bluuebunny/crossref_metadata_2025 huggingface dataset:
ХАРАКТЕРИСТИКА СОЦІАЛЬНОГО СТАНОВИЩА МОЛОДІ В УКРАЇНІ
Authors: Ступак О. Ю.
Published: July 2020

У статті представлена характеристика молоді як соціально-демографічної групи, визначені її вікові, освітні, соціальні особливості, що виступає теоретичною базою на шляху побудови соціальної роботи з молоддю. Відповідно до законодавства України молоддю вважаються громадяни віком від 14 до 35 років. У розрізі соціальної роботи молодь розглядається як категорія населення, що характеризується не лише віковими ознаками, але й особливим місцем у структурі суспільства: від пасивного спостерігача, до активного діяча. Вона проходить складний шлях здобуття професії, пошуку місця роботи, маючи конкретні запити та вимоги, зокрема потреба в керівництві, освіті тощо. Через зміни в таких соціальних інститутах як родина, заклад освіти та враховуючи зовнішні чинники (індустріалізація, урбанізація та фактори навколишнього середовища), молодь стикається з кінцевими та періодичними соціальними проблемами, зокрема: здоров’я, безробіття, умови життєдіяльності та праці, якість освіти, професійна та творча самореалізація тощо. Розуміння сфери соціальних проблем молоді, їхнього запиту до державних і громадських установ виступає не лише надійним фундаментом, але й необхідною умовою побудови конструктивної співпраці між молоддю як клієнтами соціальної роботи та соціальними працівниками як провідниками соціалізації особистості. Визначено соціальне становище молоді, спираючись на результати соціологічних досліджень за сферами: здоров’я, освіта, зайнятість, участь в громадському житті. Аналіз статистичних даних показав високу самооцінку власного здоров’я, при цьому спостерігається зростання розповсюдженості шкідливих звичок в молодіжному середовищі; усупереч високого рівня освіченості третина молоді не задоволена якістю освіти; щороку збільшується частина молоді, що не працює за різних причин; демонструється ситуативна громадянська суспільна активність молоді.
ПОЛІКУЛЬТУРНЕ ВИХОВАННЯ ЯК ПЕРЕДУМОВА РОЗВИТКУ ДУХОВНОСТІ ДІТЕЙ ДОШКІЛЬНОГО ВІКУ
Authors: Чаговець А. І. , Курганнікова О. О.
Published: July 2020

У статті розкрито сутність і особливості полікультурного виховання дітей дошкільного віку в умовах сучасного світу; визначені задачі, що постають перед полікультурним вихованням; обґрунтовано завдання виховання духовності та високих моральних почуттів дошкільника на заняттях з іноземної мови. Проведено аналіз понять «духовність» і «полікультурне виховання». Розкрито шляхи виховання духовності дітей дошкільного віку. Показано, що духовність, людяність, толерантність, товариськість, повага до людей різних національностей та інші високоморальні якості не передаються у спадок, а їх потрібно виховувати у кожному поколінні починаючи з дошкільного віку. Виховання розуміється як процес духовної взаємодії закладу дошкільної освіти, родини і дитини, як глибоке спілкування педагога з вихованцем у процесі ігрової діяльності на заняттях з іноземної мови.

Знайомство дошкільників з різноманітністю культур, можливість їх самореалізації в полікультурному світі при збереженні взаємозв’язку з рідною мовою, традиціями та культурою сприяє, на наш погляд, безконфліктній ідентифікації особистості у багатокультурному суспільстві та їх інтеграції до полікультурного світового простору. Полікультурна спрямованість іншомовного спілкування дошкільників на заняттях з іноземної мови стає невід’ємним фактором формування толерантної свідомості та високоморальних людських якостей.

Метою статті є розкриття проблеми полікультурного виховання дітей дошкільного віку у сучасних умовах розвитку полікультурного суспільства.
ДЕТЕРМІІНАНТИ ФОРМУВАННЯ ВОЛЬОВИХ ЯКОСТЕЙ У МАЙБУТНЬОГО ХОРОВОГО ДИРИГЕНТА
Authors: Чурікова-Кушнір О. Д. , Софроній З. В.
Published: July 2020

У статті розглядаються ключові детермінанти формування вольових якостей студентів у процесі хорової діяльності і напрями, які є найбільш перспективними у навчанні. Одним з таких оптимальних напрямів навчання у закладах мистецької освіти, який передбачає забезпечення втілення творчих досягнень у навчально-виховний процес і разом з тим дозволяє розкрити можливості особистісного пошуку студентів, є формування їх індивідуальних якостей, умінь, навичок.

Визначено ключові детермінанти формування вольових якостей майбутніх хорових диригентів, що впливають на  якість фахового навчання.

Проблема формування вольових якостей особливо значуща у диригентсько-хоровій практиці, оскільки потребує витримки у вивченні хорових творів та у виконанні їх перед глядацькою аудиторією. Результативність хорової діяльності в значній мірі визначається стабільністю концертних виступів. Хоровий спів це особливий вид колективної музично-творчої діяльності, який формує вольовий стан як виконавців так і диригента, їх вміння здійснювати перевтілення, самоконтроль і корекцію вокально-хорових дій.

Будучи провідним компонентом хорової діяльності, вольові якості диригента детермінують рівень вокальної, слухової, фізичної, психологічної, емоційної підготовленості, що забезпечує хорових співаків виконувати твори на відповідному рівні, не зважаючи на те, що вони знаходяться в стресовій ситуації в процесі публічних виступів.

У статті розглядаються основні вольові якості хорового диригента: цілеспрямованість (підпорядкування своїх дій поставленим цілям, визначення оптимальних шляхів і засобів досягнення мети); ініціативність (рішучість на нові творчі ідеї); самостійність (обґрунтування вольових дій та самостійне прийняття музично-художнього рішення); рішучість (швидке та впевнене обґрунтування свого творчого задуму); самовладання (вміння подолати страх, паніку у процесі концертних виступів); наполегливість (подолання труднощів у роботі з хоровим колективом, з тривалою напругою творчої енергії домагатися поставленої мети); організованість (вміння планувати свої дії і керуватися цими планами у навчальній діяльності).
TEACHERS MOTIVATION TOWARDS ASSESSMENT OF THEIR PROFESSIONAL COMPETENCES
Authors: Stranovská Eva , Lalinská Mária , Boboňová Ivana
Published: July 2020

A relevant field of research in teacher’s professional competence assessment is taking the factor of motivation into account, as this enables teachers to differentiate between, i. e. to be aware of the significance of the individual professional competences and their development through their assessment. This research supports the understanding of how important motivation is in the process of the (continual) development of a teacher’s professional competence, taking his/her perception of the importance of competences in the educational process into account. The emphasis of the current research lays on the perception of the assessment by the selected number of primary and secondary school teachers. The following is the range of teacher's motivation perception: 1) motivating, 2) discouraging, 3) unnecessary, and 4) unfair in the process of life-long development of their professional competences. The research aim is to find out the differences in the individual motivational degrees in mutual assessment (motivating, discouraging, unnecessary, unfair, and other) relating to professional competences and find out the differences between the perception of the importance of the respective professional competences in the motivational category. Seven hundred thirty respondents - primary and secondary school teachers from Slovakia – participated in the research. The results showed the difference between the perception of the importance of professional competences among teachers who consider assessment to be motivating, discouraging, unnecessary, or unfair concept. Motivation towards assessment supports student-oriented competences, educational process and self-development of the teacher. Keywords: educational process, teacher competences assessment, teachers' motivation, teachers' professional competences.
Penerapan Metode Talkshow untuk Mengembangkan Keterampilan Komunikasi Siswa dalam Pembelajaran Biologi
Authors: Putri Rahmadyah Kusuma
Published: July 2020

Penelitian ini bertujuan untuk mengetahui keefektifan metode talkshow dalam menumbuhkan keterampilan komunikasi siswa SMP Shafiyyatul Amaliyyah Medan TP 2019/2020. Penelitian ini merupakan penelitian tindakan kelas model Kemmis & Mc.Taggarte yang dilakukan sebanyak dua siklus pada bulan Agustus 2019 s.d Maret 2020. Masing – masing siklus terdiri dari empat tahap, yaitu: 1) perencanaan, 2) aksi, 3) observasi dan 4) refleksi. Keterampilan komunikasi yang dimunculkan adalah: komunikasi oral (oral communication), komunikasi reseptif (receptive communication), intensitas memperhatikan (discerns intent), menggunakan strategi komunikasi (uses communication strategies), berkomunikasi dengan jelas (communicates clearly for a purpose) dan keterampilan presentasi (presentation skill). Teknik pengumpulan data menggunakan lembar obsrvasi dan catatan lapangan. Hasil penelitian menunjukkan bahwa metode talkshow efektif dalam memunculkan enam keterampilan komunikasi. Ini dibuktikan dengan ketercapaian indikator aksi dalam penelitian tindakan kelas, yaitu sebanyak ≥50% dari total siswa mampu memunculkan keterampilan komunikasi pada tingkat teladan (exemplary).
Hubungan Antara Representasi Gambar Dan Kemampuan Observasi Pada Pelaksanaan Praktikum Anatomi Tumbuhan
Authors: Hidayah Nur , Haka Nukhbatul Bidayati , Puspita Laila , Kesumawardani Aryani Dwi
Published: July 2020

Pada pelaksanaan praktikum, mahasiswa sering melakukan observasi terhadap objek atau fenomena lalu merepresentasikannya kembali dalam bentuk gambar.Penelitian ini bertujuan untuk mengetahui hubungan antara representasi gambar dan kemampuan observasi mahasiswa pada pelaksanaan praktikum anatomi tumbuhan. Penelitian ini merupakan penelitian deskriptif korelasional. Sampel yang digunakan berjumlah 33 mahasiswa pendidikan biologi salah satu universitas di Bandung.Instrumen penelitian berupa rubrik analisis gambar dan lembar observasi. Pada instrumen rubrik analisis gambar terdiri dari 3 aspek penilaian gambar, sedangkan pada lembar observasi terdiri dari 4 indikator penilaian kemampuan observasi mahasiswa. Hasil uji prasyarat menunjukkan bahwa data berdistribusi normal dan regresinya linear.Berdasarkan hasil tersebut, dilakukan uji korelasi Pearson dengan hasil signifikasi 0.000 <0.05 yang menandakan terdapatnya hubungan antara dua variabel tersebut. Selanjutnya diperoleh nilai r sebesar 0.639 yang menunjukkan hubungan antara representasi gambar hasil praktikum dan kemampuan observasi mahasiswa dikategorikan cukup.
Pengembangan Asesmen Kemampuan Berpikir Kritis Materi Sistem Sirkulasi untuk Siswa SMA Kelas XI
Authors: Miftahussa'adiah Miftahussa'adiah , Alberida Heffi , Handayani Dezi
Published: July 2020

Kemampuan berpikir kritis perlu dikembangkan. Siswa yang berpikir kritis tidak hanya menerima informasi yang diperoleh, namun dapat menggunakan informasi tersebut untuk menyelesaikan permasalahannya. Kemampuan berpikir kritis dapat dilatih dengan memberikan asesmen yang berada pada tingkat kognitif C4-C6. Penelitian ini bertujuan untuk menghasilkan asesmen kemampuan berpikir kritis pada materi sistem sirkulasi yang valid dan praktis. Penelitian menggunakan model pengembangan 4-D yang terdiri dari tahap define, design, dan develop. Instrumen pengumpulan data berupa angket uji validitas dan uji praktikalitas (validitas logis), serta soal multiple choice with written justifification (pilihan ganda dengan menuliskan argumen). Data dianalisis dengan menggunakan statistik deskriptif. Penelitian ini menghasilkan asesmen berpikir kritis untuk materi sistem sirkulasi yang valid dan praktis. Hasil uji validitas menunjukkan soal valid (secara logis dan empiris). Reliabilitas soal tinggi yaitu 0,61, tingkat kesukaran soal  antara 0,31 sampai dengan 0,70, dan soal memiliki daya beda cukup, baik dan baik sekali. Daya beda cukup dengan persentase 10%, daya beda baik dengan persentase 60%, dan daya beda baik sekali dengan persentase 30%. Berdasarkan hal tersebut, dapat disimpulkan telah dihasilkan asesmen kemampuan berpikir kritis yang valid secara logis dan empiris, praktis, reliabel dengan tingkat kesukaran sedang, dan memiliki daya pembeda yang baik.
Fungiculture : Sistem Pertanian Fungi oleh Serangga
Authors: Putra Ivan Permana
Published: July 2020

Fungi dan serangga merupakan kelompok organisme dengan jumlah spesies yang tergolong paling banyak di dunia. Hal ini membuat peluang interaksi antara kedua kingdom ini menjadi sangat tinggi. Diantara berbagai macam bentuk asosiasi tersebut, hubungan mutualistik berupa mekanisme ‘pertanian’ fungi oleh serangga merupakan salah satu hal yang menakjubkan hingga saat ini. Interaksi ini diketahui telah ada selama  lebih dari puluhan juta tahun. Model simbiosis mutualisme ini berlangsung resiprokal dengan aspek kebermanfaatan diantara keduanya terkait nutrisi, perlindungan, dan penyebaran propagul. Berbagai kelompok serangga seperti rayap, semut, dan kumbang telah dikenal lama sebagai partner dari mikobion yang umumnya merupakan filum Ascomycota dan Basidiomycota. Rayap, semut, dan kumbang diketahui memiliki jalur evolusi kemampuan ‘bertani’ yang berbeda, namun semuanya dipengaruhi oleh kondisi lingkungan. Serangga-serangga tersebut memiliki mekanisme ‘pertanian’ yang unik, mulai dari persiapan, perawatan, hingga pemanenan fungi. Selain itu, keberlanjutan simbiosis yang terbentuk sangat begantung pada aspek manfaat yang diterima oleh masing-masing simbion.
Occurrence, Virulence and Antimicrobial Resistance-Associated Markers in Campylobacter Species Isolated from Retail Fresh Milk and Water Samples in Two District Municipalities in the Eastern Cape Province, South Africa
Authors: Igwaran Aboi , Okoh Anthony Ifeanyi
Published: July 2020

Campylobacter species are among the major bacteria implicated in human gastrointestinal infections and are majorly found in faeces of domestic animals, sewage discharges and agricultural runoff. These pathogens have been implicated in diseases outbreaks through consumption of contaminated milk and water in some parts of the globe and reports on this is very scanty in the Eastern Cape Province. Hence, this study evaluated the occurrence as well as virulence and antimicrobial-associated makers of Campylobacter species recovered from milk and water samples. A total of 56 water samples and 72 raw milk samples were collected and the samples were processed for enrichment in Bolton broth and incubated for 48 h in 10% CO2 at 42 °C under microaerobic condition. Thereafter, the enriched cultures were further processed and purified. After which, presumptive Campylobacter colonies were isolated and later confirmed by PCR using specific primers for the detection of the genus Campylobacter, target species and virulence associated genes. Antimicrobial resistance profiles of the isolates were determined by disk diffusion method against a panel of 12 antibiotics and relevant genotypic resistance genes were assessed by PCR assay. A total of 438 presumptive Campylobacter isolates were obtained; from which, 162 were identified as belonging to the genus Campylobacter of which 36.92% were obtained from water samples and 37.11% from milk samples. The 162 confirmed isolates were further delineated into four species, of which, 7.41%, 27.16% and 8.64% were identified as C. fetus, C. jejuni and C. coli respectively. Among the virulence genes screened for, the iam (32.88%) was most prevalent, followed by flgR (26.87%) gene and cdtB and cadF (5.71% each) genes. Of the 12 antibiotics tested, the highest phenotypic resistance displayed by Campylobacter isolates was against clindamycin (95.68%), while the lowest was observed against imipenem (21.47%). Other high phenotypic resistance displayed by the isolates were against erythromycin (95.06%), followed by ceftriaxone (93.21%), doxycycline (87.65%), azithromycin and ampicillin (87.04% each), tetracycline (83.33%), chloramphenicol (78.27%), ciprofloxacin (77.78%), levofloxacin (59.88%) and gentamicin (56.17%). Relevant resistance genes were assessed in the isolates that showed high phenotypic resistance, and the highest resistance gene harbored by the isolates was catII (95%) gene while VIM, KPC, Ges, bla-OXA-48-like, tetC, tetD, tetK, IMI and catI genes were not detected. The occurrence of this pathogen and the detection of virulence and antimicrobial resistance-associated genes in Campylobacter isolates recovered from milk/water samples position them a risk to human health.
Antiviral Action of Native and Methylated Lactoferrin and β-Lactoglobulin against Potato Virus Y (PVY) Infected into Potato Plants Grown in an Open Field
Authors: Sitohy Mahmoud , Taha Soad , Osman Ali , Abdel-Hamid Mahmoud , Hamed Ali , Abdelbacki Ashraf
Published: July 2020

Potato plants are liable to PVY infection without efficient control. Therefore, they were cultivated under greenhouse and open field conditions, artificially infected with PVY and then treated after 15 days of infection with native lactoferrin (LF) and native β-lactoglobulin (BL) and their esterified forms, MLF (methylated lactoferrin) and BLM (methylated β-lactoglobulin) to test the efficiency of this approach. Viral replication was inhibited by the applied substances, particularly the methylated forms, in a concentration-dependent manner, where the concentration of 500 μg·mL−1 was sufficient for plant protection against the PVY infection. An open field experiment showed that one single application of the antiviral substance was enough for maximum inhibitory action against PVY. The modified milk proteins induced higher inhibitory action on PVY virus replication in the plants, compared to their native forms, which was reflected by potato growth and yield. Using the dot blot hybridization and RT-PCR techniques to detect PVY in the experimental plants showed the supremacy of native and esterified LF in inhibiting the targeted virus. The generally observed scanning electronic microscopy (SEM) structural deformations and irregular appearance in PVY particles when treated with MLF and BLM revealed their direct action. BLM, MLF and LF are efficient antiviral agents against PVY. They can not only abolish the observed PVY-induced reduction in potato growth and tuber yield, but also further increase them to higher levels than negative control.
Evolutions of CO2 Adsorption and Nanopore Development Characteristics during Coal Structure Deformation
Authors: Wang Linlin , Long Zhengjiang
Published: July 2020

The coal structure deformation attributed to actions of tectonic stresses can change characteristics of nanopore structure of coals, affecting their CO2 adsorption. Three tectonically deformed coals and one undeformed coal were chosen as the research objects. The isotherm adsorption experiments of four coal specimens were carried out at the temperature of 35 °C and the pressure of 0 to 7 MPa. Nanopore structures were characterized using the liquid nitrogen adsorption method. The results show that there exist maximum values of excess and absolute adsorption capacity, which increase with increasing coal deformation degree. As the degree of coal deformation increases, the pore volume and specific surface area present an obvious increasing trend in the case of micropores, exhibiting an increase at first (cataclastic coal and ganulitic coal) and then stabilization (crumple coal), in the case of mesopores, and showing a gradual decrease in the case of macropores. The mesopores are the key factor of CO2 adsorption of tectonically deformed coals, followed by the micropores and the limited effect of macropores at the strong coal deformation stage.
The Effectiveness of Nafion-Coated Stainless Steel Surfaces for Inhibiting Bacillus Subtilis Biofilm Formation
Authors: Zhong Lijuan , Song Yibo , Zhou Shufeng
Published: July 2020

Stainless steel is one of most commonly used materials in the world; however, biofilms on the surfaces of stainless steel cause many serious problems. In order to find effective methods of reducing bacterial adhesion to stainless steel, and to investigate the role of electrostatic effects during the formation of biofilms, this study used a stainless steel surface that was negatively charged by being coated with Nafion which was terminated by sulfonic groups. The results showed that the roughness of stainless steel discs coated with 1% Nafion was similar to an uncoated surface; however the hydrophobicity increased, and the Nafion-coated surface reduced the adhesion of Bacillus subtilis by 75% compared with uncoated surfaces. Therefore, a facile way to acquire antibacterial stainless steel was found, and it is proved that electrostatic effects have a significant influence on the formation of biofilms.
Corridor Detection from Large GPS Trajectories Datasets
Authors: Cavallaro Claudia , Vitrià Jordi
Published: July 2020

Given the widespread use of mobile devices that track their geographical location, it has become increasingly easy to acquire information related to users’ trips in real time. This availability has triggered several studies based on user’s position, such as the analysis of flows of people in cities, and also new applications, such as route recommendation systems. Given a dataset of geographical trajectories in an urban metropolitan area, we propose a new algorithm to detect corridors. Corridors can be defined as geographical paths, with a minimum length, that are commonly traversed by a minimum number of different users. We propose an efficient strategy based on the Apriori algorithm to extract frequent trajectory patterns from the geo-spatial dataset. By discretizing the data and adapting the roles of itemsets and baskets of this algorithm to our context, we find the longest corridors formed by cells shared by a minimum number of trajectories. After that, we refine the results obtained with a subsequent filtering step, by using a Radius Neighbors Graph. To illustrate the algorithm, the GeoLife dataset is analyzed by following the proposed method. Our approach is relevant for transportation analytics because it is the base to detect lacking lines in public transportation systems and also to recommend to private users which route to take when moving from one part of the city to another on the basis of behavior of the users who provided their logs.
DLBCL Cells with Acquired Resistance to Venetoclax Are Not Sensitized to BIRD-2 But Can Be Resensitized to Venetoclax through Bcl-XL Inhibition
Authors: Kerkhofs Martijn , Vervloessem Tamara , Stopa Kinga B. , Smith Victoria M. , Vogler Meike , Bultynck Geert
Published: July 2020

Anti-apoptotic Bcl-2-family members are frequently dysregulated in both blood and solid cancers, contributing to their survival despite ongoing oncogenic stress. Yet, such cancer cells often are highly dependent on Bcl-2 for their survival, a feature that is exploited by so-called BH3-mimetic drugs. Venetoclax (ABT-199) is a selective BH3-mimetic Bcl-2 antagonist that is currently used in the clinic for treatment of chronic lymphocytic leukemia patients. Unfortunately, venetoclax resistance has already emerged in patients, limiting the therapeutic success. Here, we examined strategies to overcome venetoclax resistance. Therefore, we used two diffuse large B-cell lymphoma (DLBCL) cell lines, Riva WT and venetoclax-resistant Riva (VR). The latter was obtained by prolonged culturing in the presence of venetoclax. We report that Riva VR cells did not become more sensitive to BIRD-2, a peptide targeting the Bcl-2 BH4 domain, and established cross-resistance towards BDA-366, a putative BH4-domain antagonist of Bcl-2. However, we found that Bcl-XL, another Bcl-2-family protein, is upregulated in Riva VR, while Mcl-1 expression levels are not different in comparison with Riva WT, hinting towards an increased dependence of Riva VR cells to Bcl-XL. Indeed, Riva VR cells could be resensitized to venetoclax by A-1155463, a selective BH3 mimetic Bcl-XL inhibitor. This is underpinned by siRNA experiments, demonstrating that lowering Bcl-XL-expression levels also augmented the sensitivity of Riva VR cells to venetoclax. Overall, this work demonstrates that Bcl-XL upregulation contributes to acquired resistance of DLBCL cancer cells towards venetoclax and that antagonizing Bcl-XL can resensitize such cells towards venetoclax.
The COP9 Signalosome: A Multi-DUB Complex
Authors: Dubiel Wolfgang , Chaithongyot Supattra , Dubiel Dawadschargal , Naumann Michael
Published: July 2020

The COP9 signalosome (CSN) is a signaling platform controlling the cellular ubiquitylation status. It determines the activity and remodeling of ~700 cullin-RING ubiquitin ligases (CRLs), which control more than 20% of all ubiquitylation events in cells and thereby influence virtually any cellular pathway. In addition, it is associated with deubiquitylating enzymes (DUBs) protecting CRLs from autoubiquitylation and rescuing ubiquitylated proteins from degradation. The coordination of ubiquitylation and deubiquitylation by the CSN is presumably important for fine-tuning the precise formation of defined ubiquitin chains. Considering its intrinsic DUB activity specific for deneddylation of CRLs and belonging to the JAMM family as well as its associated DUBs, the CSN represents a multi-DUB complex. Two CSN-associated DUBs, the ubiquitin-specific protease 15 (USP15) and USP48 are regulators in the NF-κB signaling pathway. USP15 protects CRL1β-TrCP responsible for IκBα ubiquitylation, whereas USP48 stabilizes the nuclear pool of the NF-κB transcription factor RelA upon TNF stimulation by counteracting CRL2SOCS1. Moreover, the CSN controls the neddylation status of cells by its intrinsic DUB activity and by destabilizing the associated deneddylation enzyme 1 (DEN1). Thus, the CSN is a master regulator at the intersection between ubiquitylation and neddylation.
Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers
Authors: Wu Yanyuan , Sarkissyan Marianna , Ogah Ochanya , Kim Juri , Vadgama Jaydutt
Published: July 2020

Background: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with cancer progression. Our study examined the role of MALAT1 in breast cancer and the mechanisms involved in the regulation of MALAT1. Methods: In vitro cell and in vivo animal models were used to examine the role of MALAT1 in breast cancer. The interaction of FOXO1 (Forkhead Box O1) at the promoter region of MALAT1 was investigated by chromatin immunoprecipitation (ChIP) assay. Results: The data shows an elevated expression of MALAT1 in breast cancer tissues and cells compared to non-cancer tissues and cells. The highest level of MALAT1 was observed in metastatic triple-negative breast cancer and trastuzumab-resistant HER2 (human epidermal growth factor receptor 2) overexpressing (HER2+) cells. Knockdown of MALAT1 in trastuzumab-resistant HER2+ cells reversed epithelial to mesenchymal transition-like phenotype and cell invasiveness. It improved the sensitivity of the cell’s response to trastuzumab. Furthermore, activation of Akt by phosphorylation was associated with the upregulation of MALAT1. The transcription factor FOXO1 regulates the expression of MALAT1 via the PI3/Akt pathway. Conclusions: We show that MALAT1 contributes to HER2+ cell resistance to trastuzumab. Targeting the PI3/Akt pathway and stabilizing FOXO1 translocation could inhibit the upregulation of MALAT1.
Study of Ras Mutations’ Prognostic Value in Metastatic Colorectal Cancer: STORIA Analysis
Authors: Ottaiano Alessandro , Normanno Nicola , Facchini Sergio , Cassata Antonino , Nappi Anna , Romano Carmela , Silvestro Lucrezia , De Stefano Alfonso , Rachiglio Anna Maria , Roma Cristin , Maiello Monica R. , Scala Stefania , Delrio Paolo , Tatangelo Fabiana , Di Mauro Annabella , Botti Gerardo , Avallone Antonio , Nasti Guglielmo
Published: July 2020

Background: Colorectal cancer (CRC) is the second most common cause of cancer-specific death in both sexes in Western countries. KRAS mutations occur in about 50% of metastatic CRCs (mCRCs). The prognostic value of specific KRAS mutations still remains unexplored and unclear. Methods: Two hundred and forty KRAS wild-type and 206 KRAS/NRAS mutant consecutive unresectable mCRC patients with PS Eastern Cooperative Oncology Group (ECOG) 0 or 1, aged < 80 years, and with a life expectancy >3 months entered into this study. DNA was extracted from paraffin-embedded formalin-fixed tumour tissues, and it was sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Data were analysed using the Torrent Suite Software v5.0 (Thermo Fisher Scientific). The primary outcome was the analysis of the prognostic role of different KRAS mutations in terms of overall survival (OS). Results: There were no significant differences among the most prevalent mutations (p.G12D, p.G12V, p.G13D, p.G12A, p.G12C, and p.G12S) in terms of age (<65 vs. ≥65 years), gender (male vs. female), grading (G1/G2 vs. G3), side of primary tumour (left vs. right), pT, and pN. At the median follow-up of 25.6 months, there were 77 deaths in KRAS-mutated patients and 94 in wild-type patients. Three homogeneous prognostic groups were identified: wild-type patients (group A, median survival: 27.5 months), p.G13D/p.G12A/p.G12V/p.G12D mutants (group B, median survival: 17.3 months), and p.G12C/p.G12S mutants (group C, median survival: 5.0 months, p < 0.0001 according to Log Rank test). Upon multivariate analysis, metastatic involvement and p.G12C/p.G12S KRAS mutation group C (vs. other mutations) emerged as independent prognostic variables for survival. Conclusions: We show that mutant KRAS is a negative prognostic factor and that p.G12C/p.G12S variants present the worst clinical courses. This information suggests a clear difference among KRAS mutations, and it will be useful to test potentiated and/or innovative therapeutic strategies in p.G12C/p.G12S metastatic CRC patients.
Cellular Virotherapy Increases Tumor-Infiltrating Lymphocytes (TIL) and Decreases their PD-1+ Subsets in Mouse Immunocompetent Models
Authors: Morales-Molina Alvaro , Rodríguez-Milla Miguel Ángel , Gimenez-Sanchez Alicia , Perisé-Barrios Ana Judith , García-Castro Javier
Published: July 2020

Oncolytic virotherapy uses viruses designed to selectively replicate in cancer cells. An alternative to intratumoral administration is to use mesenchymal stem cells (MSCs) to transport the oncolytic viruses to the tumor site. Following this strategy, our group has already applied this treatment to children and adults in a human clinical trial and a veterinary trial, with good clinical responses and excellent safety profiles. However, the development of immunocompetent cancer mouse models is still necessary for the study and improvement of oncolytic viroimmunotherapies. Here we have studied the antitumor efficacy, immune response, and mechanism of action of a complete murine version of our cellular virotherapy in mouse models of renal adenocarcinoma and melanoma. We used mouse MSCs infected with the mouse oncolytic adenovirus dlE102 (OAd-MSCs). In both models, treatment with OAd-MSCs significantly reduced tumor volumes by 50% and induced a pro-inflammatory tumor microenvironment. Furthermore, treated mice harboring renal adenocarcinoma and melanoma tumors presented increased infiltration of tumor-associated macrophages (TAMs), natural killer cells, and tumor-infiltrating lymphocytes (TILs). Treated mice also presented lower percentage of TILs expressing programmed cell death protein 1 (PD-1)—the major regulator of T cell exhaustion. In conclusion, treatment with OAd-MSCs significantly reduced tumor volume and induced changes in tumor-infiltrating populations of melanoma and renal cancer.
Cylindromatosis Lysine 63 Deubiquitinase (CYLD) Regulates NF-kB Signaling Pathway and Modulates Fibroblast and Endothelial Cells Recruitment in Nasopharyngeal Carcinoma
Authors: Deng Mingdan , Dai Wei , Yu Valen Zhuoyou , Tao Lihua , Lung Maria Li
Published: July 2020

Nasopharyngeal carcinoma (NPC) is a malignant epithelial carcinoma of the nasopharynx. Cylindromatosis lysine 63 deubiquitinase (CYLD), a NF-kB inhibitor, was reported as one of the top mutated candidate genes in NPC. NF-kB is an inducible transcription factor, contributing to cancer via regulating inflammation, angiogenesis, cell proliferation, and metastasis. In this study, the impact of CYLD on regulating the NF-kB signaling pathway and its contribution to NPC development was studied using in vitro and in vivo functional assays, together with single cell RNA sequencing to understand the NPC tumor microenvironment. CYLD was downregulated in NPC clinical specimens and multiple cell lines. Functional assays revealed CYLD inhibits NPC cell proliferation and migration in vitro and suppresses NPC tumorigenicity and metastasis in vivo by negatively regulating the NF-kB signaling pathway. Additionally, CYLD was able to inhibit fibroblast and endothelial stromal cell infiltration into the NPC tumor microenvironment. These findings suggest that CYLD inhibits NPC development and provides strong evidence supporting a role for CYLD inhibiting fibroblast and endothelial stromal cell infiltration into NPC via suppressing the NF-kB pathway.
3rd Etnean Occupational Medicine Workshop—Breast Cancer and Work
Authors: Rapisarda Venerando , Ledda Caterina
Published: July 2020

Breast cancer, the most frequently occurring cancer in women, is a major public health problem, with over 1 million estimated new cases worldwide and nearly 459,000 related deaths every year [...]
Multi-Marker Longitudinal Algorithms Incorporating HE4 and CA125 in Ovarian Cancer Screening of Postmenopausal Women
Authors: Gentry-Maharaj Aleksandra , Blyuss Oleg , Ryan Andy , Burnell Matthew , Karpinskyj Chloe , Gunu Richard , Kalsi Jatinderpal K. , Dawnay Anne , Marino Ines P. , Manchanda Ranjit , Lu Karen , Yang Wei-Lei , Timms John F. , Parmar Max , Skates Steven J. , Bast Robert C. , Jacobs Ian J. , Zaikin Alexey , Menon Usha
Published: July 2020

Longitudinal CA125 algorithms are the current basis of ovarian cancer screening. We report on longitudinal algorithms incorporating multiple markers. In the multimodal arm of United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), 50,640 postmenopausal women underwent annual screening using a serum CA125 longitudinal algorithm. Women (cases) with invasive tubo-ovarian cancer (WHO 2014) following outcome review with stored annual serum samples donated in the 5 years preceding diagnosis were matched 1:1 to controls (no invasive tubo-ovarian cancer) in terms of the number of annual samples and age at randomisation. Blinded samples were assayed for serum human epididymis protein 4 (HE4), CA72-4 and anti-TP53 autoantibodies. Multimarker method of mean trends (MMT) longitudinal algorithms were developed using the assay results and trial CA125 values on the training set and evaluated in the blinded validation set. The study set comprised of 1363 (2–5 per woman) serial samples from 179 cases and 181 controls. In the validation set, area under the curve (AUC) and sensitivity of longitudinal CA125-MMT algorithm were 0.911 (0.871–0.952) and 90.5% (82.5–98.6%). None of the longitudinal multi-marker algorithms (CA125-HE4, CA125-HE4-CA72-4, CA125-HE4-CA72-4-anti-TP53) performed better or improved on lead-time. Our population study suggests that longitudinal HE4, CA72-4, anti-TP53 autoantibodies adds little value to longitudinal serum CA125 as a first-line test in ovarian cancer screening of postmenopausal women.
Profiling of Mitochondrial DNA Heteroplasmy in a Prospective Oral Squamous Cell Carcinoma Study
Authors: Fendt Liane , Fazzini Federica , Weissensteiner Hansi , Bruckmoser Emanuel , Schönherr Sebastian , Schäfer Georg , Losso Jamie Lee , Streiter Gertraud A. , Lamina Claudia , Rasse Michael , Klocker Helmut , Kofler Barbara , Kloss-Brandstätter Anita , Huck Christian W. , Kronenberg Florian , Laimer Johannes
Published: July 2020

While a shift in energy metabolism is essential to cancers, the knowledge about the involvement of the mitochondrial genome in tumorigenesis and progression in oral squamous cell carcinoma (OSCC) is still very limited. In this study, we evaluated 37 OSCC tumors and the corresponding benign mucosa tissue pairs by deep sequencing of the complete mitochondrial DNA (mtDNA). After extensive quality control, we identified 287 variants, 137 in tumor and 150 in benign samples exceeding the 1% threshold. Variant heteroplasmy levels were significantly increased in cancer compared to benign tissues (p = 0.0002). Furthermore, pairwise high heteroplasmy frequency difference variants (∆HF% > 20) with potential functional impact were increased in the cancer tissues (p = 0.024). Fourteen mutations were identified in the protein-coding region, out of which thirteen were detected in cancer and only one in benign tissue. After eight years of follow-up, the risk of mortality was higher for patients who harbored at least one ∆HF% > 20 variant in mtDNA protein-coding regions relative to those with no mutations (HR = 4.6, (95%CI = 1.3–17); p = 0.019 in primary tumor carriers). Haplogroup affiliation showed an impact on survival time, which however needs confirmation in a larger study. In conclusion, we observed a significantly higher accumulation of somatic mutations in the cancer tissues associated with a worse prognosis.
Tele-Monitoring of Cancer Patients’ Rhythms during Daily Life Identifies Actionable Determinants of Circadian and Sleep Disruption
Authors: Lévi Francis , Komarzynski Sandra , Huang Qi , Young Teresa , Ang Yeng , Fuller Claire , Bolborea Matei , Brettschneider Julia , Fursse Joanna , Finkenstädt Bärbel , White David Pollard , Innominato Pasquale
Published: July 2020

The dichotomy index (I < O), a quantitative estimate of the circadian regulation of daytime activity and sleep, predicted overall cancer survival and emergency hospitalization, supporting its integration in a mHealth platform. Modifiable causes of I < O deterioration below 97.5%—(I < O)low—were sought in 25 gastrointestinal cancer patients and 33 age- and sex-stratified controls. Rest-activity and temperature were tele-monitored with a wireless chest sensor, while daily activities, meals, and sleep were self-reported for one week. Salivary cortisol rhythm and dim light melatonin onset (DLMO) were determined. Circadian parameters were estimated using Hidden Markov modelling, and spectral analysis. Actionable predictors of (I < O)low were identified through correlation and regression analyses. Median compliance with protocol exceeded 95%. Circadian disruption—(I < O)low—was identified in 13 (52%) patients and four (12%) controls (p = 0.002). Cancer patients with (I < O)low had lower median activity counts, worse fragmented sleep, and an abnormal or no circadian temperature rhythm compared to patients with I < O exceeding 97.5%—(I < O)high—(p < 0.012). Six (I < O)low patients had newly-diagnosed sleep conditions. Altered circadian coordination of rest-activity and chest surface temperature, physical inactivity, and irregular sleep were identified as modifiable determinants of (I < O)low. Circadian rhythm and sleep tele-monitoring results support the design of specific interventions to improve outcomes within a patient-centered systems approach to health care.
The Therapeutic Potential of Targeting BARF1 in EBV-Associated Malignancies
Authors: Lo Angela Kwok-Fung , Dawson Christopher W. , Lung Hong Lok , Wong Ka-Leung , Young Lawrence S.
Published: July 2020

Epstein-Barr virus (EBV) is closely linked to the development of a number of human cancers. EBV-associated malignancies are characterized by a restricted pattern of viral latent protein expression which is sufficient for the virus to both initiate and sustain cell growth and to protect virus-infected cells from immune attack. Expression of these EBV proteins in malignant cells provides an attractive target for therapeutic intervention. Among the viral proteins expressed in the EBV-associated epithelial malignancies, the protein encoded by the BamHI-A rightward frame 1 (BARF1) is of particular interest. BARF1 is a viral oncoprotein selectively expressed in latently infected epithelial cancers, nasopharyngeal carcinoma (NPC) and EBV-positive gastric cancer (EBV-GC). Here, we review the roles of BARF1 in oncogenesis and immunomodulation. We also discuss potential strategies for targeting the BARF1 protein as a novel therapy for EBV-driven epithelial cancers.
Pancreatic Macrophages: Critical Players in Obesity-Promoted Pancreatic Cancer
Authors: Teper Yaroslav , Eibl Guido
Published: July 2020

Obesity is a known risk factor for the development of pancreatic cancer, one of the deadliest types of malignancies. In recent years it has become clear that the pancreatic microenvironment is critically involved and a contributing factor in accelerating pancreatic neoplasia. In this context obesity-associated chronic inflammation plays an important role. Among several immune cells, macrophages have been shown to contribute to obesity-induced tissue inflammation. This review article summarizes the current knowledge about the role of pancreatic macrophages in early pancreatic cancer development. It describes the heterogenous origin and mixture of pancreatic macrophages, their role in pancreatic endocrine and exocrine pathology, and the impact of obesity on islet and stromal macrophages. A model is postulated, by which during obesity monocytes are recruited into the pancreas, where they are polarized into pro-inflammatory macrophages that drive early pancreatic neoplasia. This occurs in the presence of local inflammatory, metabolic, and endocrine signals. A stronger appreciation and more detailed knowledge about the role of macrophages in early pancreatic cancer development will lead to innovative preventive or interceptive strategies.
Use of Interferon Alfa in the Treatment of Myeloproliferative Neoplasms: Perspectives and Review of the Literature
Authors: How Joan , Hobbs Gabriela
Published: July 2020

Interferon alfa was first used in the treatment of myeloproliferative neoplasms (MPNs) over 30 years ago. However, its initial use was hampered by its side effect profile and lack of official regulatory approval for MPN treatment. Recently, there has been renewed interest in the use of interferon in MPNs, given its potential disease-modifying effects, with associated molecular and histopathological responses. The development of pegylated formulations and, more recently, ropeginterferon alfa-2b has resulted in improved tolerability and further expansion of interferon’s use. We review the evolving clinical use of interferon in essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). We discuss interferon’s place in MPN treatment in the context of the most recent clinical trial results evaluating interferon and its pegylated formulations, and its role in special populations such as young and pregnant MPN patients. Interferon has re-emerged as an important option in MPN patients, with future studies seeking to re-establish its place in the existing treatment algorithm for MPN, and potentially expanding its use for novel indications and combination therapies.
Advanced Pancreatic Ductal Adenocarcinoma: Moving Forward
Authors: Franck Caspar , Müller Christian , Rosania Rosa , Croner Roland S. , Pech Maciej , Venerito Marino
Published: July 2020

Globally, the death rate of pancreatic ductal adenocarcinoma (PDAC) has doubled over 30 years and is likely to further increase, making PDAC a leading cause of cancer-related death in the coming years. PDAC is typically diagnosed at an advanced stage, and modified FOLFIRINOX or nab-paclitaxel and gemcitabine are the mainstay of systemic therapy. For elderly patients with good performance status, low-dose treatment can preserve quality of life without compromising cancer control or survival. Maintenance therapy should be considered in PDAC patients achieving disease control with systemic therapy. In particular, olaparib has demonstrated a progression-free survival benefit of 3.6 months in a subgroup of PDAC patients with germline BRCA1/2 mutations (ca. 10% of all PDAC). Pancreatic enzyme replacement therapy is often omitted in the treatment of patients with PDAC, with possibly deleterious consequences. Small intestinal bacterial overgrowth is highly prevalent in patients with PDAC and should be considered in the diagnostic algorithm of PDAC patients with bloating and diarrhea. Rivaroxaban has been associated with a reduced risk of thrombosis without an increase in major bleeding events, and its use should be considered in every patient with advanced PDAC undergoing systemic therapy.
Impact of Tumor Genomic Mutations on Thrombotic Risk in Cancer Patients
Authors: Leiva Orly , Connors Jean M. , Al-Samkari Hanny
Published: July 2020

Venous thromboembolism (VTE) is common in patients with cancer and is an important contributor to morbidity and mortality in these patients. Early thromboprophylaxis initiated only in those cancer patients at highest risk for VTE would be optimal. Risk stratification scores incorporating tumor location, laboratory values and patient characteristics have attempted to identify those patients most likely to benefit from thromboprophylaxis but even well-validated scores are not able to reliably distinguish the highest-risk patients. Recognizing that tumor genetics affect the biology and behavior of malignancies, recent studies have explored the impact of specific molecular aberrations on the rate of VTE in cancer patients. The presence of certain molecular aberrations in a variety of different cancers, including lung, colon, brain and hematologic tumors, have been associated with an increased risk of VTE and arterial thrombotic events. This review examines the findings of these studies and discusses the implications of these findings on decisions relating to thromboprophylaxis use in the clinical setting. Ultimately, the integration of tumor molecular genomic information into clinical VTE risk stratification scores in cancer patients may prove to be a major advancement in the prevention of cancer-associated thrombosis.
Coumarins and Coumarin-Related Compounds in Pharmacotherapy of Cancer
Authors: Küpeli Akkol Esra , Genç Yasin , Karpuz Büşra , Sobarzo-Sánchez Eduardo , Capasso Raffaele
Published: July 2020

Cancer is one of the most common causes of disease-related deaths worldwide. Despite the discovery of many chemotherapeutic drugs that inhibit uncontrolled cell division processes for the treatment of various cancers, serious side effects of these drugs are a crucial disadvantage. In addition, multi-drug resistance is another important problem in anticancer treatment. Due to problems such as cytotoxicity and drug resistance, many investigations are being conducted to discover and develop effective anticancer drugs. In recent years, researchers have focused on the anticancer activity coumarins, due to their high biological activity and low toxicity. Coumarins are commonly used in the treatment of prostate cancer, renal cell carcinoma and leukemia, and they also have the ability to counteract the side effects caused by radiotherapy. Both natural and synthetic coumarin derivatives draw attention due to their photochemotherapy and therapeutic applications in cancer. In this review, a compilation of various research reports on coumarins with anticancer activity and investigation and a review of structure-activity relationship studies on coumarin core are presented. Determination of important structural features around the coumarin core may help researchers to design and develop new analogues with a strong anticancer effect and reduce the potential side effects of existing therapeutics.