bluuebunny/crossref_metadata_2025 huggingface dataset:
Wearable Device for Residential Elbow Joint Rehabilitation with Voice Prompts and Tracking Feedback APP
Authors: Wu Yi-Chao , Shao Zhen-Di , Kao Hsuan-Kai
Published: November 2021

In this paper, we propose a wearable device for residential elbow joint rehabilitation with voice prompts and a tracking feedback app (WDRTFAPP). We have developed the app as well as the Arduino embedded system, which we have integrated together. In this research, the patients were simulated by our team not real patients. By using this wearable device, the elbow joint rehabilitation could be executed at home for the simulated patients with mild and moderately mild elbow joint symptoms. During the rehabilitation, data captured by the wearable device were sent to the tracking feedback APP, using automatic real time via Bluetooth transmission. After TFAPP received the rehabilitation data from the wearable device, the rehabilitation data was sent to the cloud database by Wi-Fi or 5G communication automatically in real time. When the performance of the elbow joint rehabilitation was incorrect the patients received a voice prompt by TFAPP. The simulated patients could query their rehabilitation data using different search strategies, namely by date or TFAPP, at any time or location. In the experimental results, it showed that the correct detecting rate of elbow joint rehabilitation could be up to 90% by WDRTFAPP. The medical staff also could track the rehabilitation status of each simulated patient by the tracking feedback APP (TFAPP) with remote accessing, such as the Internet. Moreover, the rehabilitation appointments could be set up by the clinical staff with TFAPP, using the Internet. Furthermore, the medical staff could track the rehabilitation status of each simulated patient and give feedback at any time and location. The costs of the rehabilitation could be reduced (in terms of time and money spent by the simulated patients) and the manpower required by the hospital.
Broadband Spectral Analysis Algorithm with High-Frequency Resolution for Elimination of Overlap Interference between Adjacent Channels
Authors: Wang Xianhai , Wang Teng , Yin Chuan , Han Jun , Meng Qiao , Wang Chen
Published: November 2021

Spectral lines can be analysed to determine the physical properties of molecular clouds and the astrochemical processes in the formation area of massive stars. To improve the observation technology of radio astronomy, this paper proposes and compares two spectral analysis algorithms (improved weighted overlap-add (IWOLA) + FFT and IWOLA + weighted overlap-add (WOLA)). The proposed algorithms can obtain an ultra-high-frequency resolution for real-valued wideband signals, eliminate the signal overlapping interference between adjacent channels, substantially decrease the required hardware resources, especially multipliers, adders, and memory resources, and reduce the system design complexity. The IWOLA + FFT algorithm consists of an improved weighted overlap-add (IWOLA) filter bank, fast Fourier transform (FFT), a specific decimation for the output data from the IWOLA filter bank, and a selection for part of the output data from the FFT. The IWOLA + WOLA algorithm consists of the same modules as the IWOLA + FFT algorithm, with the second-stage FFT replaced by the modules of the weighted overlap-add (WOLA) filter bank and the accumulation for each sub-band. Based on an analysis of the underlying principles and characteristics of both algorithms, the IWOLA + FFT algorithm demonstrated a spectrum with a high frequency resolution and a comparable performance to an ultra-large-scale FFT, based on two smaller FFTs and a flexible architecture instead of a ultra-large-scale FFT. The IWOLA + WOLA algorithm contains the same function as the IWOLA + FFT algorithm and demonstrates a higher performance. The proposed algorithms eliminated the interference between the adjacent channels within the entire Nyquist frequency bandwidth. The simulation results verify the accuracy and spectral analysis performances of the proposed algorithms.
A System to Improve Port Navigation Safety and Its Use in Italian Harbours
Authors: Soldani Maurizio , Faggioni Osvaldo
Published: November 2021

This article describes research aimed at developing a system able to support local authorities and port communities in optimizing port navigation, avoiding or managing critical situations induced by sea-level variations in harbours and minimizing environmental damages and economic losses. In the Mediterranean basin, sea-level changes are mostly due to astronomical tides, related to the gravitational attraction between Earth, Moon and Sun. Nevertheless, sea-level variations are also influenced by meteorological tides, which are geodetic adjustments of sea surface due to atmospheric pressure variations above a water basin. So, starting from monitoring or forecasting environmental parameters in harbours, the system updates port bathymetric maps based on sea-level variations (acquired in the past, measured in real-time, or expected in the future) and detects hazardous areas for a certain ship moving inside a port at a given moment, by means of the implementation of “virtual traffic lights”. The system was tested on some real situations, including the analysis of maritime accidents (stranding of ships), providing satisfactory results by correctly signalling potentially dangerous areas variable over time. The architecture of the system and results achieved using it in the ports of Livorno and Bari, in Italy, are herewith described.
Microstructural and Chemical Characteristics of Archaeological White Elm (Ulmus laevis P.) and Poplar (Populus spp.)
Authors: Ghavidel Amir , Hosseinpourpia Reza , Gelbrich Jana , Bak Miklós , Sandu Ion
Published: November 2021

The degradation states of archaeological white elm, with an age estimation of ~350 years, and poplar, with an age approximation of ~1000–1200 years, were studied by means of different chemical and microscopy analyses. Recently cut samples from the respective species were used for comparison reasons. The chemical composition analysis of the archaeological samples showed significantly low holocellulose values, while the lignin, extractive, and ash contents were considerably high, as compared with the recently cut samples. The Fourier-transform infrared (FTIR) spectroscopy also confirmed the changes in the chemical structure of the archaeological elm and poplar samples. The light and scanning electron microscopies illustrated that the erosion bacteria were the main degrading agent in both archaeological elm and poplar, although the hyphae of rot fungi were detected inside the vessel elements of the archaeological poplar sample.
Preparation, Properties and Microstructure of Non-Calcination Rock Powder Brick with Orthogonal Experiments
Authors: Fan Jie , Wang Zhongkun , Li Gengying
Published: November 2021

In this paper, the preparation method and reasonable mix ratio of non-calcination brick with rock powder, cement, lime and fly ash ceramsite (FAC) as the raw materials were experimentally evaluated. To better understand the effects of each component on the performance of non-calcination rock powder brick (NCRPB), an orthogonal experimental design was conducted with the water–cement ratio (W/C), rock powder–cement ratio (R/C), lime content (wl) and FAC content (wf) as the main factors, which involved four factors and three factor levels. According to the orthogonal experimental design, the compressive strength, water resistance and bulk density of nine groups of NCRPB specimens were tested. The results show that R/C was the most important factor affecting the compressive strength and water resistance, while the FAC content influenced the bulk density of NCRPB greatly. In this study, the reasonable mix of W/C, R/C, wl, and wf in weight was 0.6, 3.0, 30% and 21%, respectively. In addition, the microstructure and strength formation mechanism of NCRPB were analyzed by using SEM and XRD. The test results show that the rock powder having pozzolanic activity could react with the additional Ca(OH)2 to produce hydration products, leading to the improvement of the performance of NCRPB.
Gender Characteristics on Gaze Movement in Situation Awareness
Authors: Lee Yejin , Jung Kwangtae , Lee Hyunchul
Published: November 2021

In large systems, such as nuclear power plants, the operator’s situation awareness is vital to the system’s safety. Since gaze movement is closely related to situation awareness, various studies have evaluated it through gaze movement. The number of female workers is increasing even in large systems, such as nuclear power plants, so it is relevant to compare and analyze the situation awareness and gaze movement characteristics of men and women. In this study, an experiment was conducted to compare and analyze men’s and women’s situation awareness and gaze movement characteristics by making a simulator for emergency scenarios in nuclear power plants. Gaze entropy was used as a measure to indicate gaze movement, while the Situation Awareness Rating Technique (SART) was utilized to measure situation awareness. A total of 20 engineering college students (10 male, 10 female) participated in the experiment. Loss of coolant accident (LOCA), steam generator tube rupture (SGTR), steam line break (SLB), and loss of voltage (LOV) were the nuclear power plant accident situations used as task scenarios for the experiment. For all accident scenarios, the SART score did not show a significant difference between men and women. Shannon entropy, dwell time entropy, and heat map entropy did not show a significant difference between men and women, but Markov entropy was found to be significantly higher in women. In conclusion, there was no significant difference between men and women in awareness of accident situations. In addition, there was no significant difference between men and women in the ratio of viewing the necessary information elements in the situation awareness process. However, it was found that women had more gaze movements between necessary information elements than men.
Application of Different Compositions of Apple Puree Gels and Drying Methods to Fabricate Snacks of Modified Structure, Storage Stability and Hygroscopicity
Authors: Jakubczyk Ewa , Kamińska-Dwórznicka Anna , Ostrowska-Ligęza Ewa , Górska Agata , Wirkowska-Wojdyła Magdalena , Mańko-Jurkowska Diana , Górska Agnieszka , Bryś Joanna
Published: November 2021

The aim of this study was to determine the effect of incorporation of apple puree and maltodextrin to agar sol on the sorption properties and structure of the dried gel. The effect of different drying methods on the sorption behaviour of aerated apple puree gels was also observed. The gels with the addition of 25% and 40% concentration of apple puree and with or without maltodextrin were prepared and dried. The foamed agar gel was subjected to freeze-drying, air-drying and vacuum-drying. The sorption properties of dried gels (adsorption isotherms, water uptake in time) were investigated. The relations between the glass transition temperature, water activity and water content were also obtained for some apple snacks. The increase in apple puree in freeze-dried gels increased the hygroscopicity and decreased the glass transition temperature (Tg). The water content at given activity and hygroscopicity were reduced by the addition of maltodextrin, which also caused the increase in Tg. The application of different drying methods enabled obtaining different structures of material. The open-pore, fragile materials were obtained by freeze-drying, the expanded matrix with big holes was characteristic for vacuum-dried gels, but the closed pores with thick walls were created during the air-drying.
Development of a Generic Implementation Strategy of Digital Twins in Logistics Systems under Consideration of the German Rail Transport
Authors: Jeschke Sabina , Grassmann Roman
Published: November 2021

In the course of digitalization, the concept of the digital twin (DT) has become increasingly important in recent years. Hereby, initial concept approaches focus on use cases in industrial production. Although the concept has diverse potential for the asset intensive and increasingly important German rail transport sector. Due to the still low level of research of the DT, there are few empirical values on how this promising concept can be implemented in a target-oriented manner. In a qualitative-explorative research design, this work focuses on answering the question of how a generic implementation strategy (GIS) of DTs in logistics systems of German rail transport can be designed. The central result of this work is a validated GIS which has a sufficient level of detail for the targeted implementation of DTs. Due to its socio-technical system focus, this process model enables user-oriented development and consideration of the complex framework conditions of German rail transport for the first time. The perspective use of the GIS as well as the utilization of the derived recommendations for action contribute to realizing DTs. Consequently, this work is to be regarded as an important instrument for achieving the operational optimization and intelligent management of rail transport assets.
Forecasting Hotel Room Occupancy Using Long Short-Term Memory Networks with Sentiment Analysis and Scores of Customer Online Reviews
Authors: Chang Yu-Ming , Chen Chieh-Huang , Lai Jung-Pin , Lin Ying-Lei , Pai Ping-Feng
Published: November 2021

For hotel management, occupancy is a crucial indicator. Online reviews from customers have gradually become the main reference for customers to evaluate accommodation choices. Thus, this study employed online customer rating scores and review text provided by booking systems to forecast monthly hotel occupancy using long short-term memory networks (LSTMs). Online customer reviews of hotels in Taiwan in various languages were gathered, and Google’s natural language application programming interface was used to convert online customer reviews into sentiment scores. Five other forecasting models—back propagation neural networks (BPNN), general regression neural networks (GRNN), least square support vector regression (LSSVR), random forest (RF), and gaussian process regression (GPR)—were employed to predict hotel occupancy using the same datasets. The numerical data indicated that the long short-term memory network model outperformed the other five models in terms of forecasting accuracy. Integrating hotel online customer review sentiment scores and customer rating scores can lead to more accurate results than using unique scores individually. The novelty and applicability of this study is the application of deep learning techniques in forecasting room occupancy rates in multilingual comment scenarios with data gathered from review text and customers’ rating scores. This study reveals that using long short-term memory networks with sentiment analysis of review text and customers’ rating scores is a feasible and promising alternative in forecasting hotel room occupancy.
Scaled Model Simulation and Experimental Verification of Submarine Flexible Pipeline Laying System
Authors: Gong Haixia , Zhao Tong , You Xiaofeng , Wang Liquan , Yun Feihong
Published: November 2021

In order to adapt to the complex and changeable marine environment such as wind, wave, and current, the physical simulation experiment is usually needed in the design of a deep-sea flexible pipeline-laying system. In reality, the flexible pipeline-laying system is very large, and the experimental cost is huge. Therefore, when analyzing this system, it is necessary to carry out scaled model experiments to verify the rationality of it. Taking the flexible pipeline-laying system working under four-level sea conditions as an example, this paper deduces the similarity criteria of the scaled model according to the similarity theory. According to the required experimental site, the sizes and materials of the model are selected, and then the physical quantities of the model and their similarity ratio corresponding to the prototype are determined. According to the physical quantities of the experimental model, the similarity of dynamic characteristics and structural strength between the model and the prototype are verified by Adams and ANSYS Workbench. The research shows that the scaled model and prototype based on similarity theory can meet the established similarity relationship, and the scaled model experiment is an effective way to verify the rationality of the design of a flexible pipeline-laying system.
Multi-Time and Multi-Band CSP Motor Imagery EEG Feature Classification Algorithm
Authors: Yang Jun , Ma Zhengmin , Shen Tao
Published: November 2021

The effective decoding of motor imagination EEG signals depends on significant temporal, spatial, and frequency features. For example, the motor imagination of the single limbs is embodied in the μ (8–13 Hz) rhythm and β (13–30 Hz) rhythm in frequency features. However, the significant temporal features are not necessarily manifested in the whole motor imagination process. This paper proposes a Multi-Time and Frequency band Common Space Pattern (MTF-CSP)-based feature extraction and EEG decoding method. The MTF-CSP learns effective motor imagination features from a weak Electroencephalogram (EEG), extracts the most effective time and frequency features, and identifies the motor imagination patterns. Specifically, multiple sliding window signals are cropped from the original signals. The multi-frequency band Common Space Pattern (CSP) features extracted from each sliding window signal are fed into multiple Support Vector Machine (SVM) classifiers with the same parameters. The Effective Duration (ED) algorithm and the Average Score (AS) algorithm are proposed to identify the recognition results of multiple time windows. The proposed method is trained and evaluated on the EEG data of nine subjects in the 2008 BCI-2a competition dataset, including a train dataset and a test dataset collected in other sessions. As a result, the average cross-session recognition accuracy of 78.7% was obtained on nine subjects, with a sliding window length of 1 s, a step length of 0.4 s, and the six windows. Experimental results showed the proposed MTF-CSP outperforming the compared machine learning and CSP-based methods using the original signals or other features such as time-frequency picture features in terms of accuracy. Further, it is shown that the performance of the AS algorithm is significantly better than that of the Max Voting algorithm adopted in other studies.
Application of Wavelet Scattering and Machine Learning on Structural Health Diagnosis for Quadcopter
Authors: Lai Wei-Hsiang , Tsai Sung-Ting , Cheng De-Li , Liang Yih-Rong
Published: November 2021

The aim of this study was to examine the health diagnosis classification method of quadcopter structures with different mixed faults. The loosening of the motor mount, damage to the propeller, and the loosening of the arm mount were the main fault conditions investigated. Data were first acquired under non-fault conditions and the conditions of the three types of fault. Then, the features of the vibration and pulse width modulation signals were extracted by root mean square, standard deviation, and sample entropy. Moreover, the features of the audio signal were extracted by wavelet scattering, which contains time-frequency domain information that provides significant power for classification. In this paper, we propose a simple machine learning method, based on the k-Nearest Neighbor (kNN), not only for classification but also demonstrating the efficacy of the features. To test the limits of accuracy, different configurations of kNN parameters are deployed, in addition to the features. In summary, as a result of the highly efficacious features, despite mixed fault conditions, the accuracy reached 90.73%. This method improves the accuracy of mixed faults’ classification and maintains a certain level of classification effectiveness.
The Economic Loss Prediction of Flooding Based on Machine Learning and the Input-Output Model
Authors: Chen Anqi , You Shibing , Li Jiahao , Liu Huan
Published: November 2021

As climate change becomes increasingly widespread, rapid, and intense, the frequency of heavy rainfall and floods continues to increase. This article establishes a prediction system using feature sets with multiple data dimensions, including meteorological data and socio-economic data. Based on data of historical floods in 31 provinces and municipalities in China from 2006 to 2018, five machine learning methods are compared to predict the direct economic losses. Among them, GBR performs the best with a goodness-of-fit of 90%. Combined with the input-output (IO) model, the indirect economic losses of agriculture to other sectors are calculated, and the total economic losses caused by floods can be predicted effectively by using the GBR-IO model. The model has a strong generalization ability with a minimum requirement of 80 pieces of data. The results of the data show that in China, provinces heavily reliant on agriculture suffered the most with the proportion of direct economic losses to provincial GDP exceeding 1‰. Therefore, some policy implications are provided to assist the government to take timely pre-disaster preventive measures and conduct post-disaster risk management, thereby reducing the economic losses caused by floods.
Remote Impacts from El Niño and La Niña on Climate Variables and Major Crops Production in Coastal Bangladesh
Authors: Sattar Md. Abdus , Mia Shamim , Shanta Afroza Akter , Biswas A. K. M. Abdul Ahad , Ludwig Fulco
Published: November 2021

El Niño and La Niña Southern Oscillation (ENSO) are major drivers that affect climatic variables in many countries. Therefore, ENSO mediated variation in climatic factors have significant consequences for crop production. We studied ENSO mediated variations in temperature and rainfall in the five coastal districts of Bangladesh during 1951–2017, and the impacts on major crops production were analyzed using growing degree day (GDD) index. Statistical analyses were performed on different climatic parameters in relation to ENSO events and locations. Results indicate that ENSO events had significant influence on monthly, seasonal and annual temperature and rainfall amounts (p < 0.05). Specifically, maximum temperature under ENSO phases were higher during Kharif-I and Kharif-II seasons than neutral years. In contrast, the minimum temperature was higher in neutral years than ENSO events during Rabi season. Averaged across stations, annual mean maximum temperature was 0.5 and 0.23 °C higher during El Niño and La Niña compared to neutral years. Rainfall was higher during neutral years compared to El Niño and La Niña. These changes in seasonal temperature variably changed crop GDD in different locations and thus, crop growth duration and crop yield. Therefore, this study provides a general understanding to ENSO mediated impacts on coastal agriculture in Bangladesh.
Insight into the Prospects for Nanotechnology in Wheat Biofortification
Authors: Khan Mohd. , Pandey Anamika , Hamurcu Mehmet , Gezgin Sait , Athar Tabinda , Rajput Vishnu , Gupta Om , Minkina Tatiana
Published: November 2021

The deficiency of nutrients in food crops is a major issue affecting the health of human beings, mainly in underdeveloped areas. Despite the development in the methods of food fortification, several barriers such as lack of proper regulations and smaller public-private partnerships hinder its successful implementation in society. Consequently, genetic and agronomic biofortification has been suggested as the potential techniques for fortifying the nutrients in diets. However, the time-consuming nature and restricted available diversity in the targeted crop gene pool limit the benefits of genetic biofortification. In agronomic biofortification, organic fertilizers face the problem of prolonged duration of nutrients release and lesser content of minerals; while in inorganic fertilizers, the large-sized fertilizers (greater than 100 nm) suffer from volatilization and leaching losses. The application of nanotechnology in agriculture holds enormous potential to cope with these challenges. The utility of nanomaterials for wheat biofortification gains its importance by supplying the appropriate dose of fertilizer at the appropriate time diminishing the environmental concerns and smoothening the process of nutrient uptake and absorption. Wheat is a major crop whose nano-biofortification can largely handle the issue of malnutrition and nutrients deficiency in human beings. Though several research experiments have been conducted at small levels to see the effects of nano-biofortification on wheat plants, a review article providing an overview of such studies and summarizing the benefits and outcomes of wheat nano-biofortification is still lacking. Although a number of review articles are available on the role of nanotechnology in wheat crop, these are mostly focused on the role of nanoparticles in alleviating biotic and abiotic stress conditions in wheat. None of them focused on the prospects of nanotechnology for wheat biofortification. Hence, in this review for the first time, the current advancement in the employment of different nanotechnology-based approaches for wheat biofortification has been outlined. Different strategies including the supply of nano-based macro- and micronutrients that have shown promising results for wheat improvement have been discussed in detail. Understanding several aspects related to the safe usage of nanomaterials and their future perspectives may enhance their successful utilization in terms of economy and fulfillment of nutritional requirements following wheat nano-biofortification.
Observing Protein One-Dimensional Sliding: Methodology and Biological Significance
Authors: Yang Xiao-Wen , Liu Jiaquan
Published: November 2021

One-dimensional (1D) sliding of DNA-binding proteins has been observed by numerous kinetic studies. It appears that many of these sliding events play important roles in a wide range of biological processes. However, one challenge is to determine the physiological relevance of these motions in the context of the protein’s biological function. Here, we discuss methods of measuring protein 1D sliding by highlighting the single-molecule approaches that are capable of visualizing particle movement in real time. We also present recent findings that show how protein sliding contributes to function.
Identification of miRNA-Target Gene Pairs Responsive to Fusarium Wilt of Cucumber via an Integrated Analysis of miRNA and Transcriptome Profiles
Authors: Xu Jun , Xian Qianqian , Zhang Ningyuan , Wang Ke , Zhou Xin , Li Yansong , Dong Jingping , Chen Xuehao
Published: November 2021

Fusarium wilt (FW) of cucumber (Cucumis sativus L.) caused by Fusarium oxysporum f. sp. cucumerinum (Foc) is a destructive soil-borne disease that severely decreases cucumber yield and quality worldwide. MicroRNAs (miRNAs) are small non-coding RNAs (sRNAs) that are important for regulating host immunity because they affect target gene expression. However, the specific miRNAs and the miRNA/target gene crosstalk involved in cucumber resistance to FW remain unknown. In this study, we compared sRNA-seq and RNA-seq data for cucumber cultivar ‘Rijiecheng’, which is resistant to FW. The integrated analysis identified FW-responsive miRNAs and their target genes. On the basis of verified expression levels, we detected two highly expressed miRNAs with down-regulated expression in response to Foc. Moreover, an analysis of 21 target genes in cucumber inoculated with Foc indicated that JRL3 (Csa2G362470), which is targeted by miR319a, and BEE1 (Csa1G024150), DAHP1 (Csa2G369040), and PERK2 (Csa4G642480), which are targeted by miR6300, are expressed at high levels, but their expression is further up-regulated after Foc inoculation. These results imply that miR319a-JRL3, miR6300-BEE1, miR6300-DAHP1 and miR6300-PERK2 regulate cucumber defenses against FW, and provide the gene resources that may be useful for breeding programs focused on developing new cucumber varieties with enhanced resistance to FW.
Emerging Biosensors to Detect Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): A Review
Authors: Lim Wei Yin , Lan Boon Leong , Ramakrishnan Narayanan
Published: November 2021

Coronavirus disease (COVID-19) is a global health crisis caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) is the gold standard test for diagnosing COVID-19. Although it is highly accurate, this lab test requires highly-trained personnel and the turn-around time is long. Rapid and inexpensive immuno-diagnostic tests (antigen or antibody test) are available, but these point of care (POC) tests are not as accurate as the RT-PCR test. Biosensors are promising alternatives to these rapid POC tests. Here we review three types of recently developed biosensors for SARS-CoV-2 detection: surface plasmon resonance (SPR)-based, electrochemical and field-effect transistor (FET)-based biosensors. We explain the sensing principles and discuss the advantages and limitations of these sensors. The accuracies of these sensors need to be improved before they could be translated into POC devices for commercial use. We suggest potential biorecognition elements with highly selective target-analyte binding that could be explored to increase the true negative detection rate. To increase the true positive detection rate, we suggest two-dimensional materials and nanomaterials that could be used to modify the sensor surface to increase the sensitivity of the sensor.
Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities
Authors: Bansod Sapana , Dodhiawala Paarth B. , Lim Kian-Huat
Published: November 2021

Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network.
Image-Based Evaluation of Irradiation Effects in Brain Tissues by Measuring Absolute Electrical Conductivity Using MRI
Authors: Kim Jin-Woong , Park Ji-Ae , Katoch Nitish , Yang Ji-ung , Park Seungwoo , Choi Bup-Kyung , Song Sang-Gook , Kim Tae-Hoon , Kim Hyung-Joong
Published: November 2021

Radiation-induced injury is damage to normal tissues caused by unintentional exposure to ionizing radiation. Image-based evaluation of tissue damage by irradiation has an advantage for the early assessment of therapeutic effects by providing sensitive information on minute tissue responses in situ. Recent magnetic resonance (MR)-based electrical conductivity imaging has shown potential as an effective early imaging biomarker for treatment response and radiation-induced injury. However, to be a tool for evaluating therapeutic effects, validation of its reliability and sensitivity according to various irradiation conditions is required. We performed MR-based electrical conductivity imaging on designed phantoms to confirm the effect of ionizing radiation at different doses and on in vivo mouse brains to distinguish tissue response depending on different doses and the elapsed time after irradiation. To quantify the irradiation effects, we measured the absolute conductivity of brain tissues and calculated relative conductivity changes based on the value of pre-irradiation. The conductivity of the phantoms with the distilled water and saline solution increased linearly with the irradiation doses. The conductivity of in vivo mouse brains showed different time-course variations and residual contrast depending on the irradiation doses. Future studies will focus on validation at long-term time points, including early and late delayed response and evaluation of irradiation effects in various tissue types.
Drug Repositioning Based on the Reversal of Gene Expression Signatures Identifies TOP2A as a Therapeutic Target for Rectal Cancer
Authors: Carvalho Robson Francisco , do Canto Luisa Matos , Cury Sarah Santiloni , Frøstrup Hansen Torben , Jensen Lars Henrik , Rogatto Silvia Regina
Published: November 2021

Rectal cancer is a common disease with high mortality rates and limited therapeutic options. Here we combined the gene expression signatures of rectal cancer patients with the reverse drug-induced gene-expression profiles to identify drug repositioning candidates for cancer therapy. Among the predicted repurposable drugs, topoisomerase II inhibitors (doxorubicin, teniposide, idarubicin, mitoxantrone, and epirubicin) presented a high potential to reverse rectal cancer gene expression signatures. We showed that these drugs effectively reduced the growth of colorectal cancer cell lines closely representing rectal cancer signatures. We also found a clear correlation between topoisomerase 2A (TOP2A) gene copy number or expression levels with the sensitivity to topoisomerase II inhibitors. Furthermore, CRISPR-Cas9 and shRNA screenings confirmed that loss-of-function of the TOP2A has the highest efficacy in reducing cellular proliferation. Finally, we observed significant TOP2A copy number gains and increased expression in independent cohorts of rectal cancer patients. These findings can be translated into clinical practice to evaluate TOP2A status for targeted and personalized therapies based on topoisomerase II inhibitors in rectal cancer patients.
Opioids and Breast Cancer Recurrence: A Systematic Review
Authors: Lucia Merlino , Luca Titi , Federica Del Prete , Cecilia Galli , Chiara Mandosi , Laura De Marchis , Carlo Della Rocca , Grazia Piccioni Maria
Published: November 2021

Breast cancer has the greatest epidemiological impact in women. Opioids represent the most prescribed analgesics, both in surgical time and in immediate postoperative period, as well as in chronic pain management as palliative care. We made a systematic review analyzing the literature’s evidence about the safety of opioids in breast cancer treatment, focusing our attention on the link between opioid administration and increased relapses. The research has been conducted using the PubMed database. Preclinical studies, retrospective and prospective clinical studies, review articles and original articles were analyzed. In the literature, there are several preclinical in vitro and in vivo studies, suggesting a possible linkage between opioids administration and progression of cancer disease. Nevertheless, these results are not confirmed by clinical studies. The most recent evidence reassures the safety of opioids during surgical time as analgesic associated with anesthetics drugs, during postoperative period for optimal cancer-related pain management and in chronic use. Currently, there is controversial evidence suggesting a possible impact of opioids on breast cancer progression, but to date, it remains an unresolved issue. Although there is no conclusive evidence, we hope to arouse interest in the scientific community to always ensure the best standards of care for these patients.
Molecular Classification of Bladder Urothelial Carcinoma Using NanoString-Based Gene Expression Analysis
Authors: Lopez-Beltran Antonio , Blanca Ana , Cimadamore Alessia , Gogna Rajan , Montironi Rodolfo , Cheng Liang
Published: November 2021

Molecular classification of bladder carcinoma is a relevant topic in modern bladder cancer oncology due to its potential to improve oncological outcomes. The available molecular classifications are generally based on transcriptomic profiles, generating highly diverse categories with limited correlation. Implementation of molecular classification in practice is typically limited due to the high complexity of the required technology, the elevated costs, and the limited availability of this technology worldwide. We have conducted a gene expression analysis using a four-gene panel related to luminal and basal subtypes in a series of 91 bladder cancer cases. NanoString-based gene expression analysis using typically luminal (GATA3+/KRT20+) and basal markers (KRT14+/KRT5+/GATA3low/-/KRT20low/-) classified urothelial bladder carcinoma samples as luminal, basal, and a third category (KRT14-/KRT5-/GATA3-/KRT20-), null/double negative (non-luminal/non-basal). These three categories were meaningful in terms of overall cancer-specific survival (p < 0.0001) or when classified as conventional urothelial carcinoma and variant histology urothelial carcinoma (p < 0.0001), NMIBC vs. MIBC (p < 0.001), or by AJCC stage category Ta (p = 0.0012) and T1 (p < 0.0001) but did not reach significance in T2-T4 (p = 0.563). PD-L1 expression (low vs. high) was also different according to molecular subtype, with high PD-L1 expression mostly seen in basal and null subtypes and carcinomas with variant histology (p = 0.002). Additionally, the luminal subtype was enriched in NMIBC with favorable cancer-specific survival (p < 0.0001). In contrast, basal and null subtypes resulted in aggressive MIBC tumors with shorter cancer-specific survival (p < 0.0001), some of which presented variant histology. In conclusion, a comprehensive evaluation of a gene classifier related to molecular taxonomy using NanoString technology is feasible. Therefore, it might represent an accessible and affordable tool in this rapidly expanding area of precision genomics.
Multiplex Quantitative Analysis of Tumor-Infiltrating Lymphocytes, Cancer-Associated Fibroblasts, and CD200 in Pancreatic Cancer
Authors: MacNeil Tyler , Vathiotis Ioannis A. , Shafi Saba , Aung Thazin Nwe , Zugazagoitia Jon , Gruver Aaron M. , Driscoll Kyla , Rimm David L.
Published: November 2021

Pancreatic cancer is marked by a desmoplastic tumor microenvironment and low tumor immunogenicity, making it difficult for immunotherapy drugs to improve outcomes for patients. Tumor-infiltrating lymphocytes (TILs) and cancer-associated fibroblasts (CAFs) are seen in the tumor microenvironment of patients with pancreatic ductal adenocarcinoma (PDAC). In this work, we sought to characterize the expression levels and potential prognostic value of TILs (CD4, CD8, and CD20) and CAFs (Thy-1, FAP, and SMA) in a large retrospective cohort of PDAC patients. Additionally, we investigated the expression levels and prognostic significance of CD200, an immunoinhibitory protein that has shown interest as a potential target for immune checkpoint blockade. We measured the expression levels of these seven proteins with multiplexed immunofluorescence staining and quantitative immunofluorescence (QIF). We found CD8 and FAP to be independent predictors of progression-free survival and overall survival. CD200 was found to be heterogeneously expressed in both the tumor and stromal compartments of PDAC, with the majority of patients having positive stromal expression and negative tumor expression. This work demonstrates the potential clinical utility of CD8 and FAP in PDAC patients, and it sheds light on the expression patterns of CD200 in pancreatic cancer as the protein is being tested as a target for immune checkpoint blockade.
Single-Shot Local Injection of Microfragmented Fat Tissue Loaded with Paclitaxel Induces Potent Growth Inhibition of Hepatocellular Carcinoma in Nude Mice
Authors: Alessandri Giulio , Pessina Augusto , Paroni Rita , Bercich Luisa , Paino Francesca , Dei Cas Michele , Cadei Moris , Caruso Arnaldo , Schiariti Marco , Restelli Francesco , Zeira Offer , Tremolada Carlo , Portolani Nazario
Published: November 2021

Hepatocellular carcinoma (HCC) is poorly beneficiated by intravenous chemotherapy due to inadequate availability of drugs at the tumor site. We previously demonstrated that human micro-fragmented adipose tissue (MFAT) and its devitalized counterpart (DMFAT) could be effective natural scaffolds to deliver Paclitaxel (PTX) to tumors in both in vitro and in vivo tests, affecting cancer growth relapse. Here we tested the efficacy of DMFAT-PTX in a well-established HCC in nude mice. MFAT-PTX and DMFAT-PTX preparations were tested for anti-cancer activity in 2D and 3D assays using Hep-3B tumor cells. The efficacy of DMFAT-PTX was evaluated after a single-shot subcutaneous injection near a Hep-3B growing tumor by assessing tumor volumes, apoptosis rate, and drug pharmacokinetics in an in vivo model. Potent antiproliferative activity was seen in both in vitro 2D and 3D tests. Mice treated with DMFAT-PTX (10 mg/kg) produced potent Hep-3B growth inhibition with 33% complete tumor regressions. All treated animals experienced tumor ulceration at the site of DMFAT-PTX injection, which healed spontaneously. Lowering the drug concentration (5 mg/kg) prevented the formation of ulcers, maintaining statistically significant efficacy. Histology revealed a higher number of apoptotic cancer cells intratumorally, suggesting prolonged presence of PTX that was confirmed by the pharmacokinetic analysis. DMFAT may be a potent and valid new tool for local chemotherapy of HCC in an advanced stage of progression, also suggesting potential effectiveness in other human primary inoperable cancers.
Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase
Authors: Rana Sandeep , Mallareddy Jayapal Reddy , Singh Sarbjit , Boghean Lidia , Natarajan Amarnath
Published: November 2021

The cyclin-dependent kinase (CDK) family of proteins play prominent roles in transcription, mRNA processing, and cell cycle regulation, making them attractive cancer targets. Palbociclib was the first FDA-approved CDK inhibitor that non-selectively targets the ATP binding sites of CDK4 and CDK6. In this review, we will briefly inventory CDK inhibitors that are either part of over 30 active clinical trials or recruiting patients. The lack of selectivity among CDKs and dose-limiting toxicities are major challenges associated with the development of CDK inhibitors. Proteolysis Targeting Chimeras (PROTACs) and Molecular Glues have emerged as alternative therapeutic modalities to target proteins. PROTACs and Molecular glues utilize the cellular protein degradation machinery to destroy the target protein. PROTACs are heterobifunctional molecules that form a ternary complex with the target protein and E3-ligase by making two distinct small molecule–protein interactions. On the other hand, Molecular glues function by converting the target protein into a “neo-substrate” for an E3 ligase. Unlike small molecule inhibitors, preclinical studies with CDK targeted PROTACs have exhibited improved CDK selectivity. Moreover, the efficacy of PROTACs and molecular glues are not tied to the dose of these molecular entities but to the formation of the ternary complex. Here, we provide an overview of PROTACs and molecular glues that modulate CDK function as emerging therapeutic modalities.
Comparison of Clinical Outcomes of Definitive and Postoperative Radiotherapy for Adenoid Cystic Carcinoma of the Head and Neck: Can Definitive Radiotherapy Be a Treatment Option?
Authors: Mizoguchi Nobutaka , Kano Kio , Shima Satoshi , Tsuchida Keisuke , Takakusagi Yosuke , Serizawa Itsuko , Akahane Keiko , Kawahara Masahiro , Yoshida Manatsu , Kitani Yuka , Hashimoto Kaori , Furukawa Madoka , Kamada Tadashi , Katoh Hiroyuki , Yoshida Daisaku , Shirai Katsuyuki
Published: November 2021

Background: The standard treatment for adenoid cystic carcinoma of the head and neck is surgical resection followed by postoperative radiotherapy (PORT). Currently, definitive radiotherapy (defRT) is considered an inadequate treatment; however, its data are based on studies using classical radiotherapy techniques. Therefore, the therapeutic effects of current radiotherapy techniques have not been adequately evaluated, and it may have underestimated the efficacy of defRT. Methods: We retrospectively analyzed 44 adenoid cystic carcinoma patients treated with radiotherapy based on modern treatment techniques from 1993 to 2017. Results: Twenty-four patients underwent PORT and 20 patients underwent defRT. The 5-year overall survival rates for patients treated with PORT and defRT were 85.3% and 79.7%, respectively. The 5-year local control rates were 82.5% and 83.1%, respectively. There were no statistically significant differences in the overall survival and local control of patients treated with PORT and defRT (p = 0.4392 and p = 0.0904, respectively). Conclusion: Our results show that defRT is comparable to surgical resection followed by PORT with respect to overall survival and local control. The results suggest that defRT can be an effective treatment option for adenoid cystic carcinoma of the head and neck.
Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC
Authors: Godet Inês , Mamo Mahelet , Thurnheer Andrea , Rosen D. Marc , Gilkes Daniele M.
Published: November 2021

Hypoxia occurs in 90% of solid tumors and is associated with treatment failure, relapse, and mortality. HIF-1α signaling promotes resistance to chemotherapy in cancer cell lines and murine models via multiple mechanisms including the enrichment of breast cancer stem cells (BCSCs). In this work, we utilize a hypoxia fate-mapping system to determine whether triple-negative breast cancer (TNBC) cells that experience hypoxia in the primary tumor are resistant to chemotherapy at sites of metastasis. Using two orthotopic mouse models of TNBC, we demonstrate that cells that experience intratumoral hypoxia and metastasize to the lung and liver have decreased sensitivity to doxorubicin and paclitaxel but not cisplatin or 5-FU. Resistance to therapy leads to metastatic recurrence caused by post-hypoxic cells. We further determined that the post-hypoxic cells that metastasize are enriched in pathways related to cancer stem cell gene expression. Overall, our results show that even when hypoxic cancer cells are reoxygenated in the bloodstream they retain a hypoxia-induced cancer stem cell-like phenotype that persists and promotes resistance and eventually recurrence.