bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction to the LIVECAT web-based computerized adaptive testing platform
Authors: Seo Dong Gi , Choi Jeongwook
Published: September 2020

This study introduces LIVECAT, a web-based computerized adaptive testing platform. This platform provides many functions, including writing item content, managing an item bank, creating and administering a test, reporting test results, and providing information about a test and examinees. The LIVECAT provides examination administrators with an easy and flexible environment for composing and managing examinations. It is available at http://www.thecatkorea.com/. Several tools were used to program LIVECAT, as follows: operating system, Amazon Linux; web server, nginx 1.18; WAS, Apache Tomcat 8.5; database, Amazon RDMS—Maria DB; and languages, JAVA8, HTML5/CSS, Javascript, and jQuery. The LIVECAT platform can be used to implement several item response theory (IRT) models such as the Rasch and 1-, 2-, 3-parameter logistic models. The administrator can choose a specific model of test construction in LIVECAT. Multimedia data such as images, audio files, and movies can be uploaded to items in LIVECAT. Two scoring methods (maximum likelihood estimation and expected a posteriori) are available in LIVECAT and the maximum Fisher information item selection method is applied to every IRT model in LIVECAT. The LIVECAT platform showed equal or better performance compared with a conventional test platform. The LIVECAT platform enables users without psychometric expertise to easily implement and perform computerized adaptive testing at their institutions. The most recent LIVECAT version only provides a dichotomous item response model and the basic components of CAT. Shortly, LIVECAT will include advanced functions, such as polytomous item response models, weighted likelihood estimation method, and content balancing method.
Effect of cultivar, timing of establishment and cutting interval on yield and seed set of arrowleaf clover
Authors: Muir Paul D. , Thomson Beverly C. , Smith Noel B.
Published: September 2020

Arrowleaf clover is an erect hard-seeded annual clover with potential to improve the typically low legume content of dryland hill country. A number of small plot experiments were undertaken to better understand arrowleaf management. Cultivar maturity impacted on single-cut yields, with later maturing cultivars (‘Arrotas’ and ‘Zulu 11’) having significantly higher yields than an early maturing cultivar (‘Cefalu’). When autumn oversowing was practised, the slow growth of arrowleaf during winter caused weed issues. Delaying sowing of arrowleaf clover from April to winter (July) did not affect dry matter yield, seed set or seed viability and avoided the need for a weed spray as the vigorous spring growth of arrowleaf out-competed weed species. Arrowleaf oversown on hill country and allowed to set seed to build a large bank of hard seed resulted in a bulk of fibrous trash that was difficult to clean-up with grazing stock. Four mowings to simulate grazing encouraged weed invasion and reduced legume yields (and trash). Whilst two mowings were optimal for seed yield, up to three mowings provided a compromise between setting seed, utilising feed for grazing and reducing trash after flowering.
Penggunaan Ungkapan Beri-Terima Bahasa Jepang dalam Novel Shiro no Naka no Hito Karya Hoshi Shinâ€™ichi
Authors: Retnaningrum Ana Wuri
Published: September 2020

This paper discusses the use of yari-morai phrase (jujuhyougen) found in a novel data source titled Shiro no Naka no Hito. The purpose of this study is to describe the use of expressions of acceptance using Natsuko Tsujimura's theory. The items analyzed in this study are the function, role, and social distance of each argument. From the data analysis, it is found that when analyzed in a syntactic way, each argument functions as a subject and is a direct object or an indirect object. In semantic analysis, from the use of his verb, every argument plays the role of agent and beneficiary. Whereas from the use of passive expressions, each argument acts as a source and a goal. If pragmatic analysis is used, the use of the expressions is influenced by the vertical distance. However, formal situations are more important than existing vertical distances. So that also affects the use of proper expressions.
Pemaknaan Lirik Lagu Shabondama Karya Ujo Noguchi Berdasarkan Analisis Semiotika Michael Riffaterre
Authors: Noviana Fajria , Saifudin Akhmad
Published: September 2020

Shabondama is a children's song whose lyrics are composed by Ujo Noguchi. This song tells about a game of soap balloons. Interestingly, even though it tells about children's play, this song seems mysterious. There are nuances of sadness when listening to this song. The diction used has a negative connotation, unlike most other children's songs which are cheerful and use words that have a positive connotation. This is what motivates the writer's interest in examining more deeply what the real meaning is contained in the song. The semiotic theory of Riffaterre's poetry was used to study it. Through the process of heuristic reading, hermeneutic reading, and intertext studies, the result shows that the meaning contained in this song is helplessness or weakness. Keywords: semiotics, poetry, Riffaterre, semantic indirectionShabondama adalah lagu anak yang liriknya dikarang oleh Ujo Noguchi. Lagu ini menceritakan permainan balon sabun. Menariknya, meskipun bercerita tentang permainan anak namun lagu ini terkesan misterius. Ada nuansa kesedihan ketika mendengarkan lagu ini. Diksi yang digunakan pun berkonotasi negatif, tidak seperti kebanyakan lagu anak lainnya yang ceria dan menggunakan kata-kata yang berkonotasi positif. Inilah yang melatarbelakangi ketertarikan penulis untuk mengkaji lebih dalam apa makna sebenarnya yang terkandung di dalam lagu itu. Untuk mengkajinya digunakan teori semiotika puisi Riffaterre. Melalui proses pembacaan heuristik, hermeneutik, dan studi interteks, diperoleh hasil bahwa makna yang terkandung dalam lagu ini adalah ketidakberdayaan.Kata Kunci: semiotika, puisi, Riffaterre, ketidaklangsungan semantik
Analysis (LibQual) on Loyalty and Library Satisfaction; A Case Study in YARSI University Library Service Center
Authors: Rizky Tiko Dhafin , Huda Nurul , Muslikh Muslikh , Rini Nova
Published: September 2020

This study aims to analyze (LibQual): the effect of the performance of officers (affect of service) on user satisfaction; the effect of information access on user satisfaction; the influence of instructions and means of access (personal control) to the satisfaction of users; the effect of facilities and infrastructure (library as a place) on user satisfaction; the effect of the satisfaction of the visitors on the user loyalty; the effect (LibQual) on the loyalty of the visitors; the effect (LibQual) on the loyalty of the visitors through the variable user satisfaction. The data analysis method uses Structural Equation Model (SEM) with Lisrel 8.8 software. Respondents in this study were 180 students from YARSI University. This study presents a relative risk as a measure of effect size for categorical outcomes. Findings. The results of this study indicate that the LibQual component has a positive and significant influence on the visitors’ satisfaction and loyalty directly. Library satisfaction has a positive and significant effect on the loyalty of users directly. The LibQual component has a positive and significant indirect effect on loyalty through user satisfaction.
The Call To Holiness: The Effect Of Understanding Concept Of Second Coming At Gpdi Rajawali’s Youth Surabaya
Authors: Karina Nina Astrid
Published: September 2020

Holiness is the condition, means and purpose for all believers that distinguishes them as God's people. In contrast to the condition of the world which is increasingly immersed in sin, the holiness of the believer will continue to progress until it reaches perfection. Starting from believing until finally when Christ comes the second time.

This research was conducted to prove that the understanding of the concept of the second coming of Christ affects the holiness of the GPdI Rajawali Surabaya’s youth. From the quantitative research that has been done, it is evident that understanding this concept has a positive effect in the moderate category.
Sexual Allometric Monomorphism in Araucan Pig from Colombia: Preliminary Results
Authors: Salamanca-Carreño Arcesio , Jordana-Vidal Jordi , Crosby-Granados René Alejandro , Arias-Landazábal José Norberto , Parés-Casanova Pere M.
Published: September 2020

This study aimed to evaluate the allometric growth of the Araucan pig breed, a creole breed from Arauca, East Colombia, locally known as “Sabaneros”, in relation to different quantitative traits and considering genders separately. To do this, a total of 31 male and 27 female Araucan pigs, ranging from 4 to 48 months of age, were studied in order to evaluate their growth patterns, using a multivariate approach. Animals belonged to different farms (“fincas”) of the Department of Arauca, Colombia. From each individual, 10 quantitative traits were obtained: face width, croup height, croup length, croup width, tail base height, hock height, loin height, cannon length, and length and width of ear. Our results, which must be interpreted as preliminary, showed that the Araucan pig is allometrically monomorphic as sexual differences do not increase with body size. We suggest that although males and females have evidently different reproductive roles, during growth they shift the allocation of energy to structures linked to environmental adaptation rather than those linked to reproduction.
Recombinase Polymerase Amplification Based Multiplex Lateral Flow Dipstick for Fast Identification of Duck Ingredient in Adulterated Beef
Authors: Fu Ming , Zhang Quanwang , Zhou Xiang , Liu Bang
Published: September 2020

Meat adulteration has become a global social problem. In order to protect consumers from meat adulteration, several methods have been developed to identify meat species. However, the conventional methods are labor-intensive, time-consuming and require instruments. In the present study, a rapid and visual method based on recombinase polymerase amplification (RPA) and multiplex lateral flow dipstick (MLFD) was developed to detect duck ingredient in adulterated beef. Using recombinase and strand displacement polymerase enable RPA to amplify different double-labeled DNA amplicons at room temperature, which can be further detected by MLFD. The whole reaction process can be finished within 35 min, and the results can be determined by naked eyes. As low as 5% of duck ingredient in adulterated beef can be easily measured. Moreover, we confirmed that our new method held good potential in the detection of commercially processed meat samples. In conclusion, this study reported a useful animal derived meat adulteration detection method, which have potential application in future.
Hospitalization for Acute Respiratory Tract Infection in a Low-Antibiotic-Prescribing Setting: Cross-Sectional Data from General Practice
Authors: Löffler Christin , Altiner Attila , Diener Annette , Berner Reinhard , Feldmeier Gregor , Helbig Christian , Kern Winfried V. , Köchling Anna , Schmid Michaela , Schön Gerhard , Schröder Helmut , Wegscheider Karl , Wollny Anja
Published: September 2020

Background: Acute respiratory tract infections (ARTI) are the main cause of inappropriate antibiotic prescribing. To date, there is limited evidence concerning whether low levels of antibiotic prescribing may impact patient safety. We investigate whether antibiotic prescribing for patients seeking primary care for ARTI correlates with the odds for hospitalization. Methods: Analysis of patient baseline data (n = 3669) within a cluster-randomized controlled trial. Adult patients suffering from ARTI in German primary care are included. The main outcome measure is acute hospitalization for respiratory infection and for any acute disease from 0 to 42 days after initial consultation. Results: Neither the antibiotic status of individual patients (OR 0.91; 95% CI: 0.49 to 1.69; p-value = 0.769) nor the physician-specific antibiotic prescription rates for ARTI (OR 1.22; 95% CI: 1.00 to 1.49; p-value = 0.054) had a significant effect on hospitalization. The following factors increased the odds for hospitalization: patient’s age, the ARTI being defined as lower respiratory tract infections (such as bronchitis) by the physician, the physician’s perception of disease severity, and being cared for within group practices (versus treated in single-handed practices). Conclusions: In a low-antibiotic-prescribing primary care setting such as Germany, lack of treatment with antibiotics for ARTI did not result in higher odds for hospitalization in an adult population.
Novel Combination of COX-2 Inhibitor and Antioxidant Therapy for Modulating Oxidative Stress Associated with Intestinal Ischemic Reperfusion Injury and Endotoxemia
Authors: Gugliandolo Enrico , Cordaro Marika , Siracusa Rosalba , D’Amico Ramona , Peritore Alessio Filippo , Genovese Tiziana , Impellizzeri Daniela , Paola Rosanna Di , Crupi Rosalia , Cuzzocrea Salvatore , Fusco Roberta
Published: September 2020

Background: Intestinal ischemic reperfusion (I/R) injury is associated with a high mortality rate; this condition is also related to significant endotoxemia and systemic inflammation. The preservation of tissue perfusion and a sufficient blood flow are required to deliver nutrients and oxygen, preserve metabolic pathways, and eliminate waste products. Oxidative stress plays a fundamental role in intestinal I/R injury and leads to disruption of the mucosal barrier and necrosis, allowing the migration of endotoxins and luminal bacteria into the systemic circulation. In this study, we evaluated the beneficial effects of a cyclooxygenase (COX)-2 inhibitor—firocoxib—plus the antioxidant vitamin C in a rat model of intestinal I/R injury. Methods: We used a rat model of I/R injury in which the superior mesenteric artery was clamped for 30 min by a vascular clamp, and the animals were then allowed 1 h of reperfusion. Results: Our results show the importance of combined anti-inflammatory and antioxidant treatment for the prevention of intestinal I/R injury that leads to reduced systemic endotoxemia. We observed a significantly synergistic effect of firocoxib and vitamin C in reducing intestinal wall damage and oxidative stress, leading to a significant reduction of inflammation and endotoxemia. Conclusions: Our results indicate that this approach could be a new pharmacological protocol for intestinal colic or ischemic injury-induced endotoxemia.
Dietary Mitophagy Enhancer: A Strategy for Healthy Brain Aging?
Authors: Varghese Nimmy , Werner Selina , Grimm Amandine , Eckert Anne
Published: September 2020

Recently, nutritional interventions have received attention as promising approaches to promote human health during a lifespan. The Mediterranean and Okinawan diets have been associated with longevity and decreasing risk for age-related diseases in contrast to the Western diet. The effect might be due to several antioxidative bioactive compounds highly consumed in both diets, namely, resveratrol, hydroxytyrosol, oleuropein, curcumin, and spermidine. This review aims to address the underlying mechanisms of these compounds to enhance mental fitness throughout life with a focus on brain mitophagy. Mitophagy is the autophagic clearance of dysfunctional, redundant, and aged mitochondria. In aging and neurodegenerative disorders, mitophagy is crucial to preserve the autophagy mechanism of the whole cell, especially during oxidative stress. Growing evidence indicates that curcumin, astaxanthin, resveratrol, hydroxytyrosol, oleuropein, and spermidine might exert protective functions via antioxidative properties and as well the enhanced induction of mitophagy mediators. The compounds seem to upregulate mitophagy and thereby alleviate the clearance of dysfunctional and aged mitochondria as well as mitogenesis. Thus, the Mediterranean or Okinawan diet could represent a feasible nutritional approach to reduce the risk of developing age-related cognitive impairment and corresponding disorders via the stimulation of mitophagy and thereby ensure a balanced redox state of brain cells.
Analysis of Photosynthetic Systems and Their Applications with Mathematical and Computational Models
Authors: Badu Shyam , Melnik Roderick , Singh Sundeep
Published: September 2020

In biological and life science applications, photosynthesis is an important process that involves the absorption and transformation of sunlight into chemical energy. During the photosynthesis process, the light photons are captured by the green chlorophyll pigments in their photosynthetic antennae and further funneled to the reaction center. One of the most important light harvesting complexes that are highly important in the study of photosynthesis is the membrane-attached Fenna–Matthews–Olson (FMO) complex found in the green sulfur bacteria. In this review, we discuss the mathematical formulations and computational modeling of some of the light harvesting complexes including FMO. The most recent research developments in the photosynthetic light harvesting complexes are thoroughly discussed. The theoretical background related to the spectral density, quantum coherence and density functional theory has been elaborated. Furthermore, details about the transfer and excitation of energy in different sites of the FMO complex along with other vital photosynthetic light harvesting complexes have also been provided. Finally, we conclude this review by providing the current and potential applications in environmental science, energy, health and medicine, where such mathematical and computational studies of the photosynthesis and the light harvesting complexes can be readily integrated.
ERF-IMCS: An Efficient and Robust Framework with Image-Based Monte Carlo Scheme for Indoor Topological Navigation
Authors: Xu Song , Zhou Huaidong , Chou Wusheng
Published: September 2020

Conventional approaches to global localization and navigation mainly rely on metric maps to provide precise geometric coordinates, which may cause the problem of large-scale structural ambiguity and lack semantic information of the environment. This paper presents a scalable vision-based topological mapping and navigation method for a mobile robot to work robustly and flexibly in large-scale environment. In the vision-based topological navigation, an image-based Monte Carlo localization method is presented to realize global topological localization based on image retrieval, in which fine-tuned local region features from an object detection convolutional neural network (CNN) are adopted to perform image matching. The combination of image retrieval and Monte Carlo provide the robot with the ability to effectively avoid perceptual aliasing. Additionally, we propose an effective visual localization method, simultaneously employing the global and local CNN features of images to construct discriminative representation for environment, which makes the navigation system more robust to the interference of occlusion, translation, and illumination. Extensive experimental results demonstrate that ERF-IMCS exhibits great performance in the robustness and efficiency of navigation.
Real-Time Inter-Vehicle Data Fusion Based on a New Metric for Evidence Distance in Autonomous Vehicle Systems
Authors: Cho In-Sop , Lee Yuna , Baek Seung Jun
Published: September 2020

Safety is a major concern for autonomous vehicle driving. The autonomous vehicles relying solely on ego-vehicle sensors have limitations in dealing with collisions. The risk can be reduced by communicating with other vehicles sharing sensed information. In this paper, we study a real-time multisource data fusion scheme based on Dempster–Shafer theory of evidence (DS) through cooperative vehicle-to-vehicle (V2V) communications. The classical DS can produce erroneous outputs when confidences are highly conflicting. In particular, a false negative error on object detection may lead to serious accidents. We propose a novel metric to measure distance between confidences on the collected data taking the asymmetry in the importance of sensed events into account. Based on the proposed distance, we consider the weighted DS combination in order to fuse multiple confidences. The proposed scheme is simple, and enables the vehicles to combine confidences in real-time. From real-world experiments, we show that it is feasible to lower the false negative rate by the proposed data fusion scheme, and to avoid accidents using the proposed collision warning system.
A New Self-Balancing Assembly Line Based on Collaborative Ant Behavior
Authors: Koo Pyung-Hoi
Published: September 2020

In most mass-production assembly lines, workers perform a set of tasks repetitively predefined by assembly line balancing techniques. The static task assignment often leads to low productivity when the assembly system faces disruptions or uncertainties such as machine breakdown and uneven worker capabilities. The idea of bucket brigades (BB) has been introduced to address the static assignment problems where cooperative behavior of ants is applied to flow line control. This paper examines possible efficiency losses associated with the existing BB-based assembly cell and presents an improved version for assembly cells under uncertain environments. The new system attempts to enhance productivity by assigning assembly tasks to workers dynamically and possibly adding buffers for decoupling consecutive workers. The proposed assembly system is evaluated through simulation experiments under various manufacturing environments. The experimental results show that the new system provides higher productivity than the naïve BB-based assembly cell as well as traditional assembly cells, especially for uncertain assembly environments.
Verification of Weather and Seasonal Forecast Information Concerning the Peri-Urban Farmers’ Needs in the Lower Ganges Delta in Bangladesh
Authors: Paparrizos Spyridon , Smolenaars Wouter , Gbangou Talardia , Slobbe Erik , Ludwig Fulco
Published: September 2020

Skillful weather and seasonal predictions have considerable socio-economic potential and could provide meaningful information to farmers and decision-makers towards agricultural planning and decision-making. Peri-urban farmers in the Lower Ganges Delta need skillful forecast information to deal with increased hydroclimatic variability. In the current study, verification of European Centre for Medium-Range Weather Forecasts’ System 5 (ECMWF SEAS5) seasonal prediction system is performed against ground observations for the Lower Ganges Delta using three skills assessment metrics. Additionally, meteoblue hindcasts are verified for Khulna station according to the peri-urban farmers’ needs and an assessment of onset/offset dates of rainy season is also conducted using the same ground observations. The results indicated that the skill of both examined products is limited during the pre-monsoon and monsoon periods, especially in the west side of the Bay of Bengal. However, during the dry winter season, skill is high, which could lead to potential agricultural benefits concerning irrigation planning. Interannual variability and trend indicated that onset dates have become later and that the length of the rainy season reduced. This could increase the pressure on the already challenging situation the farmers are experiencing, in relation to hydro-climatic variability.
Thymoquinone-Loaded Polymeric Films and Hydrogels for Bacterial Disinfection and Wound Healing
Authors: Haq Anika , Kumar Suneel , Mao Yong , Berthiaume Francois , Michniak-Kohn Bozena
Published: September 2020

The purpose of this study was to synthesize and characterize novel biocompatible topical polymeric film and hydrogel systems that have the potential to deliver the antibacterial agent thymoquinone (TQ) directly to the skin target site to manage the local wound infection and thereby wound healing. The polyvinyl pyrrolidone (PVP) matrix-type films containing TQ were prepared by the solvent casting method. In vitro skin permeation studies on human cadaver skin produced a mean flux of 2.3 µg TQ/cm2/h. Human keratinocyte monolayers subjected to a scratch wound (an in vitro wound healing assay) showed 85% wound closure at day 6 in the TQ group (100 ng/mL TQ) as compared to 50% in the vehicle control group (p = 0.0001). In a zone-of-inhibition (ZOI) assay, TQ-containing films and hydrogels completely wiped out Staphylococcus aureus in 10 cm diameter Tryptic Soy Agar plates while 500 µg/mL gentamicin containing filters gave 10 mm of ZOI. In an ex vivo model, TQ-containing films eradicated bacterial colonization on human cadaver skin. Furthermore, in a full-thickness wound infection model in mice, TQ-containing films showed significant activity in controlling Staphylococcus aureus infection, thereby disinfecting the skin wound. In summary, TQ-containing PVP films and hydrogels developed in this study have the potential to treat and manage wound infections.
Advances in Multimodal Emotion Recognition Based on Brain–Computer Interfaces
Authors: He Zhipeng , Li Zina , Yang Fuzhou , Wang Lei , Li Jingcong , Zhou Chengju , Pan Jiahui
Published: September 2020

With the continuous development of portable noninvasive human sensor technologies such as brain–computer interfaces (BCI), multimodal emotion recognition has attracted increasing attention in the area of affective computing. This paper primarily discusses the progress of research into multimodal emotion recognition based on BCI and reviews three types of multimodal affective BCI (aBCI): aBCI based on a combination of behavior and brain signals, aBCI based on various hybrid neurophysiology modalities and aBCI based on heterogeneous sensory stimuli. For each type of aBCI, we further review several representative multimodal aBCI systems, including their design principles, paradigms, algorithms, experimental results and corresponding advantages. Finally, we identify several important issues and research directions for multimodal emotion recognition based on BCI.
A Naturalistic Study of Youth Referred to a Tertiary Care Facility for Acute Hypomanic or Manic Episode
Authors: Masi Gabriele , Berloffa Stefano , Muratori Pietro , Mucci Maria , Viglione Valentina , Villafranca Arianna , Inguaggiato Emanuela , Levantini Valentina , Placini Francesca , Pfanner Chiara , D’Acunto Giulia , Lenzi Francesca , Liboni Francesca , Milone Annarita
Published: September 2020

Background: Bipolar Disorders (BD) in youth are a heterogeneous condition with different phenomenology, patterns of comorbidity and outcomes. Our aim was to explore the effects of gender; age at onset (prepubertal- vs. adolescent-onset) of BD; and elements associated with attention deficit hyperactivity disorder (ADHD) and Substance Use Disorder (SUD) comorbidities, severe suicidal ideation or attempts, and poorer response to pharmacological treatments. Method: 117 youth (69 males and 57 females, age range 7 to 18 years, mean age 14.5 ± 2.6 years) consecutively referred for (hypo)manic episodes according to the Diagnostic and Statistical Manual of Mental Disorders, 54th ed (DSM 5) were included. Results: Gender differences were not evident for any of the selected features. Prepubertal-onset BD was associated with higher rates of ADHD and externalizing disorders. SUD was higher in adolescent-onset BD and was associated with externalizing comorbidities and lower response to treatments. None of the selected measures differentiated patients with or without suicidality. At a 6-month follow up, 51.3% of the patients were responders to treatments, without difference between those receiving and not receiving a psychotherapy. Clinical severity at baseline and comorbidity with Conduct Disorder (CD) and SUD were associated with poorer response. Logistic regression indicated that baseline severity and number of externalizing disorders were associated with a poorer outcome. Conclusions: Disentangling broader clinical conditions in more specific phenotypes can help timely and focused preventative and therapeutic interventions.
Characteristics and Clinical Outcome of Breast Cancer Patients with Asymptomatic Brain Metastases
Authors: Laakmann Elena , Witzel Isabell , Neunhöffer Tanja , Weide Rudolf , Schmidt Marcus , Park-Simon Tjoung-Won , Möbus Volker , Mundhenke Christoph , Polasik Arkadius , Lübbe Kristina , Hesse Tobias , Riecke Kerstin , Thill Marc , Fasching Peter A. , Denkert Carsten , Fehm Tanja , Nekljudova Valentina , Rey Julia , Loibl Sibylle , Müller Volkmar
Published: September 2020

Background: Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods: The aim of this analysis was to characterize patients with asymptomatic BM (n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results: Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80–100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions: These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM.
Dual-Time Point [68Ga]Ga-PSMA-11 PET/CT Hybrid Imaging for Staging and Restaging of Prostate Cancer
Authors: Hoffmann Manuela A. , Buchholz Hans-Georg , Wieler Helmut J , Rosar Florian , Miederer Matthias , Fischer Nicolas , Schreckenberger Mathias
Published: September 2020

Routine [68Ga]Ga-PSMA-11 PET/CT (one hour post-injection) has been shown to accurately detect prostate cancer (PCa) lesions. The goal of this study is to evaluate the benefit of a dual-time point imaging modality for the staging and restaging of PCa patients. Biphasic [68Ga]Ga-PSMA-11 PET/CT of 233 patients, who underwent early and late scans (one/three hours post-injection), were retrospectively studied. Tumor uptake and biphasic lesion detection for 215 biochemically recurrent patients previously treated for localized PCa (prostatectomized patients (P-P)/irradiated patients (P-I) and 18 patients suspected of having primary PCa (P-T) were separately evaluated. Late [68Ga]Ga-PSMA-11 PET/CT imaging detected 554 PCa lesions in 114 P-P patients, 187 PCa lesions in 33 P-I patients, and 47 PCa lesions in 13 P-T patients. Most patients (106+32 P-P/P-I, 13 P-T) showed no additional PCa lesions. However, 11 PSMA-avid lesions were only detected in delayed images, and 33 lesions were confirmed as malignant by a SUVmax increase. The mean SUVmax of pelvic lymph node metastases was 25% higher (p < 0.001) comparing early and late PET/CT. High positivity rates from routine [68Ga]Ga-PSMA-11 PET/CT for the staging and restaging of PCa patients were demonstrated. There was no decisive influence of additional late imaging with PCa lesion detection on therapeutic decisions. However, in a few individual cases, additional delayed scans provided an information advantage in PCa lesion detection due to higher tracer uptake and improved contrast.
Interleukin-18 and Hematopoietic Recovery after Allogeneic Stem Cell Transplantation
Authors: Radujkovic Aleksandar , Kordelas Lambros , Bogdanov Rashit , Müller-Tidow Carsten , Beelen Dietrich W. , Dreger Peter , Luft Thomas
Published: September 2020

Interleukin-18 (IL-18) is an immunoregulatory cytokine and a context-dependent regulator of hematopoietic stem/progenitor cell (HSPC) quiescence in murine models. In a previous study, high pre-conditioning levels of IL-18 were associated with increased non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). To investigate the clinical impact of IL-18 status on hematopoietic function, the associations of pre-conditioning and day 0–3 cytokine levels with platelet and neutrophil recovery were analyzed in a training cohort of 714 allografted patients. In adjusted logistic regression analyses, both increasing pre-conditioning and day 0–3 IL-18 levels had a significantly higher adjusted odds ratio (aOR) of delayed platelet and neutrophil recovery on day +28 post-transplant (aOR per two-fold increase: 1.6–2.0). The adverse impact of high pre-conditioning IL-18 on day +28 platelet recovery was verified in an independent cohort of 673 allografted patients (aOR per two-fold increase: 1.8 and 1.7 for total and free IL-18, respectively). In both cohorts, a platelet count ≤20/nL on day +28 was associated with a significantly increased hazard of NRM (hazard ratio 2.13 and 2.94, respectively). Our findings support the hypothesis that elevated peritransplant IL-18 levels affect post-transplant HSPC function and may provide a rationale to explore modulation of IL-18 for improving alloSCT outcomes.
Progress in Clinical Trials of Photodynamic Therapy for Solid Tumors and the Role of Nanomedicine
Authors: Alsaab Hashem O. , Alghamdi Maha S. , Alotaibi Albatool S. , Alzhrani Rami , Alwuthaynani Fatimah , Althobaiti Yusuf S. , Almalki Atiah H. , Sau Samaresh , Iyer Arun K.
Published: September 2020

Current research to find effective anticancer treatments is being performed on photodynamic therapy (PDT) with increasing attention. PDT is a very promising therapeutic way to combine a photosensitive drug with visible light to manage different intense malignancies. PDT has several benefits, including better safety and lower toxicity in the treatment of malignant tumors over traditional cancer therapy. This reasonably simple approach utilizes three integral elements: a photosensitizer (PS), a source of light, and oxygen. Upon light irradiation of a particular wavelength, the PS generates reactive oxygen species (ROS), beginning a cascade of cellular death transformations. The positive therapeutic impact of PDT may be limited because several factors of this therapy include low solubilities of PSs, restricting their effective administration, blood circulation, and poor tumor specificity. Therefore, utilizing nanocarrier systems that modulate PS pharmacokinetics (PK) and pharmacodynamics (PD) is a promising approach to bypassing these challenges. In the present paper, we review the latest clinical studies and preclinical in vivo studies on the use of PDT and progress made in the use of nanotherapeutics as delivery tools for PSs to improve their cancer cellular uptake and their toxic properties and, therefore, the therapeutic impact of PDT. We also discuss the effects that photoimmunotherapy (PIT) might have on solid tumor therapeutic strategies.
Role of Oral Bacteria in the Development of Oral Squamous Cell Carcinoma
Authors: Li Qinyang , Hu Yao , Zhou Xuedong , Liu Shiyu , Han Qi , Cheng Lei
Published: September 2020

Oral squamous cell carcinoma (OSCC) is an invasive epithelial neoplasm that is influenced by various risk factors, with a low survival rate and an increasing death rate. In the past few years, with the verification of the close relationship between different types of cancers and the microbiome, research has focused on the compositional changes of oral bacteria and their role in OSCC. Generally, oral bacteria can participate in OSCC development by promoting cell proliferation and angiogenesis, influencing normal apoptosis, facilitating invasion and metastasis, and assisting cancer stem cells. The study findings on the association between oral bacteria and OSCC may provide new insight into methods for early diagnosis and treatment development.
Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells
Authors: Tishchenko Alexander , Azorín Daniel D. , Vidal-Brime Laia , Muñoz María José , Arenas Pol Jiménez , Pearce Christopher , Girao Henrique , Ramón y Cajal Santiago , Aasen Trond
Published: September 2020

Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR/Cas9 system to knockout (KO) Cx43. We found that the loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by the inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, the drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type (WT) cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer.
Three-Dimensional Culture Systems in Gastric Cancer Research
Authors: Alzeeb George , Metges Jean-Philippe , Corcos Laurent , Le Jossic-Corcos Catherine
Published: September 2020

Gastric cancer (GC), which includes cancer of the esophagus, the oesophagogastric junction, and the stomach fundus, is highly deadly with strong regional influence, Asia being the most affected. GC is often detected at late stages, with 30% of metastatic cases at diagnosis. Many authors have devised models to both unravel the mechanisms of GC development and to evaluate candidate therapeutics. Among these models, 2D-cell cultures are progressively replaced by 3D-cell cultures that recapitulate, much more comprehensively, tumor cellular and genetic heterogeneity, as well as responsiveness to environmental changes, such as exposure to drugs or irradiation. With respect to the specifics of GC, there are high hopes from such model systems, especially with the aim of identifying prognostic markers and novel drug targets.
Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review
Authors: Proietti Ilaria , Skroza Nevena , Bernardini Nicoletta , Tolino Ersilia , Balduzzi Veronica , Marchesiello Anna , Michelini Simone , Volpe Salvatore , Mambrin Alessandra , Mangino Giorgio , Romeo Giovanna , Maddalena Patrizia , Rees Catherine , Potenza Concetta
Published: September 2020

This systematic review investigated the literature on acquired v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor resistance in patients with melanoma. We searched MEDLINE for articles on BRAF inhibitor resistance in patients with melanoma published since January 2010 in the following areas: (1) genetic basis of resistance; (2) epigenetic and transcriptomic mechanisms; (3) influence of the immune system on resistance development; and (4) combination therapy to overcome resistance. Common resistance mutations in melanoma are BRAF splice variants, BRAF amplification, neuroblastoma RAS viral oncogene homolog (NRAS) mutations and mitogen-activated protein kinase kinase 1/2 (MEK1/2) mutations. Genetic and epigenetic changes reactivate previously blocked mitogen-activated protein kinase (MAPK) pathways, activate alternative signaling pathways, and cause epithelial-to-mesenchymal transition. Once BRAF inhibitor resistance develops, the tumor microenvironment reverts to a low immunogenic state secondary to the induction of programmed cell death ligand-1. Combining a BRAF inhibitor with a MEK inhibitor delays resistance development and increases duration of response. Multiple other combinations based on known mechanisms of resistance are being investigated. BRAF inhibitor-resistant cells develop a range of ‘escape routes’, so multiple different treatment targets will probably be required to overcome resistance. In the future, it may be possible to personalize combination therapy towards the specific resistance pathway in individual patients.
Extracellular Vesicles as an Efficient and Versatile System for Drug Delivery
Authors: Dang Xuan T. T. , Kavishka Jayasinghe Migara , Zhang Daniel Xin , Pirisinu Marco , Le Minh T. N.
Published: September 2020

Despite the recent advances in drug development, the majority of novel therapeutics have not been successfully translated into clinical applications. One of the major factors hindering their clinical translation is the lack of a safe, non-immunogenic delivery system with high target specificity upon systemic administration. In this respect, extracellular vesicles (EVs), as natural carriers of bioactive cargo, have emerged as a promising solution and can be further modified to improve their therapeutic efficacy. In this review, we provide an overview of the biogenesis pathways, biochemical features, and isolation methods of EVs with an emphasis on their many intrinsic properties that make them desirable as drug carriers. We then describe in detail the current advances in EV therapeutics, focusing on how EVs can be engineered to achieve improved target specificity, better circulation kinetics, and efficient encapsulation of therapeutic payloads. We also identify the challenges and obstacles ahead for clinical translation and provide an outlook on the future perspective of EV-based therapeutics.
Dissecting Gq/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1
Authors: Blankenbach Kira Vanessa , Claas Ralf Frederik , Aster Natalie Judith , Spohner Anna Katharina , Trautmann Sandra , Ferreirós Nerea , Black Justin L. , Tesmer John J. G. , Offermanns Stefan , Wieland Thomas , Meyer zu Heringdorf Dagmar
Published: September 2020

Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphK1), thereby enabling inside-out signaling of sphingosine-1-phosphate. We have shown before that Gq-coupled receptors and constitutively active Gαq/11 specifically induced a rapid and long-lasting SphK1 translocation, independently of canonical Gq/phospholipase C (PLC) signaling. Here, we further characterized Gq/11 regulation of SphK1. SphK1 translocation by the M3 receptor in HEK-293 cells was delayed by expression of catalytically inactive G-protein-coupled receptor kinase-2, p63Rho guanine nucleotide exchange factor (p63RhoGEF), and catalytically inactive PLCβ3, but accelerated by wild-type PLCβ3 and the PLCδ PH domain. Both wild-type SphK1 and catalytically inactive SphK1-G82D reduced M3 receptor-stimulated inositol phosphate production, suggesting competition at Gαq. Embryonic fibroblasts from Gαq/11 double-deficient mice were used to show that amino acids W263 and T257 of Gαq, which interact directly with PLCβ3 and p63RhoGEF, were important for bradykinin B2 receptor-induced SphK1 translocation. Finally, an AIXXPL motif was identified in vertebrate SphK1 (positions 100–105 in human SphK1a), which resembles the Gαq binding motif, ALXXPI, in PLCβ and p63RhoGEF. After M3 receptor stimulation, SphK1-A100E-I101E and SphK1-P104A-L105A translocated in only 25% and 56% of cells, respectively, and translocation efficiency was significantly reduced. The data suggest that both the AIXXPL motif and currently unknown consequences of PLCβ/PLCδ(PH) expression are important for regulation of SphK1 by Gq/11.
Microbiota-Dependent Effects of IL-22
Authors: Sabihi Morsal , Böttcher Marius , Pelczar Penelope , Huber Samuel
Published: September 2020

Cytokines are important contributors to immune responses against microbial and environmental threats and are of particular importance at epithelial barriers. These interfaces are continuously exposed to external factors and thus require immune components to both protect the host from pathogen invasion and to regulate overt inflammation. Recently, substantial efforts have been devoted to understanding how cytokines act on certain cells at barrier sites, and why the dysregulation of immune responses may lead to pathogenesis. In particular, the cytokine IL-22 is involved in preserving an intact epithelium, maintaining a balanced microbiota and a functioning defense system against external threats. However, a tight regulation of IL-22 is generally needed, since uncontrolled IL-22 production can lead to the progression of autoimmunity and cancer. Our aim in this review is to summarize novel findings on IL-22 and its interactions with specific microbial stimuli, and subsequently, to understand their contributions to the function of IL-22 and the clinical outcome. We particularly focus on understanding the detrimental effects of dysregulated control of IL-22 in certain disease contexts.
Multi-Method Complex Approach for Hydration Assessment Does Not Detect a Hydration Difference in Hemodialysis versus Peritoneal Dialysis Patient
Authors: Adamska-Wełnicka Anna , Wełnicki Marcin , Krzesiński Paweł , Niemczyk Stanisław , Lubas Arkadiusz
Published: September 2020

Assessment of hydration status is essential in monitoring the effectiveness of renal replacement therapy and is usually based on physical examination. However, comparisons of hydration status achieved with different dialysis methods are not conclusive. We compared the hydration status of patients on chronic hemodialysis (HD, n = 60) and peritoneal dialysis (PD, n = 20) in a comprehensive assessment including physical examination and additional methods. The mean age of the 80 chronically dialyzed patients (53 males, 27 females) was 58.1 ± 13.9 years. The clinical evaluation took into account the presence of peripheral edema, dyspnea, and crackling over the lung fields. Additional tests included lung ultrasound, electrical bioimpedance (performed in 79 patients), impedance cardiography, ultrasound assessment of large abdominal vessels (performed in 79 patients), select echocardiographic parameters (obtained in 78 patients), and serum NT-proBNP concentration. Residual diuresis volume was significantly higher in the PD group. We found no significant differences between the two groups in any other baseline characteristics or in the results of the clinical examination or additional tests. The use of different methods for assessing hydration does not allow differentiation of patients treated with dialysis in terms of the dialysis technique used. Therefore, it seems reasonable to use common algorithms to objectify the hydration status of these patients.