bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a Gene Prognostic Model of Gastric Cancer Based on Analysis of Tumor Mutation Burden
Authors: Ma Weijun , Li Weidong , Xu Lei , Liu Lu , Xia Yu , Yang Liping , Da Mingxu
Published: September 2021

Introduction: Gastric cancer is one of the most common cancers. Although some progress has been made in the treatment of gastric cancer with the improvement of surgical methods and the application of immunotherapy, the prognosis of gastric cancer patients is still unsatisfactory. In recent years, there has been increasing evidence that tumor mutational load (TMB) is strongly associated with survival outcomes and response to immunotherapy. Given the variable response of patients to immunotherapy, it is important to investigate clinical significance of TMB and explore appropriate biomarkers of prognosis in patients with gastric cancer (GC).

Material and Methods: All data of patients with gastric cancer were obtained from the database of The Cancer Genome Atlas (TCGA). Samples were divided into two groups based on median TMB. Differently expressed genes (DEGs) between the high- and low-TMB groups were identified and further analyzed. We identified TMB-related genes using Lasso, univariate and multivariate Cox regression analysis and validated the survival result of 11 hub genes using Kaplan-Meier Plotter. In addition, “CIBERSORT” package was utilized to estimate the immune infiltration.

Results: Single nucleotide polymorphism (SNP), C > T transition were the most common variant type and single nucleotide variant (SNV), respectively. Patients in the high-TMB group had better survival outcomes than those in the low-TMB group. Besides, eleven TMB-related DEGs were utilized to construct a prognostic model that could be an independent risk factor to predict the prognosis of patients with GC. What’s more, the infiltration levels of CD4+ memory-activated T cells, M0 and M1 macrophages were significantly increased in the high-TMB group compared with the low-TMB group.

Conclusions: Herein, we found that patients with high TMB had better survival outcomes in GC. In addition, higher TMB might promote immune infiltration, which could provide new ideas for immunotherapy.
La formación del compromiso ético en investigación educativa: resultados de una experiencia de innovación docente en educación superior
Authors: Corbella Molina Laura , Sanz Escutia Clara , Arnau Sabates Laura
Published: September 2021

La formación inicial de los investigadores en educación es determinante para garantizar la adquisición de conocimientos y de técnicas que contribuyan a la calidad de la investigación, y también para el desarrollo de su competencia ética. Este trabajo presenta los resultados de la aplicación de una innovación educativa para mejorar la competencia ética en una asignatura de investigación educativa. El objetivo es evaluar la adquisición de dicha competencia en un grupo de 80 estudiantes de los grados de Pedagogía y Educación Social. Para ello, a través de un enfoque cuantitativo, se llevó a cabo un diseño pre-experimental pretest-postest. El instrumento de recogida de información fue un cuestionario en el que se exponían ciertos dilemas éticos comunes en los procesos de investigación. Para analizar los resultados cuantitativos se usó la prueba T-test, y para las respuestas abiertas se llevó a cabo un análisis de contenido siguiendo un proceso de categorización deductivo-inductivo. El estudio pone de manifiesto que el proceso de innovación docente ha contribuido a desarrollar y mejorar la competencia ética en la investigación educativa, aunque el discurso de los estudiantes tiende a ser muy normativo, justificando el carácter ético de sus decisiones apelando a protocolos y/o normas. Surge la necesidad de fomentar más la reflexión crítica y la responsabilidad individual. Se concluye que el desarrollo de la competencia ética en la investigación educativa no solamente necesita el compromiso de los docentes y del alumnado, sino también de las instituciones de educación superior.
El modelo de aprendizaje TPACK y su impacto en la innovación educativa desde un análisis bibliométrico
Authors: Vásconez Paredes Carlos Darío , Inga Ortega Esteban Mauricio
Published: September 2021

El TPACK sintetiza los conocimientos que se espera que el docente deba tener a la hora del proceso de enseñanza-aprendizaje. Esta investigación contextualiza el Conocimiento del Contenido Pedagógico Tecnológico (TPACK), a la vez que presenta una revisión y un análisis sistemático de la bibliografía hallada a nivel regional y mundial en las bases de datos Web of Science y Scopus entre los años 2016 y 2020, en el cuál hemos considerado los criterios de mayor número de citas y artículos más relevantes dentro de la búsqueda general con la palabra clave TPACK. De igual forma hemos nutrido este análisis con datos estadísticos provenientes de la Organización para la Cooperación Económica y el Desarrollo (OECD). Los métodos usados para la investigación han sido el método Histórico-Descriptivo y el método Analítico-Sintético.  En consecuencia, como fruto de este hemos identificado los problemas o variables más comunes dentro de la aplicación del modelo del TPACK y las (posibles) soluciones o consideraciones planteadas desde las investigaciones con las que se alimenta este estudio lo que constituye un punto de partida para analizar la implementación de TPACK.
El tamaño de la empresa y su influencia en la productividad del sector comercio
Authors: Haro Sarango Alexander Fernando
Published: September 2021

En el entorno investigativo empresarial existe una discusión constante sobre sí, el tamaño de la empresa es un elemento circunstancial para la supervivencia económica, conjuntamente, sobre los riesgos existentes y los factores que pueden generar problemas en una organización; este estudio pretende indagar sobre la influencia del tamaño de la empresa en la productividad perpetuada, la temporalidad radica en el periodo 2016 al 2020, CIIU “G”; los sujetos de estudio para esta investigación son: 15% (139) empresas grandes, 39% (361) medianas y 47% (445) pequeñas; los indicadores a usar son: índice Dupont, margen de rentabilidad neta sobre ventas, rotación de activos, multiplicador de capital, costo de financiamiento y operativos, la metodología para conocer la influencia de las variables usadas serán los modelos efectos fijos y aleatorios, previa consideración de Hausman, asimismo, una correlación con la finalidad de encontrar una relación entre variables directa o inversamente proporcional; por otro lado, para discernir sobre la influencia del tamaño de las empresas en los estratificaciones usadas se consentirá mediante ANOVA para grupos y Turkey para secciones. Los resultados del estudio determinan que el costo financiero y operativo no son variables significativas en la productividad, por otro lado, existe una alta afinidad en la gestión de las empresas grandes y medianas, adicional a esto, las empresas pequeñas presentan menor costo financiero y operativo y un mayor índice Dupont, con lo cual se determina que existe una ligera diferencia en algunas variables con respecto al tamaño de la empresa.
Smart Mixes in International Supply Chains: A Definition and Analytical Tool, Illustrated with the Example of Organic Imports into Switzerland
Authors: Home Robert , Weiner Mareike , Schader Christian
Published: September 2021

Combinations of national and international, hard and soft powers, known as Smart Mixes, have been proposed as a way for governments in consumer countries to influence the behaviour of supply chain actors who operate outside their jurisdiction. However, the Smart Mix concept has not yet been precisely defined, which has hindered its operationalization as a means of analyzing the governance of long and complex international supply chains. The aim of this contribution is to derive a working definition of Smart Mixes and use it to create and demonstrate a generalizable analytical tool that facilitates identification of whether a Smart Mix exists in an international supply chain. To address this aim, we reviewed existing literature on Smart Mixes to define the concept, which led to a three-step process for analyzing a supply chain. In a second stage, we demonstrate the process by applying it to the example of organic imports into Switzerland, using data from expert interviews and existing public documentation. The application showed that the governance of the organic sector in Switzerland related to imported products fulfils the criteria for it to be considered a Smart Mix that enables the Swiss Government to influence the behaviour of supply chain actors outside its jurisdiction. This example shows that the proposed Smart Mix concept is sound under particular circumstances: in this case, when the interests of the public and private sectors are aligned so that binding public measures provide protection to the private sector. These circumstances are not unique to organic imports into Switzerland, which allows the conclusion that Smart Mixes may provide sustainability solutions in other international supply chains.
Training and Validating a Machine Learning Model for the Sensor-Based Monitoring of Lying Behavior in Dairy Cows on Pasture and in the Barn
Authors: Schmeling Lara , Elmamooz Golnaz , Hoang Phan Thai , Kozar Anastasiia , Nicklas Daniela , Sünkel Michael , Thurner Stefan , Rauch Elke
Published: September 2021

Monitoring systems assist farmers in monitoring the health of dairy cows by predicting behavioral patterns (e.g., lying) and their changes with machine learning models. However, the available systems were developed either for indoors or for pasture and fail to predict the behavior in other locations. Therefore, the goal of our study was to train and evaluate a model for the prediction of lying on a pasture and in the barn. On three farms, 7–11 dairy cows each were equipped with the prototype of the monitoring system containing an accelerometer, a magnetometer and a gyroscope. Video observations on the pasture and in the barn provided ground truth data. We used 34.5 h of datasets from pasture for training and 480.5 h from both locations for evaluating. In comparison, random forest, an orientation-independent feature set with 5 s windows without overlap, achieved the highest accuracy. Sensitivity, specificity and accuracy were 95.6%, 80.5% and 87.4%, respectively. Accuracy on the pasture (93.2%) exceeded accuracy in the barn (81.4%). Ruminating while standing was the most confused with lying. Out of individual lying bouts, 95.6 and 93.4% were identified on the pasture and in the barn, respectively. Adding a model for standing up events and lying down events could improve the prediction of lying in the barn.
Bobolink (Dolichonyx oryzivorus) Declines Follow Bison (Bison bison) Reintroduction on Private Conservation Grasslands
Authors: Kaplan Rachel H. , Rosamond Kristen M. , Goded Sandra , Soultan Alaaeldin , Glass Alex , Kim Daniel H. , Arcilla Nico
Published: September 2021

Among the most rapidly declining birds in continental North America, grassland birds evolved with American bison (Bison bison) until bison nearly became extinct due to overhunting. Bison populations have subsequently rebounded due to reintroductions on conservation lands, but the impacts of bison on grassland nesting birds remain largely unknown. We investigated how bison reintroduction, together with other land management and climate factors, affected breeding populations of a grassland bird species of conservation concern, the Bobolink (Dolichonyx oryzivorus). We quantified population changes in Bobolinks over an 18-year period in conservation grasslands where bison were reintroduced, compared with adjacent grasslands grazed by cattle and where hay was harvested after the bird breeding season. Four years after bison reintroduction, the bison population in the study area had doubled, while Bobolink abundance declined 62% and productivity declined 84%. Our findings suggest that bison reintroduction as a conservation strategy may be counterproductive in grassland fragments where overgrazing, trampling, and other negative impacts drive declines in grassland breeding birds. Where bird conservation is an objective, small grassland reserves may therefore be inappropriate sites for bison reintroduction. To maximize conservation benefits to birds, land managers should prioritize protecting grassland birds from disturbance during the bird breeding season.
Domestication Explains Two-Thirds of Differential-Gene-Expression Variance between Domestic and Wild Animals; The Remaining One-Third Reflects Intraspecific and Interspecific Variation
Authors: Chadaeva Irina , Ponomarenko Petr , Kozhemyakina Rimma , Suslov Valentin , Bogomolov Anton , Klimova Natalya , Shikhevich Svetlana , Savinkova Ludmila , Oshchepkov Dmitry , Kolchanov Nikolay A. , Markel Arcady , Ponomarenko Mikhail
Published: September 2021

Belyaev’s concept of destabilizing selection during domestication was a major achievement in the XX century. Its practical value has been realized in commercial colors of the domesticated fox that never occur in the wild and has been confirmed in a wide variety of pet breeds. Many human disease models involving animals allow to test drugs before human testing. Perhaps this is why investigators doing transcriptomic profiling of domestic versus wild animals have searched for breed-specific patterns. Here we sequenced hypothalamic transcriptomes of tame and aggressive rats, identified their differentially expressed genes (DEGs), and, for the first time, applied principal component analysis to compare them with all the known DEGs of domestic versus wild animals that we could find. Two principal components, PC1 and PC2, respectively explained 67% and 33% of differential-gene-expression variance (hereinafter: log2 value) between domestic and wild animals. PC1 corresponded to multiple orthologous DEGs supported by homologs; these DEGs kept the log2 value sign from species to species and from tissue to tissue (i.e., a common domestication pattern). PC2 represented stand-alone homologous DEG pairs reversing the log2 value sign from one species to another and from tissue to tissue (i.e., representing intraspecific and interspecific variation).
Comment on Li, Y.; Héroux, P. Magnetic Fields Trump Oxygen in Controlling the Death of Erythro-Leukemia Cells. Appl. Sci. 2019, 9, 5318
Authors: Swanson Eric Scott
Published: September 2021

Li and Héroux [...]
First Report and 3D Reconstruction of a Presumptive Microscopic Liver Lipoma in a Black Barbel (Barbus balcanicus) from the River Bregalnica in the Republic of North Macedonia
Authors: Rebok Katerina , Jordanova Maja , Azevedo Júlia , Rocha Eduardo
Published: September 2021

A lipoma is a benign tumour of mature adipocytes which may appear in various species, including marine and freshwater fish. It usually occurs in isolated locations, such as a superficial or deep mass, mainly in the skin and seldom in other organs. In non-mammalian vertebrates, there is no agreed minimal size for the mass to be considered a lipoma. This study histologically describes a case proposed to be a microlipoma in the liver of Barbus balcanicus. The structure was an oval-shaped mass of well-differentiated adipocytes, surrounded by hepatic parenchyma. The adipocyte cluster did not contact with major vascular or biliary tracts, the liver capsule, or the hilum. The cell mass reached a maximal linear length and width of ~0.5 mm and ~0.4 mm. A three-dimensional and software-assisted reconstruction of the adipocytic mass showed that it had the shape of a flattened prolate spheroid (~0.01 mm3). Given the histological criteria currently used in the literature, we consider the mass as a lipoma, or, better, a microlipoma because it was tiny. We interpret this structure as an early growing lipoma. This work is the second description of a liver lipoma in a fish to the best of our knowledge.
MosAIc: A Classical Machine Learning Multi-Classifier Based Approach against Deep Learning Classifiers for Embedded Sound Classification
Authors: Lhoest Lancelot , Lamrini Mimoun , Vandendriessche Jurgen , Wouters Nick , da Silva Bruno , Chkouri Mohamed Yassin , Touhafi Abdellah
Published: September 2021

Environmental Sound Recognition has become a relevant application for smart cities. Such an application, however, demands the use of trained machine learning classifiers in order to categorize a limited set of audio categories. Although classical machine learning solutions have been proposed in the past, most of the latest solutions that have been proposed toward automated and accurate sound classification are based on a deep learning approach. Deep learning models tend to be large, which can be problematic when considering that sound classifiers often have to be embedded in resource constrained devices. In this paper, a classical machine learning based classifier called MosAIc, and a lighter Convolutional Neural Network model for environmental sound recognition, are proposed to directly compete in terms of accuracy with the latest deep learning solutions. Both approaches are evaluated in an embedded system in order to identify the key parameters when placing such applications on constrained devices. The experimental results show that classical machine learning classifiers can be combined to achieve similar results to deep learning models, and even outperform them in accuracy. The cost, however, is a larger classification time.
Vibration Analysis of the Third Rail Structure of a Mass Rapid Transit System with Structural Defects
Authors: Paudel Milan , Lim Li Jie , Yap Fook Fah , Kho Kevin
Published: September 2021

The third rail is a critical piece of railway infrastructure that provides a continuous supply of electricity to power mass rapid transit trains. The vibration of the third rail may excite different resonant modes and affect its structural integrity and reliability by degrading the mechanical properties leading to the damaged or missing structural components. This paper examines vibrational characteristics of the third rail of Singapore Mass Rapid Transit system with damaged and missing structural components. Using the mathematical model, the first five, pin-to-pin modes of vibration and natural frequencies were identified and compared with modal and harmonic response obtained from ANSYS finite element models. A good agreement was observed between the analytical and numerical solutions. The study was further extended to study the sagging of the third rail due to structural failure and its impact on collector shoes. It was found that the structural defects could produce resonance modes below 5 Hz. In addition, the sagging and contact force on collector shoes increased by multiple folds when more than 2 claw structures are broken. The methods and the results presented in this article can be used as a tool for predictive maintenance by detecting possible structural failure or defects.
Modified, Reliability-Based Robust Geotechnical Design Method, in Accordance with Eurocode 7
Authors: Dodigović Filip , Ivandić Krešo , Kovačević Meho-Saša , Soldo Božo
Published: September 2021

In this paper a modification of the reliability-based robust geotechnical design (RGD) method is proposed. The intention of the proposed modifications is to simplify the method, make it less computationally expensive, and harmonise of the results with Eurocode 7. The complexity of the RGD method mainly stems from the calculation of the design’s robustness measure, which is the feasibility robustness index (ββ). Due to this fact, the replacing of the existing robustness measure with a generalised reliability index (β) is considered. It was demonstrated that β fits into the robustness concept, and is traditionally used as a construction reliability measure, making it intuitive and “user friendly”. It is proposed to conduct a sensitivity analysis using Soboli indices, with the aim of freezing the variables whose contribution to the system response variance is negligible, which will further simplify the method. By changing the robustness measure, the number of the required reliability analyses is significantly decreased. Further reduction is achieved by conducting analyses only for the designs chosen in the scope of the genetic algorithm. The original RGD method is used as an extension of traditional reliability-based design. By applying the proposed modifications, the RGD method can be used as an alternative to the classic and reliability-based design method.
Pavilions in Architecture Studio—Assessment of Design-Build Approach in Architecture Education
Authors: Gutai Matyas , Palaiologou Garyfalia
Published: September 2021

Pavilion construction projects are an emergent paradigm in architecture education. Nevertheless, their efficiency has not yet been assessed in terms of their added contribution to learning experience and pedagogical outcomes. This paper reviews the development, challenges and learning outcomes of the ‘Element Pavilion’ projects for Year One undergraduate architecture students and offers a quantitative and qualitative assessment over their impact on learning. A systematic analysis on students’ perceived learning outcomes using psychometric evaluation is presented here for the first time. The paper introduces a hypothetical pavilion project pedagogy model (HPPP model) which can be used and developed further by architects and educators. Analysis results and the model identify four aspects that students perceive as critical factors in pavilion design-build learning experience: construction, design process, engagement and participation, and teamwork.
Svalbard’s Mesoscale Environmental Factor Impact on the Wind Field
Authors: Kitowska Małgorzata , Petelski Tomasz
Published: September 2021

The mesoscale circulation along the west shore of Spitsbergen is largely controlled by the difference in temperature between the glaciers and surface sea temperatures. We describe how the mesoscale effect influences the atmospheric circulation patterns. The conducted research was based on reanalysis data, model data, and atmospheric measurements; wind data from different sources and scales were compared and analysed. We discuss the situations wherein the mesoscale effect can be identified by analysing the wind direction or its velocity. This study shows the role of the mesoscale effect on the wind in the Svalbard region. Different situations according to the atmospheric patterns taken from a catalogue of 21 circulation types for each day created for Svalbard are analysed and compared with cases of land-sea breeze type circulation for the 20-year period between 1994 and 2013. It is proved that even if it is not possible to distinguish this mesoscale effect based on the difference between local and large-scale wind directions, this factor can be observed by studying the wind speeds. It is claimed that as long as there are glaciers on Spitsbergen, there will be a mesoscale land-sea breeze type circulation controlled by the difference in air temperature over land and water.
ZmWRKY104 Transcription Factor Phosphorylated by ZmMPK6 Functioning in ABA-Induced Antioxidant Defense and Enhance Drought Tolerance in Maize
Authors: Zhao Lili , Yan Jingwei , Xiang Yang , Sun Yue , Zhang Aying
Published: September 2021

Mitogen-activated protein kinase (MAPK) cascades are primary signaling pathways involved in various signaling pathways triggered by abiotic and biotic stresses in plants. The downstream substrate proteins of MAPKs in maize, however, are still limited. Here, we screened a WRKY IIa transcription factor (TF) in maize (Zeamays L.), ZmWRKY104, and found that it is a substrate of ZmMPK6. ZmWRKY104 physically interacts with ZmMPK6 in vitro and in vivo. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis results showed that threonine-59 (Thr-59, T59) was the major phosphorylation site of ZmWRKY104 by ZmMPK6. Subcellular localization analysis suggested that ZmWRKY104 acts in the nucleus and that ZmMPK6 acts in the nucleus and cytoplasmic membrane in the cytosol. Functional analysis revealed that the role of ZmWRKY104 in ABA-induced antioxidant defense depends on ZmMPK6. Moreover, overexpression of ZmWRKY104 in maize can enhance drought tolerance and relieve drought-induced oxidative damage in transgenic lines. The above results help define the mechanism of the function of ZmWRKY104 phosphorylated by ZmMPK6 in ABA-induced antioxidant defense and drought tolerance in maize.
Mediating Roles of hsCRP, TNF-α and Adiponectin on the Associations between Body Fat and Fatty Liver Disease among Overweight and Obese Adults
Authors: Xie Ming , Tang Haokai , Li Feifei , Wu Si , Dong Yanhui , Yang Yide , Baker Julien Steven , Ma Jun
Published: September 2021

Body fat has been reported to be associated with a higher risk of fatty liver disease (FLD). However, few studies have explored the mediating roles of an inflammatory biomarker or adipokine on the relationships. Here, we examined the potential mediating roles of high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-α (TNF-α) and adiponectin (APN) in relationships between body fat and FLD in overweight and obese adults. Additionally, gender differences will be investigated. In total, 1221 participants aged 19–56 years were included in our study. Body fat percentage was measured with Dual Energy X-ray Absorptiometry (DEXA) and FLD by abdominal ultrasound. Mediation analysis was performed to assess the mediating effect of hsCRP, TNF-α and APN on the associations between BF (%) and FLD by gender differences. We found that hsCRP was significantly associated with body fat percentage in both genders (b = 0.2014, p < 0.0001 and b = 0.1804, p < 0.0001 for male and female, respectively), while hsCRP was associated with FLD only in the female group (b = 0.1609, p = 0.0109) but not in male group (b = 0.4800, p = 0.0603). We observed that hsCRP has a significant mediating effect on the association between body fat percentage and FLD (b = 0.0290, p = 0.0201, mediation ratio: 13.6%) in the female group independent of potential covariates (age, smoking, alcohol drinking and physical activity). TNF-α was not significantly associated with body fat percentage or FLD, with no mediating effect on the association between body fat percentage and FLD in either gender. In conclusion, there is a gender-specific mediation role of hsCRP in the association between body fat and FLD. HsCRP was a potential mediator on the association between adiposity and FLD in the female gender, but not in the male gender. Higher body fat was associated with a higher risk of FLD, and the inflammation level might play a potential mediating role in the association between body fat and FLD among female overweight and obese adults.
The Regulation of Rab GTPases by Phosphorylation
Authors: Xu Lejia , Nagai Yuki , Kajihara Yotaro , Ito Genta , Tomita Taisuke
Published: September 2021

Rab proteins are small GTPases that act as molecular switches for intracellular vesicle trafficking. Although their function is mainly regulated by regulatory proteins such as GTPase-activating proteins and guanine nucleotide exchange factors, recent studies have shown that some Rab proteins are physiologically phosphorylated in the switch II region by Rab kinases. As the switch II region of Rab proteins undergoes a conformational change depending on the bound nucleotide, it plays an essential role in their function as a ‘switch’. Initially, the phosphorylation of Rab proteins in the switch II region was shown to inhibit the association with regulatory proteins. However, recent studies suggest that it also regulates the binding of Rab proteins to effector proteins, determining which pathways to regulate. These findings suggest that the regulation of the Rab function may be more dynamically regulated by phosphorylation than just through the association with regulatory proteins. In this review, we summarize the recent findings and discuss the physiological and pathological roles of Rab phosphorylation.
Establishment and Characterization of a Novel Fibroblastic Cell Line (SCI13D) Derived from the Broncho-Alveolar Lavage of a Patient with Fibrotic Hypersensitivity Pneumonitis
Authors: Giannoni Paolo , Grosso Marco , Fugazza Giuseppina , Nizzari Mario , Capra Maria Cristina , Bianchi Rita , Fiocca Roberto , Salvi Sandra , Montecucco Fabrizio , Bertolotto Maria , Fais Franco , Salio Mario , Barisione Emanuela , de Totero Daniela
Published: September 2021

Hypersensitivity pneumonitis (HP) is a diffuse interstitial lung disease (ILD) caused by the inhalation of a variety of antigens in susceptible individuals. Patients with fibrotic HP (fHP) may show histopathological and radiological manifestations similar to patients with idiopathic pulmonary fibrosis (usual interstitial pneumonia-like pattern of fibrosis) that are associated with a worse prognosis. We describe here the establishment and characterization of a fibroblastic cell line derived from the broncho-alveolar lavage (BAL) of a patient with fHP, a 53 year old man who presented at our Pneumology Unit with cough and dyspnea. The fHP diagnosis was based on international criteria and multidisciplinary discussion. Primary fibroblasts were expanded in vitro until passage 36. These fibroblasts displayed morpho/phenotypical features of myofibroblasts, showing high positivity for α-smooth muscle actin, type I collagen, and fibronectin as determined by quantitative RT-PCR and cyto-fluorographic analysis. Cytogenetic analyses further evidenced trisomy of chromosome 10, which interestingly harbors the FGF2R gene. To our knowledge, this is the first fibroblastic cell line derived from an fHP patient and might, therefore, represent a suitable tool to model the disease in vitro. We preliminarily assessed here the activity of pirfenidone, further demonstrating a consistent inhibition of cells growth by this antifibrotic drug.
The Azurin-Derived Peptide CT-p19LC Exhibits Membrane-Active Properties and Induces Cancer Cell Death
Authors: Garizo Ana Rita , Coelho Lígia F. , Pinto Sandra , Dias Tiago P. , Fernandes Fábio , Bernardes Nuno , Fialho Arsénio M.
Published: September 2021

Peptides have been thoroughly studied as new therapeutic strategies for cancer treatment. In this work, we explored in vitro the anticancer potential of three novel peptides derived from the C-terminal of azurin, an anticancer bacterial protein produced by Pseudomonas aeruginosa. CT-p26, CT-p19 and CT-p19LC peptides were previously obtained through an in silico peptide design optimization process, CT-p19LC being the most promising as it presented higher hydrophobicity and solubility, positive total charge and, most importantly, greater propensity for anticancer activity. Therefore, in this study, through proliferation and apoptosis assays, CT-p19LC was tested in four cancer cell lines—A549, MCF-7, HeLa and HT-29—and in two non-cancer cell lines—16HBE14o- and MCF10A. Its membrane-targeting activity was further evaluated with zeta potential measurements and membrane order was assessed with the Laurdan probe. The results obtained demonstrated that CT-p19LC decreases cell viability through induction of cell death and binds to the plasma membrane of cancer cells, but not to non-cancer cells, making them less rigid. Overall, this study reveals that CT-p19LC is an auspicious selective anticancer peptide able to react with cancer cell membranes and cause effective action.
A Vascular Intervention Assist Device Using Bi-Motional Roller Cartridge Structure and Clinical Evaluation
Authors: Choi Jueun , Park Sangeun , Kim Young-Hak , Moon Youngjin , Choi Jaesoon
Published: September 2021

Conventional vascular intervention procedures present issues including X-ray exposure during operation, and an experience-dependent success rate and clinical outcome. This paper presents a novel robotic system using modularized bi-motional roller cartridge assemblies for robotic vascular interventions, specifically percutaneous coronary interventions (PCIs). The patient-side robot manipulates instruments such as the guiding catheter, guidewire, balloon/stent catheter, and diagnostic sensor catheter via commands from the user interface device, which is controlled by the physician. The proposed roller cartridge assembly can accommodate instruments of various sizes with an active clamping mechanism, and implements simultaneous translation and rotation motions. It also implements force feedback in the physician-side system, to effectively monitor the patient-side system’s status. The positioning accuracy and precision in using the robotic system showed satisfactory performance in a phantom-based test. It was also confirmed, through animal experiments and a pilot clinical trial, that the system demonstrates feasibility for clinical use.
Feasibility and Outcomes of the Early Start Denver Model Delivered within the Public Health System of the Friuli Venezia Giulia Italian Region
Authors: Devescovi Raffaella , Colonna Vissia , Dissegna Andrea , Bresciani Giulia , Carrozzi Marco , Colombi Costanza
Published: September 2021

The Early Start Denver Model (ESDM) is an evidence-based early intervention model for young children with autism spectrum disorder (ASD). It is crucial to investigate the feasibility of the ESDM in community settings in contexts that are culturally different from American universities in which the model was originally developed. The aim was to further evaluate the effectiveness of the ESDM delivered within the Italian community setting at low intensity. We compared a group aged 19 to 43 months receiving the ESDM for 2 h per week over the course of 1 year with a concurrent, comparable, non-randomized control group receiving treatment as usual (TAU). Children were evaluated at baseline (T0) and after 6 months (T1) and 12 months (T2) of intervention. Feasibility was evaluated by parent and therapist questionnaires, retention rate, and therapist treatment fidelity. Both groups made similar gains in cognition and language abilities. The ESDM group made larger improvement in domains measured by the ESDM Curriculum Checklist, including communication, social skills, and maladaptive behaviors. Feasibility seemed well supported by retentions, therapists and parent satisfaction, and treatment fidelity. Our study further supports the feasibility of the ESDM implemented within the Italian public health system and suggests a better response in the ESDM-treated group than in the control group.
ERP Indicators of Self-Pain and Other Pain Reductions due to Placebo Analgesia Responding: The Moderating Role of the Fight-Flight-Freeze System
Authors: Vecchio Arianna , De Pascalis Vilfredo
Published: September 2021

This study evaluates the modulation of phasic pain and empathy for pain induced by placebo analgesia during pain and empathy for pain tasks. Because pain can be conceptualized as a dangerous stimulus that generates avoidance, we evaluated how approach and avoidance personality traits modulate pain and empathy for pain responses. We induced placebo analgesia to test whether this also reduces self-pain and other pain. Amplitude measures of the N1, P2, and P3 ERPs components, elicited by electric stimulations, were obtained during a painful control, as well as during a placebo treatment expected to induce placebo analgesia. The placebo treatment produced a reduction in pain and unpleasantness perceived, whereas we observed a decrease in the empathy unpleasantness alone during the empathy pain condition. The moderator effects of the fight-flight-freeze system (FFFS) in the relationships linking P2 and P3 amplitude changes with pain reduction were both significant among low to moderate FFFS values. These observations are consistent with the idea that lower FFFS (active avoidance) scores can predict placebo-induced pain reduction. Finally, in line with the revised Reinforcement Sensitivity Theory (r-RST), we can assume that phasic pain is an aversive stimulus activating the active-avoidance behavior to bring the system back to homeostasis.
Facile Generation of Potent Bispecific Fab via Sortase A and Click Chemistry for Cancer Immunotherapy
Authors: Bai Xuefei , Liu Wenhui , Jin Shijie , Zhao Wenbin , Xu Yingchun , Zhou Zhan , Chen Shuqing , Pan Liqiang
Published: September 2021

Bispecific antibodies (BsAbs) for T cell engagement have shown great promise in cancer immunotherapy, and their clinical applications have been proven in treating hematological malignance. Bispecific antibody binding fragment (BiFab) represents a promising platform for generating non-Fc bispecific antibodies. However, the generation of BiFab is still challenging, especially by means of chemical conjugation. More conjugation strategies, e.g., enzymatic conjugation and modular BiFab preparation, are needed to improve the robustness and flexibility of BiFab preparation. We successfully used chemo-enzymatic conjugation approach to generate bispecific antibody (i.e., BiFab) with Fabs from full-length antibodies. Paired click handles (e.g., N3 and DBCO) was introduced to the C-terminal LPETG tag of Fabs via sortase A mediated transpeptidation, followed by site-specific conjugation between two click handle-modified Fabs for BiFab generation. Both BiFabCD20/CD3 (EC50 = 0.26 ng/mL) and BiFabHer2/CD3 exhibited superior efficacy in mediating T cells, from either PBMC or ATC, to kill target tumor cell lines while spared antigen-negative tumor cells in vitro. The BiFabCD20/CD3 also efficiently inhibited CD20-positive tumor growth in mouse xenograft model. We have established a facile sortase A-mediated click handle installation to generate homogeneous and functional BiFabs. The exemplary BiFabs against different targets showed superior efficacy in redirecting and activating T cells to specifically kill target tumor cells, demonstrating the robustness of sortase A-mediated “bio-click” chemistry in generating various potent BiFabs. This approach also holds promise for further efficient construction of a Fab derivative library for personalized tumor immunotherapy in the future.
A Principal Component of Quality-of-Life Measures Is Associated with Survival: Validation in a Prospective Cohort of Lung Cancer Patients Treated with Stereotactic Body Radiation Therapy
Authors: Farrugia Mark K. , Yu Han , Videtic Gregory M. , Stephans Kevin L. , Ma Sung Jun , Groman Adrienne , Bogart Jeffrey A. , Gomez-Suescun Jorge A. , Singh Anurag K.
Published: September 2021

The association between HRQOL metrics and survival has not been studied in early stage non-small-cell lung cancer (NSCLC) patients undergoing SBRT. The cohort was derived via a post-hoc analysis of a prospective randomized clinical trial examining definitive SBRT for peripheral, early-stage NSCLC with a single or multi-fraction regimen. Patients completed HRQOL questionnaires prior to and 3 months after treatment. Using principal component analysis (PCA), changes in each HRQOL scale following treatment were reduced to two eigenvectors, PC1 and PC2. Cox regression was employed to analyze associations with survival-based endpoints. A total of 70 patients (median age 75.6 years; median follow-up 41.1 months) were studied. HRQOL and symptom comparisons at baseline and 3 months were vastly unchanged except for improved coughing (p = 0.02) and pain in the chest at 3 months (p = 0.033). PC1 and PC2 explained 21% and 9% of variance, respectively. When adjusting for covariates, PC1 was significantly correlated with progression-free (PFS) (HR = 0.78, 95% CI 0.67–0.92, p = 0.003) and overall survival (OS) (HR = 0.76, 95% CI 0.46, p = 0.041). Changes in global health status, functional HRQOL performance, and/or symptom burden as described by PC1 values are significantly associated with PFS and OS. The PC1 quartile may facilitate the identification of at-risk patients for additional interventions.
Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer
Authors: Gong Jun , Hendifar Andrew , Gangi Alexandra , Zaghiyan Karen , Atkins Katelyn , Nasseri Yosef , Murrell Zuri , Figueiredo Jane C. , Salvy Sarah , Haile Robert , Hitchins Megan
Published: September 2021

Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highlight landmark studies that have formed the basis for ongoing studies on the clinically applicability of plasma ctDNA assays in resected, stage I–III CRC and metastatic CRC. We discuss clinical settings by which ctDNA may have the most immediate impact in routine clinical practice. These include the potential for ctDNA to (1) guide surveillance and intensification or de-intensification strategies of adjuvant therapy in resected, stage I–III CRC, (2) predict treatment response to neoadjuvant therapy in locally advanced rectal cancer inclusive of total neoadjuvant therapy (TNT), and (3) predict response to systemic and surgical therapies in metastatic disease. We end by considering clinical variables that can influence our ability to reliably interpret ctDNA dynamics in the clinic.
Transition Metal Ions as Ozonation Catalysts: An Alternative Process of Heterogeneous Catalytic Ozonation
Authors: Psaltou Savvina , Sioumpoura Konstantina , Kaprara Efthimia , Mitrakas Manassis , Zouboulis Anastasios
Published: September 2021

The aim of this study is to elucidate the mechanism of micropollutants’ removal in drinking water by the application of catalytic ozonation, using transition metals as appropriate catalysts. For that purpose, the degradation of 500 μg/L of p-chlorobenzoic acid (p-CBA) and benzotriazole with the addition of 2 mg/L of ozone in the presence of 1 mg/L of Co(II) or Fe(II) and at pH 7.8 were examined. It was found that in distilled water experiments, both metal ions can be characterized as catalysts, enhancing the ozonation process; however, in the natural water matrix, only iron presented higher removal rates of examined organic pollutants, when compared to single ozonation. The metal ions present catalytic activity, when they can form precipitates, hence converting the initially homogeneous process of catalytic ozonation towards a heterogeneous one. However, when 2 mg/L of ozone was applied in natural water experiments, Co(II)—unlike Fe(II)—could not be oxidized into its trivalent form, hence it cannot precipitate as Co(OH)3. Therefore, under these experimental conditions, this metal was not found to present any catalytic activity. Nevertheless, the addition of phosphates (PO43−) in concentrations higher than 100 mg/L can increase the oxidation ability of the Co(II)/O3 system, due to the resulting sufficient formation of Co3(PO4)2 precipitates. Although cobalt can enhance the •OH production (and therefore, the ozonation procedure) under these conditions, the relatively highly added concentration of phosphate ions makes the treated water non-potable, resulting in the application of further treatment to remove the excess phosphates. Therefore, only Fe(II) can be considered as a sufficient catalyst to enhance the ozonation processes.
Addition of Different Biochars as Catalysts during the Mesophilic Anaerobic Digestion of Mixed Wastewater Sludge
Authors: Chiappero Marco , Cillerai Francesca , Berruti Franco , Mašek Ondřej , Fiore Silvia
Published: September 2021

Biochar (BC) recently gained attention as an additive for anaerobic digestion (AD). This work aims at a critical analysis of the effect of six BCs, with different physical and chemical properties, on the AD of mixed wastewater sludge at 37 °C, comparing their influence on methane production and AD kinetics. AD batch tests were performed at the laboratory scale operating 48 reactors (0.25 L working volume) for 28 days with the addition of 10 g L−1 of BC. Most reactors supplemented with BCs exhibited higher (up to 22%) methane yields than the control reactors (0.15 Nm3 kgVS−1). The modified Gompertz model provided maximum methane production rate values, and in all reactors the lag-phase was equal to zero days, indicating a good adaptation of the inoculum to the substrate. The potential correlations between BCs’ properties and AD performance were assessed using principal component analysis (PCA). The PCA results showed a reasonable correlation between methane production and the BCs’ O–C and H–C molar ratios, and volatile matter, and between biogas production and BCs’ pore volume, specific surface area, and fixed and total carbon. In conclusion, the physic-chemical properties of BC (specifically, hydrophobicity and morphology) showed a key role in improving the AD of mixed wastewater sludge.
Mitochondrial Disruption by Amyloid Beta 42 Identified by Proteomics and Pathway Mapping
Authors: Sinclair Patricia , Baranova Ancha , Kabbani Nadine
Published: September 2021

Alzheimer’s disease (AD) is marked by chronic neurodegeneration associated with the occurrence of plaques containing amyloid β (Aβ) proteins in various parts of the human brain. An increase in several Aβ fragments is well documented in patients with AD and anti-amyloid targeting is an emerging area of therapy. Soluble Aβ can bind to various cell surface and intracellular molecules with the pathogenic Aβ42 fragment leading to neurotoxicity. Here we examined the effect of Aβ42 on network adaptations in the proteome of nerve growth factor (NGF) differentiated PC12 cells using liquid-chromatography electrospray ionization mass spectrometry (LC-ESI MS/MS) proteomics. Whole-cell peptide mass fingerprinting was coupled to bioinformatic gene set enrichment analysis (GSEA) in order to identify differentially represented proteins and related gene ontology (GO) pathways within Aβ42 treated cells. Our results underscore a role for Aβ42 in disrupting proteome responses for signaling, bioenergetics, and morphology in mitochondria. These findings highlight the specific components of the mitochondrial response during Aβ42 neurotoxicity and suggest several new biomarkers for detection and surveillance of amyloid disease.
The Oncogenic Signaling Disruptor, NDRG1: Molecular and Cellular Mechanisms of Activity
Authors: Chekmarev Jason , Azad Mahan Gholam , Richardson Des R.
Published: September 2021

NDRG1 is an oncogenic signaling disruptor that plays a key role in multiple cancers, including aggressive pancreatic tumors. Recent studies have indicated a role for NDRG1 in the inhibition of multiple tyrosine kinases, including EGFR, c-Met, HER2 and HER3, etc. The mechanism of activity of NDRG1 remains unclear, but to impart some of its functions, NDRG1 binds directly to key effector molecules that play roles in tumor suppression, e.g., MIG6. More recent studies indicate that NDRG1s-inducing drugs, such as novel di-2-pyridylketone thiosemicarbazones, not only inhibit tumor growth and metastasis but also fibrous desmoplasia, which leads to chemotherapeutic resistance. The Casitas B-lineage lymphoma (c-Cbl) protein may be regulated by NDRG1, and is a crucial E3 ligase that regulates various protein tyrosine and receptor tyrosine kinases, primarily via ubiquitination. The c-Cbl protein can act as a tumor suppressor by promoting the degradation of receptor tyrosine kinases. In contrast, c-Cbl can also promote tumor development by acting as a docking protein to mediate the oncogenic c-Met/Crk/JNK and PI3K/AKT pathways. This review hypothesizes that NDRG1 could inhibit the oncogenic function of c-Cbl, which may be another mechanism of its tumor-suppressive effects.