bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioconvection peristaltic transport of Williamson hybrid nanofluid with motile microorganism, Ohmic heating, and entropy generation through an endoscope
Authors: Kotnurkar Asha S. , Talawar Vijaylaxmi T.
Published: May 2022

On account of the significance of entropy generation and bioconvection in biomedical and bioengineering, valuable contributions have been made by scientists in the present decade. The current study explores the impact of entropy generation, bioconvection of microorganisms, and Ohmic heating on the peristaltic transport of Williamson fluid containing molybdenum disulfide and silver nanoparticles through an endoscope with a long wavelength and low Reynolds number assumptions. The second law of thermodynamics is used to examine the entropy generation, and also Ohmic heating effect is used in the system. Between two coaxial tubes, a non-Newtonian Williamson fluid with molybdenum disulfide and silver nanoparticles is considered. The Homotopy perturbation method (HPM) is applied to describe the nonlinear partial differential equations. We were able to arrive at analytical solutions for velocity, nanoparticle concentration, microbes’ density, and temperature. In the end, the impact of distinct physical parameters on temperature, nanoparticle concentration, velocity, microorganism density, entropy generation, Bejan number, and the heat transfer rate was graphically depicted. The significant outcome of the present study is that the impact of the Peclet number enhances the velocity profile. But Peclet number and bioconvection constantly decline the density of motile microorganisms. One more significant outcome is that the Brinkman number declines the entropy generation near the inner tube and in the rest of the part, enhances the entropy generation. Brinkman number enhances the heat transfer rate. These findings have applications in biological sciences, engineering, geothermal energy, and industry, including the construction of microbial fuel cells and bio-convection nanotechnology devices. Microorganisms are beneficial in the degradation of biomaterials, resulting in the production of oxygen and the preservation of human health.
Currency Dominance and National Power in the Era of Distributed Ledger Technology and Cryptocurrency
Authors: Cherian Johann M.
Published: May 2022

Currency dominance has been the symbol of national power, influence, and dominance. After the Second World War, the Dollar has maintained its unrivaled influence as a currency reserve by central banks and as a global transaction currency. Recently, cryptocurrency and the distributed ledger system were seen as a challenge. However, due to the challenge it poses to the sovereignty of nation-states, central banks have resorted to developing the central bank digital currencies (CBDCs). China is the only major economy to have tested a CBDC, a symbol of its increasing economic power and innovation. Contrary to Mearsheimer’s theory of offensive realism, developments show that China can use its offensive economic capabilities to build a regional order through the belt and road initiative (BRI). With the recent release of its Central Bank Electronic Payment and the Blockchain-based Network System, China can seek to regionalize the use of its renminbi (RMB) and rival the power of the Dollar.
Where and What
Authors: Rong Yao , Kassautzki Naemi-Rebecca , Fuhl Wolfgang , Kasneci Enkelejda
Published: May 2022

Human drivers use their attentional mechanisms to focus on critical objects and make decisions while driving. As human attention can be revealed from gaze data, capturing and analyzing gaze information has emerged in recent years to benefit autonomous driving technology. Previous works in this context have primarily aimed at predicting "where" human drivers look at and lack knowledge of "what" objects drivers focus on. Our work bridges the gap between pixel-level and object-level attention prediction. Specifically, we propose to integrate an attention prediction module into a pretrained object detection framework and predict the attention in a grid-based style. Furthermore, critical objects are recognized based on predicted attended-to areas. We evaluate our proposed method on two driver attention datasets, BDD-A and DR(eye)VE. Our framework achieves competitive state-of-the-art performance in the attention prediction on both pixel-level and object-level but is far more efficient (75.3 GFLOPs less) in computation.
Modelling online debates with argumentation theory
Authors: Young Anthony P. , Joglekar Sagar , Agarwal Vibhor , Sastry Nishanth
Published: May 2022

It is important to study and understand Internet debates because they often have consequences in the offline world, for better or worse. We show that argumentation theory, a branch of AI concerned with the resolution of disagreements, provides a powerful toolbox with which we can represent and reason about such debates. After summarising the relevant ideas of argumentation theory, we overview three recent contributions from the authors and their collaborators: (1) on how to automatically identify reply polarity (agreement or disagreement) between arguments submitted in online debates, (2) on locating where the justified arguments are likely to be and how that depends on the "degree of antagonism" of the debate, and (3) on how to present the arguments made in debates such that a reader would get as many of the justified arguments as possible without having to read the entire debate. We hope that this will lead to further work that applies argumentation theory to model and analyse online debates.
Surface Functionalized Barium Titanate Nanoparticles: A Combined Experimental and Computational Study
Authors: Domrzalski Jessica N. , Stevens Tyler E. , Van Ginhoven Renee M. , Fritzsching Keith J. , Walder Brennan J. , Johnson Emily M. , Lewis Riley E. , Vreeland Erika C. , Pearce Charles J. , Vargas David A. , Coker Eric N. , Martinez Estevan J. , Grey John K. , Monson Todd C.
Published: May 2022

Barium titanate (BTO) nanoparticles show great potential for use in electrostatic capacitors with high energy density. This includes both polymer composite and sintered capacitors. However, questions about the nanoparticles’ size distribution, amount of agglomeration, and surface ligand effect on performance properties remain. Reducing particle agglomeration is a crucial step to understanding the properties of nanoscale particles, as agglomeration has significant effects on the composite dielectric constant. BTO surface functionalization using phosphonic acids is known reduce BTO nanoparticle agglomeration. We explore solution synthesized 10 nm BTO particles with tert-butylphosphonic acid ligands. Recent methods to quantifying agglomeration using an epoxy matrix before imaging shows that tert-butylphosphonic acid ligands reduce BTO agglomeration by 33%. Thermometric, spectroscopic, and computational methods provide confirmation of ligand binding and provide evidence of multiple ligand binding modes on the BTO particle surface.
In vivo localized gastrocnemius subtendon representation within the healthy and ruptured human Achilles tendon
Authors: Khair Ra’ad M. , Stenroth Lauri , Cronin Neil J. , Reito Aleksi , Paloneva Juha , Finni Taija
Published: May 2022

Using selective electrical stimulation, we report the distributions of medial and lateral gastrocnemius subtendon representations within the healthy and ruptured Achilles tendon. In the majority of our sample, lateral gastrocnemius subtendon was found in the most anterior region adjacent to medial gastrocnemius both in the healthy and ruptured, nonsurgically treated tendon. The tendon internal displacement pattern does not seem to differ, but displacement amplitude and nonuniformity differed between healthy and ruptured tendons 1 yr after rupture.
In Vitro Alpha-Amylase Enzyme Assay of Hydroalcoholic Polyherbal Extract: Proof of Concept for the Development of Polyherbal Teabag Formulation for the Treatment of Diabetes
Authors: Quazi Aamir , Patwekar Mohsina , Patwekar Faheem , Alghamdi Saad , Rajab Bodour S. , Babalghith Ahmad O. , Islam Fahadul
Published: May 2022

For the treatment and maintenance of postprandial blood glucose increases (i.e., diabetes mellitus), alpha (α)-amylase is a well-known therapeutic target. In this paper, we report an initial exploration of the work, i.e., in vitro alpha-amylase activity of the hydroalcoholic polyherbal extract of the selected plants. After drying, the plant material is ground individually, and at least 100 gm of the crude powder is prepared from each plant. 100 gm of each plant was combined, and a total of 500 gm of the crude powder (Ichnocarpus frutescens (100 gm) + Ficus dalhousie (100 gm) + Crateva magna (100 gm) + Alpinia galangal (100 gm) + Swertia chirata (100 gm)) was prepared to carry out the extraction. This obtained extract was subjected to preliminary phytochemical screening and in vitro alpha-amylase activity. At 16 mg/mL, acarbose displayed 78.40 ± 0.36% inhibition, whereas the extract exhibited 72.96 ± 0.70% inhibition, which is significantly comparable. The IC50 value of acarbose was 12.9 ± 1.12, whereas the extract exhibited 13.31 ± 1.12 mg/mL. The extract possesses numerous classes of chemicals such as alkaloids, glycosides, tannins, polyphenols, and terpenoids, which can contribute to the antidiabetic activity through alpha-amylase inhibition. This was an initial exploration of the work as a proof of concept for the development of polyherbal tea bag formulation for the treatment of diabetes. In the future, we are aiming to investigate the effectiveness of polyherbal tea bags in the treatment of diabetes using more in vitro and in vivo models. From the present investigation, we have concluded that this extract can be used for the treatment of diabetes.
Local Gravitation Clustering-Based Semisupervised Online Sequential Extreme Learning Machine
Authors: Wang Xingbiao , Gu Bin , Zou Quanyi , Lei Rui
Published: May 2022

Due to the limited number of labeled samples, semisupervised learning often leads to a considerable empirical distribution mismatch between labeled samples and unlabeled samples. To this end, this paper proposes a novel semisupervised algorithm named Local Gravitation-based Semisupervised Online Sequential Extreme Learning Machine (LGS-OSELM), learning to unlabeled samples follows from easy to difficult. Each sample is formulated as an object with mass and associated with local gravitation generated from its neighbors. The similarity between samples is measurable by the local gravitation measures (centrality CE and coordination CO). First, the LGS-OSELM uses the labeled samples to learn the initialization model by implementing ELM. Second, the unlabeled samples with a high confidence level that is easy to learn are labeled with the pseudo label. Then, these samples are utilized to iterate the neural network by implementing OS-ELM. The proposed approach ultimately realizes effective learning of all samples through successive learning unlabeled samples and iterating neural networks. We implement experiments on several standard benchmark data sets to verify the performance of the proposed LGS-OSELM, which demonstrates that our proposed approach outperforms state-of-the-art methods in terms of accuracy.
Software Defect Prediction Using Artificial Neural Networks: A Systematic Literature Review
Authors: Khan Muhammad Adnan , Elmitwally Nouh Sabri , Abbas Sagheer , Aftab Shabib , Ahmad Munir , Fayaz Muhammad , Khan Faheem
Published: May 2022

The demand for automated online software systems is increasing day by day, which triggered the need for high-quality and maintainable softwares at lower cost. Software defect prediction is one of the crucial tasks of the quality assurance process which improves the quality at lower cost by reducing the overall testing and maintenance efforts. Early detection of defects in the software development life cycle (SDLC) leads to the early corrections and ultimately timely delivery of maintainable software, which satisfies the customer and makes him confident towards the development team. In the last decade, many machine learning-based approaches for software defect prediction have been proposed to achieve the higher accuracy. Artificial Neural Network (ANN) is considered as one of the widely used machine learning techniques, which is included in most of the proposed defect prediction frameworks and models. This research provides a critical analysis of the latest literature, published from year 2015 to 2018 on the use of Artificial Neural Networks for software defect prediction. In this study, a systematic research process is followed to extract the literature from three widely used digital libraries including IEEE, Elsevier, and Springer, and then after following a thorough process, 8 most relevant research publications are selected for critical review. This study will serve the researchers by exploring the current trends in software defect prediction with the focus on ANNs and will also provide a baseline for future innovations, comparisons, and reviews.
N-TiO2-δ/g-C3N4 Dual Photocatalysts for Efficient Oxytetracycline Hydrochloride Photodegradation and CO2 Photoreduction
Authors: Nguyen Thanh-Binh , Dinh Thi Thuy Hang , Dinh Thi Kim Hue , Bui Minh Hien , Nguyen Thi Ngoc Quynh , Vu Ngoc Duy , Nguyen Dinh Bang
Published: May 2022

A series of [Formula: see text] (wt) N-TiO2- δ/g-C3N4 composites was synthesized by calcination and hydrothermal methods (labeled [Formula: see text]TiCN, [Formula: see text]: 5, 10, and 15). All composites were characterized by X-ray diffraction, Fourier transform infrared spectroscopy, UV-vis diffuse reflectance spectroscopy, transmission electron microscopy, and X-ray photoelectron spectroscopy. The photocatalytic activity of these composites was evaluated through oxytetracycline hydrochloride (denoted as OTC) photodegradation and CO2 photoreduction. The [Formula: see text]TiCN composites exhibited higher OTC photodegradation than bulk g-C3N4. 10TiCN was slightly more active than 5TiCN and 15TiCN, with a photodegradation yield of 97% after 5 h of light irradiation and constant rate of 0.647 h-1. For CO2 photoreduction, it was observed that 5TiCN exhibited the highest activity among the synthesized composites, with 7.0 ppm CH4 formed. This CH4 concentration was 7.8 times higher than the concentration formed by bulk g-C3N4 (0.9 ppm). A [Formula: see text]-scheme mechanism was proposed to explain the enhanced photocatalysis by [Formula: see text] (wt) N-TiO2- δ/g-C3N4 composites. The [Formula: see text]-scheme structure increased redox ability, caused better separation of photogenerated electron-hole pairs, and broadened the light absorption zone of the photocatalysts.
Modelling Microbially Induced Carbonate Precipitation (MICP) in Microfluidic Porous Chips
Authors: Shu Shuang , Chen Haoran , Meng Hao
Published: May 2022

Microfluidics is a new experimental approach that investigates the processes related to fluids flowing through small channels or porous media. Microfluidic chips, the core elements of the microfluidic technique, consist of quasi-2-dimensional pore structures etched and sealed in transparent materials. Fluids are allowed to flow through the chips, and real-time observations can be made about the transport and reactions of fluids at the pore scale. In this study, we test the feasibility of using the microfluidic technique to visualise the microbially induced carbonate precipitation (MICP) process. The experimental results obtained in this study show that the generation, evolution, and morphology of calcium carbonate, the effective product in MICP, can be clearly observed during the entire spatial and temporal range of the tests. Comparative tests with different testing variables, including the concentration of treatment solutions, activity of bacterial suspensions, and particle size, were also carried out. The results show that the influence of these variables on the treatment effects, such as the production rate of the reaction, spatial distribution of calcium carbonate, type and morphology of crystals, amount of ammonia gas produced, and presence/absence of clogging issues, can be visualised in microfluidic chips. The results presented in this paper prove that the microfluidic technique could be a helpful tool for unravelling the mechanisms of the MICP process at the pore scale and understanding the factors influencing the MICP process.
Analysis on the Application of Internet Multimedia Technology in College Music Education
Authors: Cong Lili
Published: May 2022

In order to improve the effect of college music teaching, this paper combines Internet multimedia technology to construct a college music intelligent teaching system and uses the DASH multihypothesis framework to improve the transmission effect of Internet multimedia. Moreover, this paper manages the teaching resources generated in the process of music teaching and collects these resources into the library. The dynamic addition and editing of classifications are realized in the background, which is convenient for easy expansion and flexible adjustment of classifications. In addition, this paper combines the actual needs of music teaching in colleges and universities to construct the system function and get the system frame structure and work flow. Finally, this paper verifies the system of this paper in conjunction with experiments. The analysis shows that Internet multimedia technology has good effects in college music education, can effectively handle various resources of college music teaching, and can effectively improve the efficiency of college music education.
Symptomatic Apical Periodontitis of the Mandibular First Molar with the Accessory Canal in the Furcation Area Mimicking Furcation Perforation
Authors: Bolyachin Alexei , Khabadze Zurab , Mordanov Oleg , Gasbanov Magomed , Teberdiev Takhir
Published: May 2022

Apical periodontitis frequently presents as a chronic disease. To arrive at a true diagnosis, in addition to the clinical examination, it is mandatory to undertake radiographic examinations and evaluate the clinical presentation. Knowledge of the root canal morphology is a prerequisite for effective nonsurgical endodontic treatment. The internal morphological features of the pulp chamber are variable and complex. This case report describes the treatment and outcome of symptomatic apical periodontitis of a mandibular first molar with the accessory (chamber) canal. The applied treatment fully contributed to the periapical lesion regression as shown in the four-year recall periapical radiography.
Research on Psychological Emotion Recognition of College Students Based on Deep Learning
Authors: Li Yuebo , Zhou Yatong
Published: May 2022

College students’ anxiety, depression, inferiority complex, interpersonal sensitivity, and a series of mental health problems have a very serious negative impact on individuals, families, and society. In order to obtain better psychological emotion recognition effect of college students, this paper proposes a psychological emotion recognition algorithm based on multisource data. One-dimensional convolutional neural network (1D-CNN) was used to mine students’ online patterns from online behavior sequences. According to the consumption data of students in the canteen, abnormal scores are calculated to depict the dietary differences among students. At the same time, the students’ psychological state data provided by the psychological center are used as labels to improve the shortcomings of the questionnaire. Five kinds of common classification algorithms are trained by training set, and the classifier with the best effect is selected through evaluation of verification set, which is used to identify students with mental health problems in the test set. Experimental results show that precision, recall, and F1-measure reach 0.68, 0.56, and 0.67, respectively. 75% of students with mental health problems are identified. The psychological and emotional recognition system of college students based on deep learning provides systematic method and theoretical support for the school to find students with psychological problems in time and provide intervention.
Prediction of Refracturing Effect of Tight Gas Reservoirs Based on Bayesian Inversion Algorithm
Authors: Lin Hai , Zhou Fujian , Tian Yakai , Wang Yan
Published: May 2022

As a key technology for tight gas stimulation, refracturing plays an important role in tight gas development. In the production process of tight gas wells, the reservoir or fracturing process may cause the hydraulic fractures to gradually fail and the production to continuously decrease. In order to restore the productivity of a single well, it is necessary to refract the well to reopen the failed fractures or fracturing. Reasonable refracturing timing and optimization of refract fracture parameters are important guarantees to ensure the benefits of refracturing in tight gas wells, and relevant research on it can provide theoretical and technical guidance for field construction design. Based on the inverse problem of the dynamic prediction model of tight gas well productivity, this paper proposes an inversion method of formation and fracture parameters before refracturing based on Bayesian inversion algorithm. Finally, based on the geology and development data of the fractured wells in the Sulige gas field, the field application of refracting well selection, determination of refracting reasonable timing, and prediction of refracting effect is carried out. The actual production data are compared, and it is shown that this method can provide theoretical guidance for high-efficiency production-increasing construction on-site.
Impact of Social Media on Geopolitics and Economic Growth: Mitigating the Risks by Developing Artificial Intelligence and Cognitive Computing Tools
Authors: Kamruzzaman M. M.
Published: May 2022

Social media is one of the most revolutionary innovations in computer science that facilitates connecting people in the world to share information, ideas, and thoughts. In recent years, social media has demonstrated tremendous growth, which has affected individuals, businesses, communities, and economies. The focus of the present study is to identify the impact of social media on geopolitics and economic growth. The study is based on a systematic review of previous literature on the subject. It has been revealed through the findings that social media impacts geopolitics by decreasing the level of censorship and increasing the spread of news or information, while it also enables the politicians to influence individuals over online social networks through the great level of access. On the other hand, it has been identified that social media has both positive and negative impacts on geopolitics and economic growth. Social media is able to unite diverse groups and individuals spread across the planet dedicated to specific issues. The formation of communities and the ability of social media to unite groups show how social media could contribute positively to geopolitics and economic growth. But it decreases the productivity level of the individuals; on the other hand, it does contain the potential to create a participatory economy, which can be beneficial for a particular country. Some argue that social sharing has encouraged people to use computers and mobile phones to express their concerns on social issues without actually having to engage actively with campaigns in real life. Their support is limited to pressing the “Like” button or sharing content. This study performs a thorough study selection exercise and a quality assessment to ensure that the present study is valuable to academia and the relevant stakeholders, especially the experts of computer science who can develop the smartest artificial intelligence and cognitive computing tools that can help mitigate those risks of social media for the geopolitically volatile, uncertain, complex, and ambiguous world and ensure smooth economic growth.
Visual Space Design of Digital Media Art Using Virtual Reality and Multidimensional Space
Authors: Liu Peng , Song Chunyan , Ma Xiaoyan , Tang Xuchao
Published: May 2022

To effectively develop digital media art to a higher level, creators should consider incorporating VR into it to improve the quality of digital media art works, especially in light of the continuous advancement of science and technology. This paper explains the uniqueness of digital media artistic design and discusses the artistic creation method of digital media based on virtual reality. In addition, he proposed a virtual reality-based visual space design method for digital media art. This paper examines and researches the spatial visual form in digital media art design from the perspective of visual perception. This paper explains the elaborated contents in detail with design works, beginning with the construction of three-dimensional space, four-dimensional space, and surreal multidimensional space. People can gain aesthetic uniqueness by combining digital technology. Theoretically, the practice of visual space design is investigated in order to provide a reference point for digital media art to move forward in terms of timeliness, diversification, and innovation.
A Quasistraight Line Routing Protocol for Square Grid-Based Wireless Sensor Networks
Authors: Ajij Md. , Pratihar Sanjoy , Luhach Ashish Kumar , Roy Diptendu Sinha
Published: May 2022

Sensor nodes in a wireless sensor network (WSN) are both energy-constrained and vulnerable to faults and disasters. Communication between the sensor nodes is generally hop-by-hop, and the nodes are distributed throughout the area to be covered. Broadcast-based routing protocols are not preferable in sensor networks since broadcasting is considered costly in terms of battery power consumption. In this paper, a digital quasistraight line segment- (DQSS-) based approach is employed for the detection of quasistraight line segments, i.e., for quasistraight path finding between WSN sensors arranged in a square grid. Comparative results show that the method is comparable with the best-known straight line finding algorithm in terms of path lengths and computation time. Moreover, the proposed method is capable of avoiding dead nodes by updating DQSS parameters dynamically during path finding. Hence, the proposed method is promising to be used in WSN square grids as a quasistraight line routing protocol.
Optimized Systematic Review Tool: Application to Candidate Biomarkers for the Diagnosis of Hepatocellular Carcinoma
Authors: U Mei Ran Abellona , Shen Eric Yi-Liang , Cartlidge Caroline , Alkhatib Alzhraa , Thursz Mark R. , Waked Imam , Gomaa Asmaa I. , Holmes Elaine , Sharma Rohini , Taylor-Robinson Simon D.
Published: May 2022

This review aims to develop an appropriate review tool for systematically collating metabolites that are dysregulated in disease and applies the method to identify novel diagnostic biomarkers for hepatocellular carcinoma (HCC). Studies that analyzed metabolites in blood or urine samples where HCC was compared with comparison groups (healthy, precirrhotic liver disease, cirrhosis) were eligible. Tumor tissue was included to help differentiate primary and secondary biomarkers. Searches were conducted on Medline and EMBASE. A bespoke “risk of bias” tool for metabolomic studies was developed adjusting for analytic quality. Discriminant metabolites for each sample type were ranked using a weighted score accounting for the direction and extent of change and the risk of bias of the reporting publication. A total of 84 eligible studies were included in the review (54 blood, 9 urine, and 15 tissue), with six studying multiple sample types. High-ranking metabolites, based on their weighted score, comprised energy metabolites, bile acids, acylcarnitines, and lysophosphocholines. This new review tool addresses an unmet need for incorporating quality of study design and analysis to overcome the gaps in standardization of reporting of metabolomic data. Validation studies, standardized study designs, and publications meeting minimal reporting standards are crucial for advancing the field beyond exploratory studies.
Safety and Efficacy of Irradiation Boost Based on 18F-FET-PET in Patients with Newly Diagnosed Glioblastoma
Authors: Harat Maciej , Blok Maciej , Miechowicz Izabela , Wiatrowska Izabela , Makarewicz Karolina , Małkowski Bogdan
Published: May 2022

Purpose:

Dual timepoint fluoro-ethyl-tyrosine (FET)-PET acquisition (10 and 60 minutes after FET injection) improves the definition of glioblastoma (GBM) location and shape. Here we evaluated the safety and efficacy of simultaneous integrated boost (SIB) planned using dual FET-PET for postoperative GBM treatment.

Patients and Methods:

In this prospective pilot study (March 2017–December 2020), 17 patients qualified for FET-PET–based SIB intensity-modulated radiotherapy after resection. The prescribed dose was 78 and 60 Gy (2.6 and 2.0 Gy per fraction, respectively) for the FET-PET– and magnetic resonance (MR)-based target volumes. Eleven patients had FET-PET within 9 months to precisely define biological responses. Progression-free survival (PFS), overall survival (OS), toxicities, and radiation necrosis were evaluated. Six patients (35%) had tumors with MGMT promoter methylation.

Results:

The 1- and 2-year OS and PFS rates were 73% and 43% and 53% and 13%, respectively. The median OS and PFS were 24 [95% confidence interval (CI), 9–26] and 12 (95% CI, 6–18) months, respectively. Two patients developed uncontrolled seizures during radiotherapy and could not receive treatment per protocol. In patients treated per protocol, 7 of 15 presented with new or increased neurologic deficits in the first month after irradiation. Radiation necrosis was diagnosed by MRI 3 months after SIB in 5 patients and later in another 2 patients. In 2 patients, the tumor was larger in FET-PET images after 6 months.

Conclusions:

Survival outcomes using our novel dose-escalation concept (total 78 Gy) were promising, even within the MGMT unmethylated subgroup. Excessive neurotoxicity was not observed, but radionecrosis was common and must be considered in future trials.
Overall Survival with Palbociclib and Fulvestrant in Women with HR+/HER2− ABC: Updated Exploratory Analyses of PALOMA-3, a Double-blind, Phase III Randomized Study
Authors: Cristofanilli Massimo , Rugo Hope S. , Im Seock-Ah , Slamon Dennis J. , Harbeck Nadia , Bondarenko Igor , Masuda Norikazu , Colleoni Marco , DeMichele Angela , Loi Sherene , Iwata Hiroji , O'Leary Ben , André Fabrice , Loibl Sibylle , Bananis Eustratios , Liu Yuan , Huang Xin , Kim Sindy , Lechuga Frean Maria Jose , Turner Nicholas C.
Published: May 2022

Purpose:

To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA).

Patients and Methods:

Patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent.

Results:

At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8–39.9) in the palbociclib group and 28.0 months (23.5–33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65–0.99). The 6-year OS rate (95% CI) was 19.1% (14.9–23.7) and 12.9% (8.0–19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified.

Conclusions:

The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2− ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.
Pembrolizumab in Combination with Neoadjuvant Chemoradiotherapy for Patients with Resectable Adenocarcinoma of the Gastroesophageal Junction
Authors: Zhu Mojun , Chen Chunhua , Foster Nathan R. , Hartley Christopher , Mounajjed Taofic , Salomao Marcela A. , Fruth Briant F. , Beamer Staci E. , Kim Yohan , Harrington Susan M. , Pitot Henry C. , Sanhueza Cristobal T. , Feng Yening , Herrmann Joerg , McWilliams Robert R. , Lucien Fabrice , Huang Bing Q. , Ma Wen Wee , Bekaii-Saab Tanios S. , Dong Haidong , Wigle Dennis , Ahn Daniel H. , Hallemeier Chris L. , Blackmon Shanda , Yoon Harry H.
Published: May 2022

Purpose:

This phase Ib/2 trial investigated pembrolizumab-containing trimodality therapy in patients with gastroesophageal junction (GEJ) adenocarcinoma.

Patients and Methods:

Patients with GEJ adenocarcinoma (cT1–3NanyM0) received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab. The primary endpoints were tolerability in the first 16 patients and pathologic complete response [pCR (ypT0N0)]. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). An independent propensity-score-matched cohort (treated with CROSS without immunotherapy) was used for comparison. Exploratory analyses included immune biomarkers in the tumor microenvironment (TME) and plasma.

Results:

We enrolled 31 eligible patients, of whom 29 received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met. The primary efficacy endpoint was not met [7/31 (22.6%) achieved pCR]. Patients with high [i.e., combined positive score (CPS) ≥ 10] baseline expression of programmed death (PD)-L1 in the TME had a significantly higher pCR rate than those with low expression [50.0% (4/8) vs. 13.6% (3/22); P = 0.046]. Patients with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients. Among trial patients with PD-L1 CPS < 10, unprespecified analysis explored whether extracellular vesicles (EV) could identify further responders: an elevated plasma level of PD-L1–expressing EVs was significantly associated with higher pCR.

Conclusions:

Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.
The Interaction of Specific Peptide Aptamers With the DNA Binding Domain and the Dimerization Domain of the Transcription Factor Stat3 Inhibits Transactivation and Induces Apoptosis in Tumor Cells
Authors: Nagel-Wolfrum Kerstin , Buerger Claudia , Wittig Ilka , Butz Karin , Hoppe-Seyler Felix , Groner Bernd
Published: May 2022

The transcription factor signal transducer and activator of transcription (Stat) 3 is activated through the interleukin-6 family of cytokines and by binding of growth factors to the epidermal growth factor (EGF) receptor. It plays an essential role in embryonic development and assumes specialized tasks in many differentiated tissues. Constitutively activated Stat3 has been found in tumor cell lines and primary tumors and plays a crucial role in tumor cell survival and proliferation. To inhibit the oncogenic action of Stat3 in tumor cells, we have selected short peptides, so-called peptide aptamers, which specifically interact with defined functional domains of this transcription factor. The peptide aptamers were selected from a peptide library of high complexity by an adaptation of the yeast two-hybrid procedure. Peptide aptamers specifically interacting with the Stat3 dimerization domain caused inhibition of DNA binding activity and suppression of transactivation by Stat3 in EGF-responsive cells. Similarly, a peptide aptamer selected for its ability to recognize the Stat3 DNA binding domain inhibited DNA binding and transactivation by Stat3 following EGF stimulation of cells. Peptide aptamers were expressed in bacteria as fusion proteins with a protein transduction domain and introduced into human myeloma cells. This resulted in dose-dependent growth inhibition, down-regulation of Bcl-xL expression, and induction of apoptosis. The inhibition of Stat3 functions through the interaction with peptide aptamers counteracts the transformed phenotype and could become useful in targeted tumor therapy.
Cystatin C Antagonizes Transforming Growth Factor β Signaling in Normal and Cancer Cells
Authors: Sokol Jonathan P. , Schiemann William P.
Published: May 2022

Cystatin C (CystC) is a secreted cysteine protease inhibitor that regulates bone resorption, neutrophil chemotaxis, and tissue inflammation, as well as resistance to bacterial and viral infections. CystC is ubiquitously expressed and present in most bodily fluids where it inhibits the activities of cathepsins, a family of cysteine proteases that can promote cancer cell invasion and metastasis. Transforming growth factor β (TGF-β) is a multifunctional cytokine endowed with both tumor-suppressing and tumor-promoting activities. We show herein that TGF-β treatment up-regulated CystC transcript and protein in murine 3T3-L1 fibroblasts. Moreover, CystC mRNA expression was down-regulated in ∼50% of human malignancies, particularly cancers of the stomach, uterus, colon, and kidney. Overexpression of CystC in human HT1080 fibrosarcoma cells antagonized their invasion through synthetic basement membranes in part via a cathepsin-dependent pathway. Independent of effects on cathepsin activity, CystC also reduced HT1080 cell gene expression stimulated by TGF-β. Invasion of 3T3-L1 cells occurred through both cathepsin- and TGF-β-dependent pathways. Both pathways were blocked by CystC, but only the TGF-β-dependent pathway was blocked by a CystC mutant (i.e., Δ14CystC) that is impaired in its ability to inhibit cathepsin activity. Moreover, CystC and Δ14CystC both inhibited 3T3-L1 cell gene expression stimulated by TGF-β. We further show that CystC antagonized TGF-β binding to its cell surface receptors, doing so by interacting physically with the TGF-β type II receptor and antagonizing its binding of TGF-β. Collectively, our findings have identified CystC as a novel TGF-β receptor antagonist, as well as a novel CystC-mediated feedback loop that inhibits TGF-β signaling.
Constitutive and DNA Damage Inducible Activation of pig3 and MDM2 Genes by Tumor-Derived p53 Mutant C277Y
Authors: Pospı́šilová Šárka , Siligan Christine , Ban Jozet , Jug Gunhild , Kovar Heinrich
Published: May 2022

The p53 gene is compromised in most human cancers by point mutation. Evidence is accumulating that these alterations frequently do not result in a complete loss of the sequence-specific transcriptional regulatory function of p53. Here, we describe the transcriptional activity of the p53 mutant C277Y isolated from a Ewing's sarcoma with high constitutive pig3 expression. Transient transfection of this mutant into a p53 null cell line resulted in activation not only of the pig3 but also of the MDM2 gene compatible with the presence of constitutively expressed MDM2 transcripts initiated from the P2 promoter in the p53-C277Y hemizygous Ewing's sarcoma cell line. Expression of endogenous pig3 and MDM2 genes was further enhanced on irradiation of this cell line. Here, suppression of p53-C277Y by RNAi reduced pig3 promoter activity, RNA, and protein expression. Reporter gene assays revealed that the potential of p53-C277Y to up-regulate MDM2 expression was similar to wild-type p53, whereas activation of the pig3 promoter was at least 5-fold increased over wild-type p53. The pentanucleotide microsatellite sequence present in exon 1 of the pig3 gene was found to be responsible for p53-C277Y-mediated activation. In concordance with a role of PIG3 protein for cell death, we showed residual apoptotic activity of p53-C277Y to which the described Ewing's sarcoma cell line was found to be resistant. p53-C277Y has previously been reported to bind to DNA with altered sequence specificity and to be unable to activate generic p53 target genes in yeast-based functional assays. Our results, therefore, show that a p53 mutant may behave differently when tested in its authentic cellular context.
Molecular Cloning and Characterization of the Catalytic Domain of Zebrafish Homologue of the Ataxia-Telangiectasia Mutated Gene
Authors: Garg Renu , Geng Chuan-Dong , Miller Jennifer L. , Callens Shannon , Tang Xi , Appel Bruce , Xu Bo
Published: May 2022

Inherited biallelic mutations of the ATM (ataxia-telangiectasia mutated) gene in humans cause ataxia-telangiectasia, a rare autosomal recessive disorder associated with progressive neuro-degeneration, cancer predisposition, immunodeficiency, and hypersensitivity to ionizing radiation. The ATM gene is highly conserved across a wide range of species. In an attempt to establish a zebrafish (Danio rerio) model of ataxia-telangiectasia, we cloned the coding sequence of the catalytic domain of the zebrafish homologue of ATM and found it to contain an open reading frame encoding 907 amino acids at the carboxyl terminus of the zebrafish ATM (zATM). The catalytic domain of zATM shares 67% and 66% homology with human ATM (hATM) and mouse ATM (mATM), respectively. The full-length mRNA encoding zATM is found to be approximately 11 kb by Northern hybridization, and the expression of zATM is observed in different adult and embryonic tissues. Overexpression of a kinase-inactive zATM domain in human cells has a dominant-negative effect against hATM function. Expression of the altered zATM in ZF4 cells leads to an A-T–like phenotype in response to ionizing radiation. These results taken together indicate that zATM is the homologue of hATM. Furthermore, using the kinase-inactive form of zATM should allow manipulation of zATM function in fish cells.
Nucleoside Diphosphate Kinase A/nm23-H1 Promotes Metastasis of NB69-Derived Human Neuroblastoma
Authors: Almgren Malin A.E. , Henriksson K. Cecilia E. , Fujimoto Jennifer , Chang Christina L.
Published: May 2022

Nucleoside diphosphate kinase A (NDPK-A), encoded by the nm23-H1 gene, acts as a metastasis suppressor in certain human tumors such as breast carcinoma. However, evidence also points to NDPK-A functioning as a metastasis promoter in other human tumors including neuroblastoma. In fact, amplification and overexpression of nm23-H1 as well as S120G mutation of NDPK-A (NDPK-AS120G) have been detected in 14% to 30% of patients with advanced stages of neuroblastoma. To test whether NDPK-A promotes neuroblastoma metastasis, we established stable transfectants and an orthotopic xenograft animal model from the human neuroblastoma NB69 cell line. We demonstrate that overexpressed NDPK-A or NDPK-AS120G increased both incidence and colonization of neuroblastoma metastasis in animal lungs without significantly affecting primary tumor development. In vitro, these metastasis-associated NDPK-A aberrations abrogated retinoic acid-induced neuronal differentiation while increasing cloning efficiency, cell survival, and colony formation of NB69 derivatives. Furthermore, NDPK-AS120G reduced cell adhesion and increased cell migration. Compared with its wild-type, NDPK-AS120G appears more effective in promoting neuroblastoma metastasis. Our results provide the first evidence that NDPK-A behaves as a metastasis promoter at least in human neuroblastoma derived from NB69 cells. The findings not only suggest a prognostic value of NDPK-A in neuroblastoma patients but also caution NDPK-A-targeted treatment for patients with different tumor types.
Minimal 16q Genomic Loss Implicates Cadherin-11 in Retinoblastoma
Authors: Marchong Mellone N. , Chen Danian , Corson Timothy W. , Lee Cheong , Harmandayan Maria , Bowles Ella , Chen Ning , Gallie Brenda L.
Published: May 2022

Retinoblastoma is initiated by loss of both RB1 alleles. Previous studies have shown that retinoblastoma tumors also show further genomic gains and losses. We now define a 2.62 Mbp minimal region of genomic loss of chromosome 16q22, which is likely to contain tumor suppressor gene(s), in 76 retinoblastoma tumors, using loss of heterozygosity (30 of 76 tumors) and quantitative multiplex PCR (71 of 76 tumors). The sequence-tagged site WI-5835 within intron 2 of the cadherin-11 (CDH11) gene showed the highest frequency of loss (54%, 22 of 41 samples tested). A second hotspot for loss (39%, 9 of 23 samples tested) was detected within intron 2 of the cadherin-13 (CDH13) gene. Furthermore, deletion of the exons of CDH11 and/or WI-5835 was shown by quantitative multiplex PCR in 17 of 30 (57%) of previously untested tumors. Immunoblot analyses revealed that 91% (20 of 22) retinoblastoma exhibited either a complete loss or a decrease of the intact form of CDH11 and 8 of 13 showed a prevalent band suggestive of the variant form. Copy number of WI-5835 for these samples correlated with CDH11 protein expression. CDH11 staining was evident in the inner nuclear layer in early mouse retinal development and in small transgenic murine SV40 large T antigen–induced retinoblastoma tumors, but advanced tumors frequently showed loss of CDH11 expression by reverse transcription-PCR, suggestive of a role for CDH11 in tumor progression or metastasis. CDH13 protein and mRNA were consistently expressed in all human and murine retinoblastoma compared with normal adult human retina. Our analyses implicate CDH11, but not CDH13, as a potential tumor suppressor gene in retinoblastoma.
Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Mediated Activation of Mitochondria-Associated Nuclear Factor-κB in Prostatic Carcinoma Cell Lines
Authors: Guseva Natalya V. , Taghiyev Agshin F. , Sturm Mary T. , Rokhlin Oskar W. , Cohen Michael B.
Published: May 2022

It has been suggested that some nuclear transcription factors may participate in the regulation of mitochondrial functions through transcriptional control of mitochondrial DNA. Very little is known about the response of transcription factors within mitochondria to the activation of death receptors. Recent publications indicate that nuclear factor-κB (NF-κB) is localized in mitochondria of mammalian cells. Because of the critical role of mitochondria in the execution of many apoptotic pathways, we suggest that NF-κB-dependent mechanisms operating at the level of mitochondria contribute to its role in regulating death receptor signaling. We have found NF-κB p65 and p50 subunits with DNA binding activity in the mitochondria of prostatic carcinoma cell lines. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) affects DNA binding activity of mitochondria-associated NF-κB but does not change the amount of p65 in mitochondria, which suggests activation of mitochondrial NF-κB without additional translocation of NF-κB subunits to mitochondria. We have also shown that TRAIL decreases mitochondrial genome encoded mRNA levels and inhibition of NF-κB prevents this decrease. TRAIL effects on mitochondrial NF-κB-DNA binding and mitochondrial genome encoded mRNA levels also depend on Bcl-2 overexpression. In addition, transcription factor activator protein-1 with DNA binding activity is also found in mitochondria of prostatic carcinoma cells and TRAIL treatment affects this binding. In summary, NF-κB is found in mitochondria of prostatic carcinoma cells, where it is thought to regulate mitochondria genome encoded mRNA levels in response to TRAIL treatment.