations of the ibrutinib and rituximab regimen in previously untreated and unfit patients with chronic lymphocytic leukemia (CLL). Treatment consisted of ibrutinib, 420 mg daily, and until disease progression, and rituximab (375 mg/sqm, given weekly on week 1–4 of month 1 and day 1 of months 2–6). This study included 146 patients with a median age of 73 years, with IGHV unmutated in 56.9% and TP53 disrupted in 22.2%. The OR, CR, and 48-month PFS rates were 87%, 22.6%, and 77%, respectively. Responses with undetectable MRD were observed in 6.2% of all patients and 27% of CR patients. TP53 disruption (HR 2.47; p = 0.03) and B-symptoms (HR 2.91; p = 0.02) showed a significant and independent impact on PFS. The 48-month cumulative rates of treatment discontinuations due to disease progression (DP) or adverse events (AEs) were 5.6% and 29.1%, respectively. AEs leading more frequently to treatment discontinuation were atrial fibrillation in 8% of patients, infections in 8%, and non-skin cancers in 6%. Discontinuation rates due to AEs were higher in male patients (HR: 0.46; p = 0.05), patients aged ≥70 years (HR 5.43, p = 0.0017), and were managed at centers that enrolled <5 patients (HR 5.1, p = 0.04). Patients who discontinued ibrutinib due to an AE showed a 24-month next treatment-free survival rate of 63%. In conclusion, ibrutinib and rituximab combination was an effective front-line treatment with sustained disease control in more than half of unfit patients with CLL. Careful monitoring is recommended to prevent and manage AEs in this patient population.
Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers
Authors: Xu Hong-Gui , Reshetnikov Viktor , Wondrak Marit , Eckhardt Lisa , Kunz-Schughart Leoni A. , Janko Christina , Tietze Rainer , Alexiou Christoph , Borchardt Hannes , Aigner Achim , Gong Wenjie , Schmitt Michael , Sellner Leopold , Daum Steffen , Özkan Hülya Gizem , Mokhir Andriy
Published: January 2022

Radiotherapy (RT) efficacy can be improved by using radiosensitizers, i.e., drugs enhancing the effect of ionizing radiation (IR). One of the side effects of RT includes damage of normal tissue in close proximity to the treated tumor. This problem can be solved by applying cancer specific radiosensitizers. N-Alkylaminoferrocene-based (NAAF) prodrugs produce reactive oxygen species (ROS) in cancer cells, but not in normal cells. Therefore, they can potentially act as cancer specific radiosensitizers. However, early NAAF prodrugs did not exhibit this property. Since functional mitochondria are important for RT resistance, we assumed that NAAF prodrugs affecting mitochondria in parallel with increasing intracellular ROS can potentially exhibit synergy with RT. We applied sequential Cu+-catalyzed alkyne-azide cycloadditions (CuAAC) to obtain a series of NAAF derivatives with the goal of improving anticancer efficacies over already existing compounds. One of the obtained prodrugs (2c) exhibited high anticancer activity with IC50 values in the range of 5–7.1 µM in human ovarian carcinoma, Burkitt’s lymphoma, pancreatic carcinoma and T-cell leukemia cells retained moderate water solubility and showed cancer specificity. 2c strongly affects mitochondria of cancer cells, leading to the amplification of mitochondrial and total ROS production and thus causing cell death via necrosis and apoptosis. We observed that 2c acts as a radiosensitizer in human head and neck squamous carcinoma cells. This is the first demonstration of a synergy between the radiotherapy and NAAF-based ROS amplifiers.
Combination of Abemaciclib following Eribulin Overcomes Palbociclib-Resistant Breast Cancer by Inhibiting the G2/M Cell Cycle Phase
Authors: Pandey Kamal , Katuwal Nar Bahadur , Park Nahee , Hur Jin , Cho Young Bin , Kim Seung Ki , Lee Seung Ah , Kim Isaac , Lee Seung-Ryeol , Moon Yong Wha
Published: January 2022

Breast cancer remains a leading cancer burden among women worldwide. Acquired resistance of cyclin-dependent kinase (CDK) 4/6 inhibitors occurs in almost all hormone receptor (HR)-positive subtype cases, comprising 70% of breast cancers, although CDK4/6 inhibitors combined with endocrine therapy are highly effective. CDK4/6 inhibitors are not expected to cooperate with cytotoxic chemotherapy based on the basic cytotoxic chemotherapy mode of action that inhibits rapidly proliferating cells. The palbociclib-resistant preclinical model developed in the current study investigated whether the combination of abemaciclib, CDK4/6 inhibitor with eribulin, an antimitotic chemotherapy could be a strategy to overcome palbociclib-resistant HR-positive breast cancer. The current study demonstrated that sequential abemaciclib treatment following eribulin synergistically suppressed CDK4/6 inhibitor-resistant cells by inhibiting the G2/M cell cycle phase more effectively. The current study showed the significant association of the pole-like kinase 1 (PLK1) level and palbociclib resistance. Moreover, the cumulative PLK1 inhibition in the G2/M phase by each eribulin or abemaciclib proved to be a mechanism of the synergistic effect. The synergistic antitumor effect was also supported by in vivo study. The sequential combination of abemaciclib following eribulin merits further clinical trials to overcome resistance to CDK4/6 inhibitors in HR-positive breast cancer.
The Impact of Biomarkers in Pancreatic Ductal Adenocarcinoma on Diagnosis, Surveillance and Therapy
Authors: Sturm Niklas , Ettrich Thomas J. , Perkhofer Lukas
Published: January 2022

Pancreatic ductal adenocarcinoma (PDAC) is still difficult to treat due to insufficient methods for early diagnosis and prediction of therapy response. Furthermore, surveillance after curatively intended surgery lacks adequate methods for timely detection of recurrence. Therefore, several molecules have been analyzed as predictors of recurrence or early detection of PDAC. Enhanced understanding of molecular tumorigenesis and treatment response triggered the identification of novel biomarkers as predictors for response to conventional chemotherapy or targeted therapy. In conclusion, progress has been made especially in the prediction of therapy response with biomarkers. The use of molecules for early detection and recurrence of PDAC is still at an early stage, but there are promising approaches in noninvasive biomarkers, composite panels and scores that can already ameliorate the current clinical practice. The present review summarizes the current state of research on biomarkers for diagnosis and therapy of pancreatic cancer.
High Plus Low Dose Radiation Strategy in Combination with TIGIT and PD1 Blockade to Promote Systemic Antitumor Responses
Authors: Barsoumian Hampartsoum B. , Sezen Duygu , Menon Hari , Younes Ahmed I. , Hu Yun , He Kewen , Puebla-Osorio Nahum , Wasley Mark , Hsu Ethan , Patel Roshal R. , Yang Liangpeng , Cortez Maria A. , Welsh James W.
Published: January 2022

Tumors deploy various immune-evasion mechanisms that create a suppressive environment and render effector T-cells exhausted and inactive. Therefore, a rational utilization of checkpoint inhibitors may alleviate exhaustion and may partially restore antitumor functions. However, in high-tumor-burden models, the checkpoint blockade fails to maintain optimal efficacy, and other interventions are necessary to overcome the inhibitory tumor stroma. One such strategy is the use of radiotherapy to reset the tumor microenvironment and maximize systemic antitumor outcomes. In this study, we propose the use of anti-PD1 and anti-TIGIT checkpoint inhibitors in conjunction with our novel RadScopal technique to battle highly metastatic lung adenocarcinoma tumors, bilaterally established in 129Sv/Ev mice, to mimic high-tumor-burden settings. The RadScopal approach is comprised of high-dose radiation directed at primary tumors with low-dose radiation delivered to secondary tumors to improve the outcomes of systemic immunotherapy. Indeed, the triple therapy with RadScopal + anti-TIGIT + anti-PD1 was able to prolong the survival of treated mice and halted the growth of both primary and secondary tumors. Lung metastasis counts were also significantly reduced. In addition, the low-dose radiation component reduced TIGIT receptor (PVR) expression by tumor-associated macrophages and dendritic cells in secondary tumors. Finally, low-dose radiation within triple therapy decreased the percentages of TIGIT+ exhausted T-cells and TIGIT+ regulatory T-cells. Together, our translational approach provides a new treatment alternative for cases refractory to other checkpoints and may bring immunotherapy into a new realm of systemic disease control.
Is There Still a Place for Brachytherapy in the Modern Treatment of Early-Stage Oral Cancer?
Authors: Tuček Luboš , Vošmik Milan , Petera Jiří
Published: January 2022

Brachytherapy (BT) involves the direct application of radioactive sources to the tumour. This technique is characterised by a steep dose gradient, the delivery of high-dose radiation to the target volume centre, and the sparing of surrounding healthy tissues. Low-dose-rate (LDR) BT and manual afterloading played an important role in the treatment of early-stage oral cancer, with treatment outcomes that were comparable to surgery. Interest in BT as a primary treatment for oral cancer has declined in recent years due to the emergence of better surgical techniques, the switch from LDR BT to high-dose-rate (HDR) BT (which has a higher risk of complications), and to advances in external beam radiotherapy (EBRT). At present, the main indications for BT are in the postoperative setting due to the superior dose conformity and better quality of life offered by BT versus EBRT. Postoperative BT can be administered as monotherapy in early-stage (T1N0) cancers and in combination with elective neck dissection or EBRT to treat larger or deeper tumours. BT yields excellent results for lip carcinoma in older patients and in tumours with unfavourable localisations. BT is an effective salvage therapy for local recurrences in previously-irradiated areas. Despite its many advantages, brachytherapy is a complex treatment requiring meticulous technique and close cooperation between the radiation oncologist, physicist, and surgeon.
Utility of 3T MRI in Women with IB1 Cervical Cancer in Determining the Necessity of Less Invasive Surgery
Authors: Jeong Soo Young , Park Byung Kwan , Choi Chel Hun , Lee Yoo-Young , Kim Tae-Joong , Lee Jeong-Won , Kim Byoungi-Gie
Published: January 2022

Purpose: Cervical cancer that is invisible on magnetic resonance imaging (MRI) may suggest lower tumor burden than physical examination. Recently, 3 tesla (3T) MRI has been widely used prior to surgery because of its higher resolution than 1.5T MRI. The aim was to retrospectively evaluate the utility of 3T MRI in women with early cervical cancer in determining the necessity of less invasive surgery. Materials and methods: Between January 2010 and December 2015, a total of 342 women with FIGO stage IB1 cervical cancer underwent 3T MRI prior to radical hysterectomy, vaginectomy, and lymph node dissection. These patients were classified into cancer-invisible (n = 105) and cancer-visible (n = 237) groups based on the 3T MRI findings. These groups were compared regarding pathologic parameters and long-term survival rates. Results: The cancer sizes of the cancer-invisible versus cancer-visible groups were 11.5 ± 12.2 mm versus 30.1 ± 16.2 mm, respectively (p < 0.001). The depths of stromal invasion in these groups were 20.5 ± 23.6% versus 63.5 ± 31.2%, respectively (p < 0.001). Parametrial invasion was 0% (0/105) in the cancer-invisible group and 21.5% (51/237) in the cancer-visible group (odds ratio = 58.3, p < 0.001). Lymph node metastasis and lymphovascular space invasion were 5.9% (6/105) versus 26.6% (63/237) (5.8, p < 0.001) and 11.7% (12/105) versus 40.1% (95/237) (5.1, p < 0.001), respectively. Recurrence-free and overall 5-year survival rates were 99.0% (104/105) versus 76.8% (182/237) (p < 0.001) and 98.1% (103/105) versus 87.8% (208/237) (p = 0.003), respectively. Conclusions: 3T MRI can play a great role in determining the necessity of parametrectomy in women with IB1 cervical cancer. Therefore, invisible cervical cancer on 3T MRI will be a good indicator for less invasive surgery.